[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"_public_publisher_byId_9abd6176-5475-462b-8585-b1e343d8b0e5":3,"_public_publication_all{\"sortAscending\":false,\"sortField\":\"updateTime\",\"page\":0,\"size\":10,\"facet\":true,\"searchKey\":\"publisherId:9abd6176-5475-462b-8585-b1e343d8b0e5,\"}":59},{"code":4,"data":5,"meta":18},"SUCCESS",{"id":6,"createTime":7,"updateTime":8,"relativeEntities":9,"slug":10,"properties":11,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":20,"manageAffiliations":21,"indexDatabases":22,"url":38,"thumbnailPath":18,"statistic":39,"gsStatistic":18,"type":58,"analyzePriority":18},"9abd6176-5475-462b-8585-b1e343d8b0e5","2024-04-11T10:04:17.441+00:00","2025-11-21T09:59:23.394+00:00",[],"Treatments-in-Respiratory-Medicine",{"issn":12,"title":14},{"VOID":13},"1176-3450",{"EN":15},"Treatments in Respiratory Medicine","PUBLISHER","PENDING",null,0,[],[],[23],{"id":24,"indexDatabase":25,"url":35,"indexYears":36,"academicFieldIds":18,"indexDatabaseRanking":37},"cdab8740-f0cb-420b-9f6f-cc078190e412",{"id":26,"createTime":18,"updateTime":18,"relativeEntities":27,"label":28,"description":30,"key":32,"publicationTags":33,"standard":18},"3c7051d4-eb7d-4c57-a56b-36fc74c5d1e9",[],{"EN":29,"VI":29},"Scopus - Elsevier",{"EN":29,"VI":31},"Cơ sở dữ liệu Scopus thuộc Elsevier","scopus",[34],"SCOPUS","https:\u002F\u002Fwww.scopus.com\u002Fsourceid\u002F19107","2004-2006","SCOPUS__Q2","https:\u002F\u002Flink.springer.com\u002Fjournal\u002F40289",{"impactFactor":19,"impactFactorByYear":40,"i10Index":41,"i10IndexLast5Year":19,"totalPublication":42,"totalPublicationByYear":43,"totalCitation":47,"totalCitationByYear":48,"totalCitationPerPublication":52,"totalCitationPerPublicationByYear":53,"hindexLast5Year":57,"hindex":57},{},12,16,{"2004":44,"2005":44,"2006":45,"2012":46},6,3,1,505,{"2004":49,"2005":50,"2006":51},210,241,54,31.56,{"2004":54,"2005":55,"2006":56},35,40.17,18,11,"JOURNAL",{"meta":60,"data":62},{"total":61},"74",[63,217,301,427,482,552,605,677,824,881],{"id":64,"createTime":65,"updateTime":66,"relativeEntities":67,"slug":68,"properties":69,"entityType":78,"verifyStatus":79,"verifyTime":66,"verifyNote":80,"languages":18,"translateLanguages":18,"viewCount":46,"primaryUrl":81,"fullTextUrl":18,"authors":82,"publicationType":187,"publisherRelationship":188,"citationCount":18,"citationInfo":18,"publishDate":213,"publishYear":214,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":215,"openAccess":18,"references":18,"isForceReanalyzing":216},"3a7aa4ce-c7f5-4442-b534-205436e92710","2024-02-05T22:52:01.689+00:00","2025-02-26T19:41:45.079+00:00",[],"A-Cross-Sectional-Comparison-of-Direct-Medical-Care-Costs-among-COPD-and-Asthma-Patients-Living-in-the-Community-in-Northern-Ireland",{"abstract":70,"title":72,"references":74,"doi":76},{"EN":71},"\n                Introduction: Asthma and COPD are known to have significant health and economic consequences. Little is known about the costs of the latter in the UK. In this study we report the results of a comparison of the direct medical costs associated with COPD and asthma, where diagnoses are based on a robust prevalence study of a random sample of the Northern Ireland population. \n                Methods: A two-stage survey was used to identify individuals with COPD and asthma. The diagnoses of asthma and COPD were based on patient history and lung function. Patients completed a detailed questionnaire covering healthcare utilization over the past 12 months, socioeconomic characteristics, impact of the disease on quality of life, and activities of daily living. \n                Results: Forty-nine patients were diagnosed with COPD and 57 with asthma. Three asthma patients were excluded from the main analysis because they were thought to have atypical inpatient stays or other resource use. The mean direct healthcare cost for each COPD patient was estimated at £171.69 ($US309; year 2000 value) per annum, significantly less than the average cost of asthma among the 54 analyzed of £544.54 ($US980) [p \u003C 0.05]. A correlation analysis revealed that among COPD patients, disease severity, defined by lung function, was a significant predictor of costs. \n                Conclusion: Community-based costs for asthma are greater than those for COPD; this may relate in part to a relative under-diagnosis of COPD (73.5% COPD vs 15.8% asthma). As anticipated, the cost of COPD increases as FEV1 decreases. Further analysis will enable modeling of the cost consequences of both increased diagnosis and better management of COPD.",{"EN":73},"A Cross-Sectional Comparison of Direct Medical Care Costs among COPD and Asthma Patients Living in the Community in Northern Ireland",{"VOID":75},"National Institute for Health and Clinical Excellence [online]. Available from URL: http:\u002F\u002Fwww.nice.org.uk [Accessed 2006 Mar 23]\nAmerican Thoracic Society. Standard for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Resp Crit Care Med 1995; 152: S77–120\nFletcher D, Peto R, Tinker C, et al. The natural history of chronic bronchitis and emphysema: an eight year study of early chronic obstructive lung disease in working men in London. Oxford: Oxford University Press, 1976\nBergner M, Hudson LD, Conrad DA, et al. The cost and efficacy of home care for patients with chronic lung disease. Med Care 1988; 26: 566–79\nSherrill DL, Lebowitz MD, Burrows B. Epidemiology of chronic obstructive pulmonary disease. Clin Chest Med 1990; 11: 375–87\nNational Center for Health Statistics: Health E Stats [online]. Available from URL: www.cdc.gov\u002Fnchs\u002Fproducts\u002Fpubs\u002Fpubd\u002Fhestats\u002Fasthma\u002Fasthma.htm [Accessed 2002 Aug 13]\nGlobal initiative for asthma (GINA) [online]. Available from URL: http:\u002F\u002Fginasthma.com [Accessed 2006 Mar 23]\nBarbee RA, Murphy S. The natural history of asthma. J Allergy Clin Immunol 1998; 102: S65–72\nBenson V, Marano MA. Current estimates from the National Health Interview Survey, 1993. Washington, DC: National Centre for Health Statistics, Vital and Health Statistics 10 (190), 1994. DHHS Publication No. (PHS) 95-1518\nSingh GK, Matthews TJ, Clark SC, et al. Annual summary of births, marriages, divorces and deaths: United States, 1994; monthly vital statistics report (Vol. 43, No. 13). Hyattsville (MD): National Centre for Health Statistics, 1994\nWard MM, Javitz HS, Smith WM, et al. Direct medical cost of chronic obstructive pulmonary disease in the USA. Respir Med 2000; 94: 1123–9\nHilleman DE, Dewan N, Malesker M, et al. Pharmacoeconomic evaluation of COPD. Chest 2000; 118(5): 1278–85\nAmerican Lung Association. Asthma in adults fact sheet [online]. Available from URL: http:\u002F\u002Fwww.lungusa.org [Accessed 2005 Apr 18]\nSmith DH, Malone DC, Lawson KA, et al. A national estimate of the economic costs of asthma. Am J Respir Crit Care Med 1997; 156(3): 787–93\nWeiss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med 1992; 326: 862–6\nSzucs TD, Anderhub H, Rutishauser M. The economic burden of asthma: direct and indirect costs in Switzerland. Eur Respir J 1999; 13(2): 281–6\nKrahn MD, Berka C, Langlois P, et al. Direct and indirect costs of asthma in Canada, 1990. CMAJ 1996; 154(6): 821–31\nMellis CM, Peat JK, Bauman AE, et al. The cost of asthma in New South Wales. Med J Aust 1991; 155(8): 522–8\nKiivet RA, Kaur I, Lang A, et al. Costs of asthma treatment in Estonia. Eur J Public Health 2001; 11(1): 89–92\nRutten van-Molken MP, Feenstra TL. The burden of asthma and chronic obstructive pulmonary disease: data from The Netherlands. Pharmacoeconomics 2001; 19 Suppl. 2: 1–6\nPelletier-Fleury N, Lanoe JL, Fleury B, et al. The cost of treating COPD patients with long-term oxygen therapy in a French population. Chest 1996; 110(2): 411–6\nGuest JF. The annual cost of chronic obstructive pulmonary disease to the UK’s National Health Service. Dis Manage Health Outcomes 1999; 5: 93–100\nBritton M. The burden of COPD in the UK: results from the Confronting COPD survey. Respir Med 2003; 97 Suppl. C: S71–9\nMurtagh E, Heaney LG, Gingles J, et al. The prevalence of obstructive lung disease in a general population sample: the NICECOPD study. Eur J Epidemiol 2005 May; 20(5): 443–53\nFletcher CM. Standardised questionnaire on respiratory symptoms: a statement prepared and approved by the MRC Committee on the Aetiology of Chronic Bronchitis (MRC breathlessness score). BMJ 1960; 2: 1665\nQuanjer PH, Lebowitz MD, Gregg I, et al. Peak expiratory flow: conclusions and recommendations of a Working Party of the European Respiratory Society. Eur Respir J Suppl 1997; 24: 2S–8S\nEuroQol quality of life assessment (EQ5D). EuroQol Group, PO Box 4443, 3006 AK Rotterdam, The Netherlands\nNetten A, Dennet J. Unit costs of health and social care 2000. Canterbury: PSSRU University of Kent at Canterbury (UK), 2000\nBritish National Formulary. London: British Medical Association, 2000\nUngar WJ, Coyte PC, Chapman KR, et al. The patient level cost of asthma in adults in south central Ontario: Pharmacy Medication Monitoring Program Advisory Board. Can Respir J 1998; 5(6): 463–71",{"VOID":77},"10.2165\u002F00151829-200605060-00012","PUBLICATION","VERIFIED","Auto Verify","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.2165\u002F00151829-200605060-00012",[83,99,114,128,143,166],{"id":84,"sortIndex":19,"researcher":18,"roles":85,"affiliations":87,"properties":96,"displayName":98,"givenName":18,"familyName":18},"f9bcb587-1fbf-4538-b98c-7921f34b1916",[86],"AUTHOR",[88],{"id":89,"sortIndex":19,"affiliation":90,"properties":18},"ba597ff7-3b8c-4580-a891-09e622530bf5",{"id":89,"createTime":18,"updateTime":18,"relativeEntities":91,"slug":18,"properties":92,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":95,"statistic":18},[],{"title":93},{"VI":94},"Regional Respiratory Centre, Level 8, Belfast City Hospital, Belfast, Northern Ireland",[],{"title":97},{"VI":98},"Eoin Murtagh",{"id":100,"sortIndex":46,"researcher":18,"roles":101,"affiliations":102,"properties":111,"displayName":113,"givenName":18,"familyName":18},"57e167eb-0878-40fd-9d75-c9591794e775",[86],[103],{"id":104,"sortIndex":19,"affiliation":105,"properties":18},"e1fb7b65-6ce3-40c8-9c56-5ef81aeaeefa",{"id":104,"createTime":18,"updateTime":18,"relativeEntities":106,"slug":18,"properties":107,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":110,"statistic":18},[],{"title":108},{"VI":109},"School of Policy Studies, University of Ulster Jordanstown, Newtownabbey, Northern Ireland",[],{"title":112},{"VI":113},"Ciaran O’Neill",{"id":115,"sortIndex":116,"researcher":18,"roles":117,"affiliations":118,"properties":125,"displayName":127,"givenName":18,"familyName":18},"cf581a0e-d4cd-4b74-ba65-550cd2266ff6",2,[86],[119],{"id":104,"sortIndex":19,"affiliation":120,"properties":18},{"id":104,"createTime":18,"updateTime":18,"relativeEntities":121,"slug":18,"properties":122,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":124,"statistic":18},[],{"title":123},{"VI":109},[],{"title":126},{"VI":127},"Denise McAllister",{"id":129,"sortIndex":45,"researcher":18,"roles":130,"affiliations":131,"properties":140,"displayName":142,"givenName":18,"familyName":18},"ad39fc15-6f82-484a-b85d-9ce2f56b954a",[86],[132],{"id":133,"sortIndex":19,"affiliation":134,"properties":18},"28d662d9-58b9-4e2b-800f-3f013fe43e18",{"id":133,"createTime":18,"updateTime":18,"relativeEntities":135,"slug":18,"properties":136,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":139,"statistic":18},[],{"title":137},{"VI":138},"Department of Epidemiology and Public Health, Queen’s University Belfast, Belfast, Northern Ireland",[],{"title":141},{"VI":142},"Frank Kee",{"id":144,"sortIndex":145,"researcher":18,"roles":146,"affiliations":147,"properties":163,"displayName":165,"givenName":18,"familyName":18},"82cab0c7-e7c1-463a-85e1-8b08ca250ab6",4,[86],[148,154],{"id":89,"sortIndex":19,"affiliation":149,"properties":18},{"id":89,"createTime":18,"updateTime":18,"relativeEntities":150,"slug":18,"properties":151,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":153,"statistic":18},[],{"title":152},{"VI":94},[],{"id":155,"sortIndex":46,"affiliation":156,"properties":162},"d35de043-7bc6-4594-ae23-498dcc3d3f31",{"id":155,"createTime":18,"updateTime":18,"relativeEntities":157,"slug":18,"properties":158,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":161,"statistic":18},[],{"title":159},{"VI":160},"Department of Medicine, Queen’s University Belfast, Belfast, Northern Ireland",[],{},{"title":164},{"VI":165},"Joe MacMahon",{"id":167,"sortIndex":168,"researcher":18,"roles":169,"affiliations":170,"properties":184,"displayName":186,"givenName":18,"familyName":18},"fb2a6c68-d00d-4fb3-8b77-7a9c71b25e6f",5,[86],[171,177],{"id":89,"sortIndex":19,"affiliation":172,"properties":18},{"id":89,"createTime":18,"updateTime":18,"relativeEntities":173,"slug":18,"properties":174,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":176,"statistic":18},[],{"title":175},{"VI":94},[],{"id":155,"sortIndex":46,"affiliation":178,"properties":183},{"id":155,"createTime":18,"updateTime":18,"relativeEntities":179,"slug":18,"properties":180,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":182,"statistic":18},[],{"title":181},{"VI":160},[],{},{"title":185},{"VI":186},"Liam G. Heaney","ARTICLE",{"url":81,"publisher":189,"properties":208},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":190,"slug":10,"properties":191,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":194,"manageAffiliations":195,"indexDatabases":196,"url":38,"thumbnailPath":18,"statistic":203,"gsStatistic":18,"type":58,"analyzePriority":18},[],{"issn":192,"title":193},{"VOID":13},{"EN":15},[],[],[197],{"id":24,"indexDatabase":198,"url":35,"indexYears":36,"academicFieldIds":18,"indexDatabaseRanking":37},{"id":26,"createTime":18,"updateTime":18,"relativeEntities":199,"label":200,"description":201,"key":32,"publicationTags":202,"standard":18},[],{"EN":29,"VI":29},{"EN":29,"VI":31},[34],{"impactFactor":19,"impactFactorByYear":204,"i10Index":41,"i10IndexLast5Year":19,"totalPublication":42,"totalPublicationByYear":205,"totalCitation":47,"totalCitationByYear":206,"totalCitationPerPublication":52,"totalCitationPerPublicationByYear":207,"hindexLast5Year":57,"hindex":57},{},{"2004":44,"2005":44,"2006":45,"2012":46},{"2004":49,"2005":50,"2006":51},{"2004":54,"2005":55,"2006":56},{"pages":209,"volume":211},{"VOID":210},"495-501",{"VOID":212},"5","2012-08-23",2012,[],false,{"id":218,"createTime":219,"updateTime":220,"relativeEntities":221,"slug":222,"properties":223,"entityType":78,"verifyStatus":79,"verifyTime":220,"verifyNote":80,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":232,"fullTextUrl":18,"authors":233,"publicationType":187,"publisherRelationship":275,"citationCount":18,"citationInfo":18,"publishDate":213,"publishYear":214,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":300,"openAccess":18,"references":18,"isForceReanalyzing":216},"7b8a8230-d910-4e6e-b303-8143baee5405","2024-01-18T05:17:19.534+00:00","2025-02-23T04:01:59.602+00:00",[],"Biomarkers-Predicting-Response-to-Corticosteroid-Therapy-in-Asthma",{"abstract":224,"title":226,"references":228,"doi":230},{"EN":225},"International guidelines on the management of asthma support the early introduction of corticosteroids to control symptoms and to improve lung function by reducing airway inflammation. However, not all individuals respond to corticosteroids to the same extent and it would be an advantage to be able to predict the response to corticosteroid treatment. Several biomarkers have been assessed following treatment with corticosteroids including measures of lung function, peripheral blood and sputum indices of inflammation, exhaled gases and breath condensates. The most widely examined measures in predicting a response to corticosteroids are airway hyperresponsiveness, exhaled nitric oxide (eNO) and induced sputum. Of these, sputum eosinophilia has been demonstrated to be the best predictor of a short-term response to corticosteroids. More importantly, directing treatment at normalizing the sputum eosinophil count can substantially reduce severe exacerbations. The widespread utilization of sputum induction is hampered because the procedure is relatively labor intensive. The measurement of eNO is simpler, but incorporating the assessment of NO in an asthma management strategy has not led to a reduction in exacerbation rates. The challenge now is to either simplify the measurement of a sputum eosinophilia or to identify another inflammatory marker with a similar efficacy as the sputum eosinophil count in predicting both the short- and long-term responses to corticosteroids.",{"EN":227},"Biomarkers Predicting Response to Corticosteroid Therapy in Asthma",{"VOID":229},"Wardlaw AJ, Brightling C, Green R, et al. Eosinophils in asthma and other allergic diseases. Br Med Bull 2000; 56(4): 985–1003\nBrightling CE, Bradding P, Symon FA, et al. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002; 346(22): 1699–705\nKay AB. Pathology of mild, severe, and fatal asthma. Am J Respir Crit Care Med 1996; 154 (2 Pt 2): S66–9\nNational Heart, Lung and Blood Institute. Global intiative for asthma: global strategy for asthma management and prevention. Bethesda, MD; 1995\nBritish Thoracic Society. Scottish Intercollegiate Guidelines Network (SIGN). British guidelines on the management of asthma. Thorax 2003; 58 Suppl. 1: i1–94\nJuniper EF, Kline PA, Vanzieleghem MA, et al. Long-term effects of budesonide on airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthmatics. Eur Respir J 1990; 3(10): 1122–7\nJuniper EF, Kline PA, Vanzieleghem MA, et al. Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics. Am Rev Respir Dis 1990; 142(4): 832–6\nHaahtela T, Jarvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991; 325(6): 388–92\nAdams NP, Bestall JB, Jones PW. Inhaled beclomethasone versus placebo for chronic asthma. Cochrane Database Syst Rev 2000; (4): CD002738\nLoren ML, Chai H, Leung P, et al. Corticosteroids in the treatment of acute exacerbations of asthma. Ann Allergy 1980; 45(2): 67–71\nBeasley R. The burden of asthma with specific reference to the United States. J. Allergy Clin Immunol 2002; 109 (5 Suppl.): S482–9\nCrimi E, Spanevello A, Neri M, et al. Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma. Am J Respir Crit Care Med 1998; 157(1): 4–9\nRosi E, Scano G. Association of sputum parameters with clinical and functional measurements in asthma. Thorax 2000; 55(3): 235–8\nRonchi MC, Piragino C, Rosi E, et al. Do sputum eosinophils and ECP relate to the severity of asthma? Eur Respir J 1997; 10(8): 1809–13\nVeen JC, Smits HH, Ravensberg AJ, et al. Impaired perception of dyspnea in patients with severe asthma: relation to sputum eosinophils. Am J Respir Crit Care Med 1998; 158(4): 1134–41\nRoisman GL, Peiffer C, Lacronique JG, et al. Perception of bronchial obstruction in asthmatic patients: relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment. J Clin Invest 1995; 96(1): 12–21\nSalome CM, Reddel HK, Ware SI, et al. Effect of budesonide on the perception of induced airway narrowing in subjects with asthma. Am J Respir Crit Care Med 2002; 165(1): 15–21\nParameswaran K, Pizzichini E, Pizzichini MM, et al. Clinical judgement of airway inflammation versus sputum cell counts in patients with asthma. Eur Respir J 2000; 15(3): 486–90\nReddel HK, Jenkins CR, Marks GB, et al. Optimal asthma control, starting with high doses of inhaled budesonide. Eur Respir J 2000; 16(2): 226–35\nGershman NH, Wong HH, Liu JT, et al. Low- and high-dose fluticasone propionate in asthma; effects during and after treatment. Eur Respir J 2000; 15(1): 11–8\nEvans RM. The steroid and thyroid hormone receptor superfamily. Science 1988; 240(4854): 889–95\nCarson-Jurica MA, Schrader WT, O’Malley BW. Steroid receptor family: structure and functions. Endocr Rev 1990; 11(2): 201–20\nGronemeyer H. Control of transcription activation by steroid hormone receptors. FASEB J 1992; 6(8): 2524–9\nJonat C, Rahmsdorf HJ, Park KK, et al. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos\u002FJun) activity by glucocorticoid hormone. Cell 1990; 62(6): 1189–204\nAuphan N, Didonato JA, Rosette C, et al. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995; 270(5234): 286–90\nDjukanovic R, Wilson JW, Britten KM, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis 1992; 145(3): 669–74\nWard C, Pais M, Bish R, et al. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax 2002; 57(4): 309–16\nHoshino M, Nakamura Y, Sim JJ, et al. Inhaled corticosteroid reduced lamina reticularis of the basement membrane by modulation of insulin-like growth factor (IGF)-I expression in bronchial asthma. Clin Exp Allergy 1998; 28(5): 568–77\nHoshino M, Takahashi M, Takai Y, et al. Inhaled corticosteroids decrease vascularity of the bronchial mucosa in patients with asthma. Clin Exp Allergy 2001; 31(5): 722–30\nBentley AM, Hamid Q, Robinson DS, et al. Prednisolone treatment in asthma: reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med 1996; 153(2): 551–6\nOrsida BE, Li X, Hickey B, et al. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 1999; 54(4): 289–95\nKnox AJ. The scientific rationale of combining inhaled glucocorticoids and long acting Beta 2 adrenoceptor agonists. Curr Pharm Des 2002; 8(20): 1863–9\nBjornson BH, Harvey JM, Rose L. Differential effect of hydrocortisone on eosinophil and neutrophil proliferation. J Clin Invest 1985; 76(3): 924–9\nMeagher LC, Cousin JM, Seckl JR, et al. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996; 156(11): 4422–8\nMeijer RJ, Postma DS, Kauffman HF, et al. Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma. Clin Exp Allergy 2002; 32(7): 1096–103\nPavord ID, Brightling CE, Woltmann G, et al. Non-eosinophilic corticosteroid unresponsive asthma. Lancet 1999; 353(9171): 2213–4\nMondino C, Ciabattoni G, Koch P, et al. Effects of inhaled corticosteroids on exhaled leukotrienes and prostanoids in asthmatic children. J Allergy Clin Immunol 2004; 114(4): 761–7\nHunter CJ, Brightling CE, Woltmann G, et al. A comparison of the validity of different diagnostic tests in adults with asthma. Chest 2002; 121(4): 1051–7\nVerscheiden P, Cartier A, L’Archeveque J, et al. Compliance with and accuracy of daily self-assessment of peak expiratory flows (PEF) in asthmatic subjects over a three month period. Eur Respir J 1996; 9(5): 880–5\nDiner B, Brenner B, Camargo CA, et al. Inaccuracy of “personal best” peak expiratory flow rate reported by inner-city patients with acute asthma. J Asthma 2001; 38(2): 127–32\nReddel HK, Toelle BG, Marks GB, et al. Analysis of adherence to peak flow monitoring when recording of data is electronic. BMJ 2002; 324(7330): 146–7\nReddel H, Ware S, Marks G, et al. A. Differences between asthma exacerbations and poor asthma control. Lancet 1999; 353(9150): 364–9\nReddel H, Jenkins C, Woolcock A. Diurnal variability—time to change asthma guidelines? BMJ 1999; 319(7201): 45–7\nBirring SS, Heartin E, Williams TJ, et al. Peak expiratory flow sequence in acute exacerbations of asthma. BMJ 2001; 322(7297): 1281\nJuniper EF, Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: a laboratory tidal breathing protocol. Lund: Astra Draco AB, 1994\nCrapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000; 161(1): 309–29\nBarnes PJ. Effect of corticosteroids on airway hyperresponsiveness. Am Rev Respir Dis 1990; 141 (2 Pt 2): S70–6\nVathenen AS, Knox AJ, Wisniewski A, et al. Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma. Am Rev Respir Dis 1991; 143(6): 1317–21\nBoulet LP, Turcotte H, Brochu A. Persistence of airway obstruction and hyperresponsiveness in subjects with asthma remission. Chest 1994; 105(4): 1024–31\nLeuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001; 163(2): 406–12\nSont JK, Willems LN, Bel EH, et al. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med 1999; 159 (4 Pt 1): 1043–51\nGreen RH, Brightling CE, Woltmann GW, et al. Analysis of induced sputum in adults with asthma: identification of a subgroup with neutrophilic inhaled corticosteroid resistant disease. Thorax 2002; 57: 875–9\nPizzichini E, Pizzichini MM, Efthimiadis A, et al. Measuring airway inflammation in asthma: eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood. J Allergy Clin Immunol 1997; 99(4): 539–44\nBaba K, Hattori T, Koishikawa I, et al. Serum eosinophil cationic protein for predicting the prognosis of a step-down in inhaled corticosteroid therapy in adult chronic asthmatics. J Asthma 2000; 37(5): 399–408\nBaba K, Sakakibara A, Yagi T, et al. Long-term observations of the clinical course after step down of corticosteroid inhalation therapy in adult chronic asthmatics: correlation with serum levels of eosinophil cationic protein. Respirology 2002; 7(3): 255–66\nPrehn A, Seger RA, Torresani T, et al. Evaluation of a clinical algorithm involving serum eosinophil cationic protein for guiding the anti-inflammatory treatment of bronchial asthma in childhood. Pediatr Allergy Immunol 2000; 11(2): 87–94\nBosse M, Chakir J, Rouabhia M, et al. Serum matrix metalloproteinase-9: tissue inhibitor of metalloproteinase-1 ratio correlates with steroid responsiveness in moderate to severe asthma. Am J Respir Crit Care Med 1999; 159(2): 596–602\nSchedin U, Frostell C, Persson MG, et al. Contribution from upper and lower airways to exhaled endogenous nitric oxide in humans. Acta Anaesthesiol Scand 1995; 39(3): 327–32\nKharitonov SA, Yates D, Robbins RA, et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343(8890): 133–5\nPersson MG, Zetterstrom O, Agrenius V, et al. Single-breath nitric oxide measurements in asthmatic patients and smokers. Lancet 1994; 343(8890): 146–7\nHamid Q, Springall DR, Riveros-Moreno V, et al. Induction of nitric oxide synthase in asthma. Lancet 1993; 342(8886-8887): 1510–3\nSaleh D, Ernst P, Lim S, et al. Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid. FASEB J 1998; 12(11): 929–37\nKharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996; 153(1): 454–7\nMassaro AF, Gaston B, Kita D, et al. Expired nitric oxide levels during treatment of acute asthma. Am J Respir Crit Care Med 1995; 152(2): 800–3\nKharitonov SA, Yates DH, Chung KF, et al. Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients. Eur Respir J 1996; 9(2): 196–201\nJatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med 2000; 161(1): 64–72\nLittle SA, Chalmers GW, MacLeod KJ, et al. Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma. Thorax 2000; 55(3): 232–4\nSmith AD, Cowan J, Brasset KP, et al. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med 2005; 352(21): 2163–73\nZacharasiewicz A, Wilson N, Lex C, et al. Clinical use of non-invasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med 2005; 171: 1077–82\nZayasu K, Sekizawa K, Okinaga S, et al. Increased carbon monoxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1997; 156 (4 Pt 1): 1140–3\nLim S, Groneberg D, Fischer A, et al. Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: effect of inhaled corticosteroids. Am J Respir Crit Care Med 2000; 162(5): 1912–8\nOlopade CO, Zakkar M, Swedler WI, et al. Exhaled pentane levels in acute asthma. Chest 1997; 111(4): 862–5\nParedi P, Kharitonov SA, Barnes PJ. Faster rise of exhaled breath temperature in asthma: a novel marker of airway inflammation? Am J Respir Crit Care Med 2002; 165(2): 181–4\nKharitonov SA, Barnes PJ. Exhaled markers of inflammation. Curr Opin Allergy Clin Immunol 2001; 1(3): 217–24\nPavord ID, Pizzichini MM, Pizzichini E, et al. The use of induced sputum to investigate airway inflammation. Thorax 1997; 52(6): 498–501\nFahy JV, Liu J, Wong H, et al. Cellular and biochemical analysis of induced sputum from asthmatic and from healthy subjects. Am Rev Respir Dis 1993; 147(5): 1126–31\nGibson PG, Girgis-Gabardo A, Morris MM, et al. Cellular characteristics of sputum from patients with asthma and chronic bronchitis. Thorax 1989; 44(9): 693–9\nPizzichini E, Pizzichini MM, Leigh R, et al. Safety of sputum induction. Eur Respir J Suppl 2002; 37: 9S–18S\nPaggiaro PL, Chanez P, Holz O, et al. Sputum induction. Eur Respir J Suppl 2002; 37: 3S–8S\nDjukanovic R, Sterk PJ, Fahy JV, et al. Standardised methodology of sputum induction and processing. Eur Respir J Suppl 2002; 37: 1S–2S\nMaestrelli P, Saetta M, Di Stefano A, et al. Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am J Respir Crit Care Med 1995; 152 (6 Pt 1): 1926–31\nFahy JV, Wong H, Liu J, et al. Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects. Am J Respir Crit Care Med 1995; 152(1): 53–8\nBelda J, Leigh R, Parameswaran K, et al. Induced sputum cell counts in healthy adults. Am J Respir Crit Care Med 2000; 161 (2 Pt 1): 475–8\nClaman DM, Boushey HA, Liu J, et al. Analysis of induced sputum to examine the effects of prednisone on airway inflammation in asthmatic subjects. J Allergy Clin Immunol 1994; 94(5): 861–9\nGibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest 2001; 119(5): 1329–36\nWenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160(3): 1001–8\nBrightling CE, Monteiro W, Ward R, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2000; 356(9240): 1480–5\nPizzichini E, Pizzichini MM, Gibson P, et al. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med 1998; 158 (5 Pt 1): 1511–7\nPizzichini MM, Pizzichini E, Parameswaran K, et al. Nonasthmatic chronic cough: no effect of treatment with an inhaled corticosteroid in patients without sputum eosinophilia. Can Respir J 1999; 6(4): 323–30\nGodon P, Boulet LP, Malo JL, et al. Assessment and evaluation of symptomatic steroid-naive asthmatics without sputum eosinophilia and their response to inhaled corticosteroids. Eur Respir J 2002; 20(6): 1364–9\nPizzichini MM, Pizzichini E, Clelland L, et al. Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med 1997; 155(5): 1501–8\nGiannini D, Di Franco A, Cianchetti S, et al. Analysis of induced sputum before and after withdrawal of treatment with inhaled corticosteroids in asthmatic patients. Clin Exp Allergy 2000; 30(12): 1777–84\nGreen RH, Brightling CE, McKenna S, et al. Reduced asthma exacerbations with a management strategy directed at normalising the sputum eosinophil count. Lancet 2002; 360: 1715–21\nLane SJ, Lee TH. Mononuclear cells in corticosteroid-resistant asthma. Am J Respir Crit Care Med 1996; 154 (2 Pt 2): S49–51\nSher ER, Leung DY, Surs W, et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest 1994; 93(1): 33–9\nChakir J, Hamid Q, Bosse M, et al. Bronchial inflammation in corticosteroid-sensitive and corticosteroid-resistant asthma at baseline and on oral corticosteroid treatment. Clin Exp Allergy 2002; 32(4): 578-82",{"VOID":231},"10.2165\u002F00151829-200504050-00002","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.2165\u002F00151829-200504050-00002",[234,249,262],{"id":235,"sortIndex":19,"researcher":18,"roles":236,"affiliations":237,"properties":246,"displayName":248,"givenName":18,"familyName":18},"6624c5fe-da7e-4656-8f16-c979e2f1c9bd",[86],[238],{"id":239,"sortIndex":19,"affiliation":240,"properties":18},"fa5033da-0324-41d2-8f82-9292daed7f1f",{"id":239,"createTime":18,"updateTime":18,"relativeEntities":241,"slug":18,"properties":242,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":245,"statistic":18},[],{"title":243},{"VI":244},"Institute for Lung Health, University of Leicester and University Hospitals of Leicester, Leicester, UK",[],{"title":247},{"VI":248},"Christopher E. 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It is elevated in the airways of asthmatic patients and is responsible for many of the pathophysiological features in asthma. Antihistamines block the actions of histamine and also have effects on inflammation which is independent of histamine-H1-receptor antagonism. Antihistamines have been shown to have bronchodilatory effects, effects on allergen-, exercise-, and adenosine- monophosphate-challenge testing, and also to prevent allergen-induced nonspecific airways hyperresponsiveness. Clinical studies have shown mixed results, and some studies have reported beneficial effects of azelastine, cetirizine, desloratadine, and fexofenadine on asthma symptoms or physiological measures in patients with asthma. The combination of an antihistamine and a leukotriene receptor antagonist has been shown to have additive effects in certain studies. Antihistamines have also been shown to delay or prevent the development of asthma in a subgroup of atopic children. These data suggest that antihistamines may have beneficial effects in the management of asthma.",{"EN":437},"The Role of Antihistamines in Asthma Management",{"EN":439},"",{"VOID":441},"Dale HH, Laidlaw PP. The physiological action of a beta-imidazolyl-ethyl-amine. J Physiol 1910; 41: 318–44\nWhite MV. The role of histamine in allergic diseases. J Allergy Clin Immunol 1990; 86: 599–605\nBest CH, Dale HH, Dudley HW, et al. The nature of the vaso-dilator constituents of certain tissues [letter]. J Physiol 1927; 62: 397\nGravelyn TR, Pan PM, Eschenbacher WL. Mediator release in an isolated airway segment in subjects with asthma. Am Rev Respir Dis 1988; 137: 641–6\nCasale TB, Wood D, Richerson HB, et al. Direct evidence of a role for mast cells in the pathogenesis of antigen-induced bronchoconstriction. J Clin Invest 1987; 80: 1507–11\nCasale TB, Wood D, Richerson HB, et al. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness. J Clin Invest 1987; 79: 1197–203\nLouis R, Van Tulder L, Poncelet M, et al. Correlation between bronchoalveolar lavage (BAL) fluid cell lysate histamine content and BAL fluid eosinophil count in atopic and nonatopic asthmatics. Int Arch Allergy Immunol 1997; 112: 309–12\nPopa VT. Bronchodilating activity of an H1 blocker, chlorpheniramine. J Allergy Clin Immunol 1977; 59: 54–63\nPopa VT. Effect of an H1 blocker, chlorpheniramine, on inhalation tests with histamine and allergen in allergic asthma. Chest 1980; 78: 442–51\nBousquet J, Godard P, Michel FB. Antihistamines in the treatment of asthma. Eur Respir J 1992; 5: 1137–42\nSchuller DE. Adverse effects of brompheniramine on pulmonary function in a subset of asthmatic children. J Allergy Clin Immunol 1983; 72: 175–9\nSimons FE, Fraser TG, Reggin JD, et al. Comparison of the central nervous system effects produced by six H1-receptor antagonists. Clin Exp Allergy 1996; 26: 1092–7\nChurch MK, Gradidge CF. Inhibition of histamine release from human lung in vitro by antihistamines and related drugs. Br J Pharmacol 1980; 69: 663–7\nBaroody FM, Naclerio RM. Antiallergic effects of H1-receptor antagonists. Allergy 2000; 55 Suppl. 64: 17–27\nMarshall Jr GD. Therapeutic options in allergic disease: antihistamines as systemic antiallergic agents. J Allergy Clin Immunol 2000; 106: S303–9\nWalsh GM, Annunziato L, Frossard N, et al. New insights into the second generation antihistamines. Drugs 2001; 61: 207–36\nMarone G, Granata F, Spadaro G, et al. The histamine-cytokine network in allergic inflammation. J Allergy Clin Immunol 2003; 112: S83–8\nArnold R, Rihoux J, Konig W. Cetirizine counter-regulates interleukin-8 release from human epithelial cells (A549). Clin Exp Allergy 1999; 29: 1681–91\nLippert U, Moller A, Welker P, et al. Inhibition of cytokine secretion from human leukemic mast cells and basophils by H1- and H2-receptor antagonists. Exp Dermatol 2000; 9: 118–24\nTriggiani M, Gentile M, Secondo A, et al. Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J Immunol 2001; 166: 4083–91\nBakker RA, Wieland K, Timmerman H, et al. Constitutive activity of the histamine H(1) receptor reveals inverse agonism of histamine H(1) receptor antagonists. Eur J Pharmacol 2000; 387: R5–7\nAbdelaziz MM, Devalia JL, Khair OA, et al. Effect of fexofenadine on eosinophil-induced changes in epithelial permeability and cytokine release from nasal epithelial cells of patients with seasonal allergic rhinitis. J Allergy Clin Immunol 1998; 101: 410–20\nPapi A, Papadopoulos NG, Stanciu LA, et al. Effect of desloratadine and loratadine on rhinovirus-induced intercellular adhesion molecule 1 upregulation and promoter activation in respiratory epithelial cells. J Allergy Clin Immunol 2001; 108: 221–8\nCiprandi G, Pronzato C, Ricca V, et al. Terfenadine exerts antiallergic activity reducing ICAM-1 expression on nasal epithelial cells in patients with pollen allergy. Clin Exp Allergy 1995; 25: 871–8\nCiprandi G, Pronzato C, Ricca V, et al. Loratadine treatment of rhinitis due to pollen allergy reduces epithelial ICAM-1 expression. Clin Exp Allergy 1997; 27: 1175–83\nCiprandi G, Pronzato C, Passalacqua G, et al. Topical azelastine reduces eosinophil activation and intercellular adhesion molecule-1 expression on nasal epithelial cells: an antiallergic activity. J Allergy Clin Immunol 1996; 98: 1088–96\nCiprandi G, Tosca M, Ricca V, et al. Cetirizine treatment of rhinitis in children with pollen allergy: evidence of its antiallergic activity. Clin Exp Allergy 1997; 27: 1160–6\nRedier H, Chanez P, De Vos C, et al. Inhibitory effect of cetirizine on the bronchial eosinophil recruitment induced by allergen inhalation challenge in allergic patients with asthma. J Allergy Clin Immunol 1992; 90: 215–24\nBryce PJ, Geha R, Oettgen HC. Desloratadine inhibits allergen-induced airway inflammation and bronchial hyperresponsiveness and alters T-cell responses in murine models of asthma. J Allergy Clin Immunol 2003; 112: 149–58\nAllergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: first results of ETAC. Early Treatment of the Atopic Child. Pediatr Allergy Immunol 1998; 9: 116–24\nWood-Baker R, Holgate ST. The comparative actions and adverse effect profile of single doses of H1-receptor antihistamines in the airways and skin of subjects with asthma. J Allergy Clin Immunol 1993; 91(5): 1005–14\nMacFarlane PI, Heaf DP. Selective histamine blockade in childhood asthma; the effect of terfenadine on resting bronchial tone and exercise induced bronchoconstriction. Respir Med 1989; 83: 19–24\nSpector SL, Nicodemus CF, Corren J, et al. Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma. J Allergy Clin Immunol 1995; 96: 174–81\nLee DK, Bates CE, Currie GP, et al. Comparative in vivo bioactivity of modern H1-antihistamines on AMP challenge in atopic asthma. J Allergy Clin Immunol 2003; 111: 337–41\nFinnerty JP, Holgate ST. Evidence for the roles of histamine and prostaglandins as mediators in exercise-induced asthma: the inhibitory effect of terfenadine and flurbiprofen alone and in combination. Eur Respir J 1990; 3: 540–7\nMagnussen H, Reuss G, Jorres R, et al. The effect of azelastine on exercise-induced asthma. Chest 1988; 93: 937–40\nBaki A, Orhan F. The effect of loratadine in exercise-induced asthma. Arch Dis Child 2002; 86: 38–9\nGhosh SK, De Vos C, McIlroy I, et al. Effect of cetirizine on exercise induced asthma. Thorax 1991; 46: 242–4\nBentley AM, Walker S, Hanotte F, et al. A comparison of the effects of oral cetirizine and inhaled beclomethasone on early and late asthmatic responses to allergen and the associated increase in airways hyperresponsiveness. Clin Exp Allergy 1996; 26: 909–17\nRafferty P, Ghosh SK, De Vos C, et al. Effect of oral and inhaled cetirizine in allergen induced bronchoconstriction. Clin Exp Allergy 1993; 23: 528–31\nTwentyman OP, Ollier S, Holgate ST. The effect of H1-receptor blockade on the development of early- and late-phase bronchoconstriction and increased bronchial responsiveness in allergen-induced asthma. J Allergy Clin Immunol 1993; 91: 1169–78\nTown GI, Holgate ST. Comparison of the effect of loratadine on the airway and skin responses to histamine, methacholine, and allergen in subjects with asthma. J Allergy Clin Immunol 1990; 86: 886–93\nHamid M, Rafferty P, Holgate ST. The inhibitory effect of terfenadine and flurbiprofen on early and late-phase bronchoconstriction following allergen challenge in atopic asthma. Clin Exp Allergy 1990; 20: 261–7\nBalzano G, Gallo C, Masi C, et al. Effect of azelastine on the seasonal increase in non-specific bronchial responsiveness to methacholine in pollen allergic patients: a randomized, double-blind placebo-controlled, crossover study. Clin Exp Allergy 1992; 22: 371–7\nFinnerty JP, Holgate ST, Rihoux JP. The effect of 2 weeks treatment with cetirizine on bronchial reactivity to methacholine in asthma. Br J Clin Pharmacol 1990; 29: 79–84\nRuffin RE, Latimer KM. Lack of effect of 4 weeks of oral H1 antagonist on bronchial responsiveness. Eur Respir J 1991; 4: 575–9\nAubier M, Neukirch C, Peiffer C, et al. Effect of cetirizine on bronchial hyperresponsiveness in patients with seasonal allergic rhinitis and asthma. Allergy 2001; 56: 35–42\nBruin-Weller MS, Rijssenbeek-Nouwens LH, de Monchy JG. Lack of effect of cetirizine on early and late asthmatic response after allergen challenge. J Allergy Clin Immunol 1994; 94: 231–9\nVan Den Berg M, Meijer RJ, Kerstjens HA, et al. PC20 adenosine 5′-monophosphate is more closely associated with airway inflammation in asthma than PC20 methacholine. Am J Respir Crit Care Med 2001; 163: 1546–50\nPhillips GD, Polosa R, Holgate ST. The effect of histamine-H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma. Clin Exp Allergy 1989; 19: 405–9\nPhillips GD, Rafferty P, Beasley R, et al. Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5′-monophosphate in non-atopic asthma. Thorax 1987; 42: 939–45\nAzevedo M, da Costa JT, Fontes P, et al. Effect of terfenadine and ipratropium bromide on ultrasonically nebulized distilled water-induced asthma. J Int Med Res 1990; 18: 37–49\nFinnerty JP, Wilmot C, Holgate ST. Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen: evidence for the predominant role of histamine. Am Rev Respir Dis 1989; 140: 593–7\nLee DK, Jackson CM, Haggart K, et al. Repeated dosing effects of mediator antagonists in inhaled corticosteroid-treated atopic asthmatic patients. Chest 2004; 125: 1372–7\nFardon TC, Lee DK, Hodge MR, et al. Addition of fexofenadine to inhaled corticosteroid therapy to reduce inflammatory biomarkers in atopic asthma. Ann Allergy Asthma Immuol 2005; 95: 259–65\nVan Ganse E, Kaufman L, Derde MP, et al. Effects of antihistamines in adult asthma: a meta-analysis of clinical trials. Eur Respir J 1997; 10: 2216–24\nNelson HS. Prospects for antihistamines in the treatment of asthma. J Allergy Clin Immunol 2003; 112: S96–100\nBruttmann G, Pedrali P, Arendt C, et al. Protective effect of cetirizine in patients suffering from pollen asthma. Ann Allergy 1990; 64: 224–8\nDijkman JH, Hekking PR, Molkenboer JF, et al. Prophylactic treatment of grass pollen-induced asthma with cetirizine. Clin Exp Allergy 1990; 20: 483–90\nAaronson DW. Evaluation of cetirizine in patients with allergic rhinitis and perennial asthma. Ann Allergy Asthma Immunol 1996; 76: 440–6\nBousquet J, Emonot A, Germouty J, et al. Double-blind multicenter study of cetirizine in grass-pollen-induced asthma. Ann Allergy 1990; 65: 504–8\nGrant JA, Nicodemus CF, Findlay SR, et al. Cetirizine in patients with seasonal rhinitis and concomitant asthma: prospective, randomized, placebo-controlled trial. J Allergy Clin Immunol 1995; 95: 923–32\nRafferty P, Jackson L, Smith R, et al. Terfenadine, a potent histamine H1-receptor antagonist in the treatment of grass pollen sensitive asthma. Br J Clin Pharmacol 1990; 30: 229–35\nTaytard A, Beaumont D, Pujet JC, et al. Treatment of bronchial asthma with terfenadine; a randomized controlled trial. Br J Clin Pharmacol 1987; 24: 743–6\nWood-Baker R, Smith R, Holgate ST. A double-blind, placebo controlled study of the effect of the specific histamine H1-receptor antagonist, terfenadine, in chronic severe asthma. Br J Clin Pharmacol 1995; 39: 671–5\nBusse WW, Middleton E, Storms W, et al. Corticosteroid-sparing effect of azelastine in the management of bronchial asthma. Am J Respir Crit Care Med 1996; 153: 122–7\nGould CA, Ollier S, Aurich R, et al. A study of the clinical efficacy of azelastine in patients with extrinsic asthma, and its effect on airway responsiveness. Br J Clin Pharmacol 1988; 26: 515–25\nBalzano G, Gallo C, Masi C, et al. Effect of azelastine on the seasonal increase in non-specific bronchial responsiveness to methacholine in pollen allergic patients: a randomized, double-blind placebo-controlled, crossover study. Clin Exp Allergy 1992; 22: 371–7\nEkstrom T, Osterman K, Zetterstrom O. Lack of effect of loratadine on moderate to severe asthma. Ann Allergy Asthma Immunol 1995; 75: 287–9\nBaena-Cagnani CE. Desloratadine activity in concurrent seasonal allergic rhinitis and asthma. Allergy 2001; 56 Suppl. 65: 21–7\nBaena-Cagnani CE, Berger WE, DuBuske LM, et al. Comparative effects of desloratadine versus montelukast on asthma symptoms and use of beta 2-agonists in patients with seasonal allergic rhinitis and asthma. Int Arch Allergy Immunol 2003; 130: 307–13\nSpector S, Lee N, McNutt B, et al. Effect of terfenadine in asthmatic patients. Ann Allergy 1992; 69: 212–6\nGhosh SK, De Vos C, Mcllroy I, et al. Effect of cetirizine on histamine- and leukotriene D4-induced bronchoconstriction in patients with atopic asthma. J Allergy Clin Immunol 1991; 87: 1010–3\nGong Jr H, Tashkin DP, Dauphinee B, et al. Effects of oral cetirizine, a selective H1 antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol 1990; 85: 632–41\nLee DK, Gray RD, Wilson AM, et al. Single and short-term soing effect of levocetirizine on adenosine monophosphate bronchoprotection in atopic asthma. Br J Clin Pharmacol 2004; 58: 34–9\nBustos GJ, Bustos D, Bustos GJ, et al. Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study. Clin Exp Allergy 1995; 25: 568–73\nWarner JO. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment follow-up. J Allergy Clin Immunol 2001; 108: 929–37\nSampson AP, Rorke S. Combination therapy with anti-mediator drugs in allergic disease. Clin Exp Allergy 2001; 31: 11–7\nRuck LM, Rizzo CA, Anthes JC, et al. Synergistic antiallergic activity of combined histamine H1- and cysteinyl leukotriene1-receptor blockade in human bronchus. Life Sci 2001; 68: 2825–34\nRoquet A, Dahlen B, Kumlin M, et al. Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics. Am J Respir Crit Care Med 1997; 155: 1856–63\nReicin A, White R, Weinstein SF, et al. Montelukast, a leukotriene receptor antagonist, in combination with loratadine, a histamine receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 2000; 160: 2481–8\nBrannan JD, Anderson SD, Gomes K, et al. Fexofenadine decreases sensitivity to and montelukast improves recovery from inhaled mannitol. Am J Respir Crit Care Med 2001; 163: 1420–5\nEggleston PA, Kagey-Sobotka A, Lichtenstein LM. A comparison of the osmotic activation of basophils and human lung mast cells. Am Rev Respir Dis 1987; 135: 1043–8\nBrannan JD, Koskela H, Anderson SD, et al. Responsiveness to mannitol in asthmatic subjects with exercise- and hyperventilation-induced asthma. Am J Respir Crit Care Med 1998; 158: 1120–6\nLeuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001; 163: 406–12\nCurrie GP, Haggart K, Lee DK, et al. Effects of mediator antagonism on mannitol and adenosine monophosphate challenges. Clin Exp Allergy 2003; 33: 783–8\nDavid BE, Todd DC, Cockcroft DW. Effect of combined montelukast and desloratadine on the early asthmatic response to inhaled allergen. J Allergy Clin Immunol 2005; 116: 768–72\nPeroni DG, Piacentini GL, Pietrobelli A, et al. The combination of single-dose montelukast and loratadine on exercise-induced bronchospasm in children. Eur Respir J 2002; 20: 104–7\nDahlen B, Roquet A, Inman MD, et al. Influence of zafirlukast and loratadine on exercise-induced bronchoconstriction. J Allergy Clin Immunol 2002; 109: 789–93\nEggleston PA, Kagey-Sobotka A, Schleimer RP, et al. Interaction between hyper-osmolar and IgE-mediated histamine release from basophils and mast cells. Am Rev Respir Dis 1984; 130: 86–91\nLordan JL, Holgate ST. H1-antihistamines in asthma. Clin Allergy Immunol 2002; 17: 221–48\nAnderson SD, Brannan JD. Exercise-induced asthma: is there still a case for histamine? J Allergy Clin Immunol 2002; 109: 771–3\nWilson AM, Orr LC, Sims EJ, et al. Antiasthmatic effects of mediator blockade versus topical corticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med 2000; 162: 1297–301\nVignola AM, Bousquet J. Rhinitis and asthma: a continuum of disease? Clin Exp Allergy 2001; 31: 674–7\nLieberman P. A pathophysiologic link between allergic rhinitis and asthma. Pediatr Ann 2000; 29: 405–10\nSimons FE. Allergic rhinobronchitis: the asthma-allergic rhinitis link. J Allergy Clin Immunol 1999; 104: 534–40\nCorren J. Allergic rhinitis and asthma: how important is the link? J Allergy Clin Immunol 1997; 99: S781–6\nForesi A, Pelucchi A, Gherson G, et al. Once daily intranasal fluticasone propionate (200 μg) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis. J Allergy Clin Immunol 1996; 98: 274–82\nAdams RJ, Fuhlbrigge AL, Finkelstein JA, et al. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol 2002; 109: 636–42\nCorren J, Manning BE, Thompson SF, et al. Rhinitis therapy and the rpevention of hospital care for ashtma: case-control study. J Allergy Clin Immunol 2004; 113: 415–9",{"VOID":443},"10.2165\u002F00151829-200605030-00001","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.2165\u002F00151829-200605030-00001",[446],{"id":447,"sortIndex":19,"researcher":18,"roles":448,"affiliations":449,"properties":458,"displayName":460,"givenName":18,"familyName":18},"b26e4370-8c46-40aa-aa73-d64ef522af29",[86],[450],{"id":451,"sortIndex":19,"affiliation":452,"properties":18},"127afd22-6799-4bcf-b442-83919471eed9",{"id":451,"createTime":18,"updateTime":18,"relativeEntities":453,"slug":18,"properties":454,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":457,"statistic":18},[],{"title":455},{"VI":456},"Biomedicine Group, Faculty of Medicine, Health and Policy Practice, University of East Anglia, Norwich, England",[],{"title":459},{"VI":460},"Andrew M. Wilson",{"url":18,"publisher":462,"properties":18},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":463,"slug":10,"properties":464,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":467,"manageAffiliations":468,"indexDatabases":469,"url":38,"thumbnailPath":18,"statistic":476,"gsStatistic":18,"type":58,"analyzePriority":18},[],{"issn":465,"title":466},{"VOID":13},{"EN":15},[],[],[470],{"id":24,"indexDatabase":471,"url":35,"indexYears":36,"academicFieldIds":18,"indexDatabaseRanking":37},{"id":26,"createTime":18,"updateTime":18,"relativeEntities":472,"label":473,"description":474,"key":32,"publicationTags":475,"standard":18},[],{"EN":29,"VI":29},{"EN":29,"VI":31},[34],{"impactFactor":19,"impactFactorByYear":477,"i10Index":41,"i10IndexLast5Year":19,"totalPublication":42,"totalPublicationByYear":478,"totalCitation":47,"totalCitationByYear":479,"totalCitationPerPublication":52,"totalCitationPerPublicationByYear":480,"hindexLast5Year":57,"hindex":57},{},{"2004":44,"2005":44,"2006":45,"2012":46},{"2004":49,"2005":50,"2006":51},{"2004":54,"2005":55,"2006":56},[],{"id":483,"createTime":484,"updateTime":485,"relativeEntities":486,"slug":487,"properties":488,"entityType":78,"verifyStatus":79,"verifyTime":485,"verifyNote":80,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":497,"fullTextUrl":18,"authors":498,"publicationType":187,"publisherRelationship":527,"citationCount":18,"citationInfo":18,"publishDate":213,"publishYear":214,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":551,"openAccess":18,"references":18,"isForceReanalyzing":216},"100bd872-148e-4475-b210-127e504bc3c4","2023-12-06T14:33:35.531+00:00","2025-02-21T12:35:43.187+00:00",[],"Idiopathic-Pulmonary-Fibrosis",{"abstract":489,"title":491,"references":493,"doi":495},{"EN":490},"Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathologic patterns of IIP may coexist in the same patient. We propose that these different histopathologic ‘reaction’ patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in TH1\u002FTH2 cytokine profile and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF.",{"EN":492},"Idiopathic Pulmonary Fibrosis",{"VOID":494},"Schwartz DA, Helmers RA, Galvin JR, et al. Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149 (2 Pt 1): 450–4\nKingJr TE, Tooze JA, Schwarz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001; 164(7): 1171–81\nAmerican Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161 (2 Pt 1): 646–64\nCoultas DB, Zumwalt RE, Black WC, et al. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994; 150(4): 967–72\nLama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003; 168(9): 1084–90\nHanson D, Winterbauer RH, Kirtland SH, et al. Changes in pulmonary function test results after 1 year of therapy as predictors of survival in patients with idiopathic pulmonary fibrosis. Chest 1995; 108(2): 305–10\nFlaherty KR, Mumford JA, Murray S, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003; 168(5): 543–8\nGay SE, Kazerooni EA, Toews GB, et al. Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med 1998; 157 (4 Pt 1): 1063–72\nNadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128(4): 2393–9\nHunninghake GW, Lynch DA, Galvin JR, et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003; 124(4): 1215–23\nKazerooni EA, Martinez FJ, Flint A, et al. Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol 1997; 169(4): 977–83\nFlaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003; 58(2): 143–8\nFlaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001; 164(9): 1722–7\nKatzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157 (4 Pt 1): 1301–15\nKing Jr TE, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 2001; 164(6): 1025–32\nKatzenstein AL. Pathogenesis of ‘fibrosis’ in interstitial pneumonia: an electron microscopic study. Hum Pathol 1985; 16(10): 1015–24\nKasper M, Haroske G. Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol 1996; 11(2): 463–83\nChilosi M, Poletti V, Murer B, et al. Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p 63. Lab Invest 2002; 82(10): 1335–45\nKuwano K, Nomoto Y, Kunitake R, et al. Detection of adenovirus El A DNA in pulmonary fibrosis using nested polymerase chain reaction. Eur Respir J 1997; 10(7): 1445–9\nStewart JP, Egan JJ, Ross J, et al. The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1999; 159 (4 Pt 1): 1336–41\nKelly BG, Lok SS, Hasleton PS, et al. A rearranged form of Epstein-Barr virus DNA is associated with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002; 166(4): 510–3\nTang YW, Johnson JE, Browning PJ, et al. Herpesvirus DNA is consistently detected in lungs of patients with idiopathic pulmonary fibrosis. J Clin Microbiol 2003; 41(6): 2633–40\nProcop GW, Kohn DJ, Johnson JE, et al. BK and JC polyomaviruses are not associated with idiopathic pulmonary fibrosis. J Clin Microbiol 2005; 43(3): 1385–6\nBaumgartner KB, Samet JM, Stidley CA, et al. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1997; 155(1): 242–8\nBaumgartner KB, Samet JM, Coultas DB, et al. Occupational and environmental risk factors for idiopathic pulmonary fibrosis: a multicenter case-control study. Collaborating Centers Am J Epidemiol 2000; 152(4): 307–15\nLawson WE, Grant SW, Ambrosini V, et al. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax 2004; 59(11): 977–80\nGrutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J 2005; 25(5): 915–27\nWhyte M, Hubbard R, Meliconi R, et al. Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms. Am J Respir Crit Care Med 2000; 162 (2 Pt 1): 755–8\nPantelidis P, Fanning GC, Wells AU, et al. Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 163(6): 1432–6\nXaubet A, Marin-Arguedas A, Lario S, et al. Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168(4): 431–5\nKatzenstein AL, Zisman DA, Litzky LA, et al. Usual interstitial pneumonia: histologic study of biopsy and expiant specimens. Am J Surg Pathol 2002; 26(12): 1567–77\nThannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med 2004; 55: 395–417\nMartinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 2005; 142 (12 Pt 1): 963–7\nSutinen S, Rainio P, Huhti E, et al. Ultrastructure of terminal respiratory epithelium and prognosis in chronic interstitial pneumonia. Eur J Respir Dis 1980; 61(6): 325–36\nKawanami O, Ferrans VJ, Crystal RG. Structure of alveolar epithelial cells in patients with fibrotic lung disorders. Lab Invest 1982; 46(1): 39–53\nCorrin B, Dewar A, Rodriguez-Roisin R, et al. Fine structural changes in cryptogenic fibrosing alveolitis and asbestosis. J Pathol 1985; 147(2): 107–19\nCoalson JJ. The ultrastructure of human fibrosing alveolitis. Virchows Arch A Pathol Anat Histol 1982; 395(2): 181–99\nXu YD, Hua J, Mui A, et al. Release of biologically active TGF-beta1by alveolar epithelial cells results in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2003; 285(3): L527–39\nKuwano K, Kunitake R, Kawasaki M, et al. P21Wafl\u002FCipl\u002FSdil and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1996; 154 (2 Pt 1): 477–83\nUhal BD, Joshi I, Hughes WF, et al. Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung. Am J Physiol 1998; 275 (6 Pt 1): L1192–9\nBarbas-Filho JV, Ferreira MA, Sesso A, et al. Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)usual interstitial pneumonia (UIP). J Clin Pathol 2001; 54(2): 132–8\nMaeyama T, Kuwano K, Kawasaki M, et al. Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis. Eur Respir J 2001; 17(2): 180–9\nPlataki M, Koutsopoulos AV, Darivianaki K, et al. Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathic pulmonary fibrosis. Chest 2005; 127(1): 266–74\nWang R, Ibarra-Sunga O, Verlinski L, et al. Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 2000; 279 (1): L143-51\nKuwano K, Kunitake R, MaeyamaI T, et al. Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 2001; 280(2): L316–25\nBlobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med 2000; 342(18): 1350–8\nLee CG, Cho SJ, Kang MJ, et al. Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis. J Exp Med 2004; 200(3): 377–89\nCantin AM, North SL, Fells GA, et al. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J Clin Invest 1987; 79(6): 1665–73\nThannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 2000; 279(6): L1005–28\nThannickal VJ, Fanburg BL. Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor beta 1. J Biol Chem 1995; 270(51): 30334–8\nThannickal VJ, Aldweib KD, Fanburg BL. Tyrosine phosphorylation regulates H2O2 production in lung fibroblasts stimulated by transforming growth factor beta 1. J Biol Chem 1998; 273(36): 23611–5\nWaghray M, Cui Z, Horowitz JC, et al. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J 2005 May; 19(7): 854–6\nHagimoto N, Kuwano K, Miyazaki H, et al. Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen. Am J Respir Cell Mol Biol 1997; 17(3): 272–8\nKuwano K, Hagimoto N, Kawasaki M, et al. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest 1999; 104(1): 13–9\nAoshiba K, Yasui S, Tamaoki J, et al. The Fas\u002FFas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2000; 162 (2 Pt 1): 695–700\nUhal BD, Gidea C, Bargout R, et al. Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am J Physiol 1998; 275 (5 Pt 1): L1013–7\nWang R, Zagariya A, Ang E, et al. Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction. Am J Physiol 1999; 277 (6 Pt 1): L1245–50\nPapp M, Li X, Zhuang J, et al. Angiotensin receptor subtype AT (1) mediates alveolar epithelial cell apoptosis in response to ANG II. Am J Physiol Lung Cell Mol Physiol 2002; 282(4): L713–8\nLi X, Rayford H, Uhal BD. Essential roles for angiotensin receptor ATla in bleomycin-induced apoptosis and lung fibrosis in mice. Am J Pathol 2003; 163(6): 2523–30\nOtsuka M, Takahashi H, Shiratori M, et al. Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist. Thorax 2004; 59(1): 31–8\nShiratori M, Michalopoulos G, Shinozuka H, et al. Hepatocyte growth factor stimulates DNA synthesis in alveolar epithelial type II cells in vitro. Am J Respir Cell Mol Biol 1995; 12(2): 171–80\nInoue T, Okada H, Kobayashi T, et al. Hepatocyte growth factor counteracts transforming growth factor-beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5\u002F6 nephrectomized mice. FASEB J 2003; 17(2): 268–70\nLazar MH, Christensen PJ, Du M, et al. Plasminogen activator inhibitor-1 impairs alveolar epithelial repair by binding to vitronectin. Am J Respir Cell Mol Biol 2004; 31(6): 672–8\nMizuno S, Matsumoto K, Li MY, et al. HGF reduces advancing lung fibrosis in mice: a potential role for MMP-dependent myofibroblast apoptosis. FASEB J 2005; 19(6): 580–2\nMarchand-Adam S, Marchai J, Cohen M, et al. Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168(10): 1156–61\nDworkin LD, Gong R, Tolbert E, et al. Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury. Kidney Int 2004; 65(2): 409–19\nDohi M, Hasegawa T, Yamamoto K, et al. Hepatocyte growth factor attenuates collagen accumulation in a murine model of pulmonary fibrosis. Am J Respir Crit Care Med 2000; 162(6): 2302–7\nTaniyama Y, Morishita R, Nakagami H, et al. Potential contribution of a novel antifibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotensin II blockade in cardiomyopathic hamsters. Circulation 2000; 102(2): 246–52\nNagahori T, Dohi M, Matsumoto K, et al. Interferon-gamma upregulates the c-Met\u002F hepatocyte growth factor receptor expression in alveolar epithelial cells. Am J Respir Cell Mol Biol 1999; 21(4): 490–7\nRubin JS, Osada H, Finch PW, et al. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A 1989; 86(3): 802–6\nFinch PW, Rubin JS, Miki T, et al. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 1989; 245(4919): 752–5\nDeterding RR, Jacoby CR, Shannon JM. Acidic fibroblast growth factor and keratinocyte growth factor stimulate fetal rat pulmonary epithelial growth. Am J Physiol 1996; 271 (4 Pt 1): L495–505\nZhang F, Nielsen LD, Lucas JJ, et al. Transforming growth factor-beta antagonizes alveolar type II cell proliferation induced by keratinocyte growth factor. Am J Respir Cell Mol Biol 2004; 31(6): 679–86\nDeterding RR, Havill AM, Yano T, et al. Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor. Proc Assoc Am Physicians 1997; 109(3): 254–68\nMarchand-Adam S, Plantier L, Bernuau D, et al. Keratinocyte growth factor expression by fibroblasts in pulmonary fibrosis: poor response to interleukin-1beta. Am J Respir Cell Mol Biol 2005; 32(5): 470–7\nChristensen PJ, Bailie MB, Goodman RE, et al. Role of diminished epithelial GM-CSF in the pathogenesis of bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2000; 279(3): L487–95\nEitzman DT, McCoy RD, Zheng X, et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996; 97(1): 232–7\nSisson TH, Hattori N, Xu Y, et al. Treatment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes. Hum Gene Ther 1999; 10(14): 2315–23\nHattori N, Degen JL, Sisson TH, et al. Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 2000; 106(11): 1341–50\nSisson TH, Hanson KE, Subbotina N, et al. Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice. Am J Physiol Lung Cell Mol Physiol 2002; 283(5): L1023–32\nChan JC, Duszczyszyn DA, Castellino FJ, et al. Accelerated skin wound healing in plasminogen activator inhibitor-1-deficient mice. Am J Pathol 2001; 159(5): 1681–8\nLegrand C, Polette M, Tournier JM, et al. uPA\u002Fplasmin system-mediated MMP-9 activation is implicated in bronchial epithelial cell migration. Exp Cell Res 2001; 264(2): 326–36\nBitterman PB, Wewers MD, Rennard SI, et al. Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators. J Clin Invest 1986; 77(3): 700–8\nLama V, Moore BB, Christensen P, et al. Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent. Am J Respir Cell Mol Biol 2002; 27(6): 752–8\nWhite ES, Atrasz RG, Dickie EG, et al. Prostaglandin E (2) inhibits fibroblast migration by E-prostanoid 2 receptor-mediated increase in PTEN activity. Am J Respir Cell Mol Biol 2005; 32(2): 135–41\nKolodsick JE, Peters-Golden M, Larios J, et al. Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation. Am J Respir Cell Mol Biol 2003; 29(5): 537–44\nGoldstein RH, Polgar P. The effect and interaction of bradykinin and prostaglandins on protein and collagen production by lung fibroblasts. J Biol Chem 1982; 257(15): 8630–3\nKeerthisingam CB, Jenkins RG, Harrison NK, et al. Cyclooxygenase-2 deficiency results in a loss of the anti-proliferative response to transforming growth factor-beta in human fibrotic lung fibroblasts and promotes bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 2001; 158(4): 1411–22\nPeters-Golden M, Bailie M, Marshall T, et al. Protection from pulmonary fibrosis in leukotriene-deficient mice. Am J Respir Crit Care Med 2002; 165(2): 229–35\nBorok Z, Gillissen A, Buhl R, et al. Augmentation of functional prostaglandin E levels on the respiratory epithelial surface by aerosol administration of prostaglandin E. Am Rev Respir Dis 1991; 144(5): 1080–4\nWilborn J, Bailie M, Coffey M, et al. Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis. J Clin Invest 1996; 97(8): 1827–36\nKrause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105(3): 369–77\nKotton DN, Ma BY, Cardoso WV, et al. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 2001; 128(24): 5181–8\nKotton DN, Fabian AJ, Mulligan RC. Failure of bone marrow to reconstitute lung epithelium. Am J Respir Cell Mol Biol 2005; 33(4): 328–34\nGrove JE, Lutzko C, Priller J, et al. Marrow-derived cells as vehicles for delivery of gene therapy to pulmonary epithelium. Am J Respir Cell Mol Biol 2002; 27(6): 645–51\nWillis BC, Liebler JM, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-(beta)1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 2005; 166(5): 1321–32\nDesmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 2005; 13(1): 7–12\nKuhn C, McDonald JA. The roles of the myofibroblast in idiopathic pulmonary fibrosis: ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am J Pathol 1991; 138(5): 1257–65\nSinger AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999; 341(10): 738–46\nTomasek JJ, Gabbiani G, Hinz B, et al. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002; 3(5): 349–63\nGabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003; 200(4): 500–3\nPhan SH. The myofibroblast in pulmonary fibrosis. Chest 2002; 122 (6 Suppl.): 286S–9S\nPhillips RJ, Burdick MD, Hong K, et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 2004; 114(3): 438–46\nMoore BB, Kolodsick JE, Thannickal VJ, et al. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol 2005; 166(3): 675–84\nHashimoto N, Jin H, Liu T, et al. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 2004; 113(2): 243–52\nYao HW, Xie QM, Chen JQ, et al. TGF-beta1 induces alveolar epithelial to mesenchymal transition in vitro. Life Sci 2004; 76(1): 29–37\nKasai H, Allen JT, Mason RM, et al. TGF-beta1induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005; 6(1): 56\nDesmouliere A, Redard M, Darby I, et al. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol 1995; 146(1): 56–66\nBorder WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331(19): 1286–92\nChapman HA. Disorders of lung matrix remodeling. J Clin Invest 2004; 113(2): 148–57\nSime PJ, Xing Z, Graham FL, et al. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest 1997; 100(4): 768–76\nKolb M, Bonniaud P, Galt T, et al. Differences in the fibrogenic response after transfer of active transforming growth factor-beta1 gene to lungs of ‘fibrosis-prone’ and ‘fibrosis-resistant’ mouse strains. Am J Respir Cell Mol Biol 2002; 27(2): 141–50\nKolb M, Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med 2001; 163 (3 Pt 1): 770–7\nHorowitz JC, Lee DY, Waghray M, et al. Activation of the pro-survival phosphatidylinositol 3-kinase\u002FAKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem 2004; 279(2): 1359–67\nZhang HY, Phan SH. Inhibition of myofibroblast apoptosis by transforming growth factor beta (1). Am J Respir Cell Mol Biol 1999; 21(6): 658–65\nSun G, Stacey MA, Bellini A, et al. Endothelin-1 induces bronchial myofibroblast differentiation. Peptides 1997; 18(9): 1449–51\nBogatkevich GS, Tourkina E, Silver RM, et al. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. J Biol Chem 2001; 276(48): 45184–92\nMorishima Y, Nomura A, Uchida Y, et al. Triggering the induction of myofibroblast and fibrogenesis by airway epithelial shedding. Am J Respir Cell Mol Biol 2001; 24(1): 1–11\nMarshall RP, McAnulty RJ, Laurent GJ. Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. Am J Respir Crit Care Med 2000; 161(6): 1999–2004\nNguyen L, Ward WF, Ts’ao CH, et al. Captopril inhibits proliferation of human lung fibroblasts in culture: a potential antifibrotic mechanism. Proc Soc Exp Biol Med 1994; 205(1): 80–4\nKetteler M, Noble NA, Border WA. Transforming growth factor-beta and angiotensin II: the missing link from glomerular hyperfiltration to glomerulosclerosis? Annu Rev Physiol 1995; 57: 279–95\nCampbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol 1997; 29(7): 1947–58\nSerini G, Bochaton-Piallat ML, Ropraz P, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta 1. J Cell Biol 1998; 142(3): 873–81\nHinz B, Mastrangelo D, Iselin CE, et al. Mechanical tension controls granulation tissue contractile activity and myofibroblast differentiation. Am J Pathol 2001; 159(3): 1009–20\nArora PD, Narani N, McCulloch CA. The compliance of collagen gels regulates transforming growth factor-beta induction of alpha-smooth muscle actin in fibroblasts. Am J Pathol 1999; 154(3): 871–82\nZhu YK, Umino T, Liu XD, et al. Contraction of fibroblast-containing collagen gels: initial collagen concentration regulates the degree of contraction and cell survival. In Vitro Cell Dev Biol Anim 2001; 37(1): 10–6\nThannickal VJ, Lee DY, White ES, et al. Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003; 278(14): 12384–9\nUhal BD, Joshi I, True AL, et al. Fibroblasts isolated after fibrotic lung injury induce apoptosis of alveolar epithelial cells in vitro. Am J Physiol 1995; 269 (6 Pt 1): L819–28\nLarios JM, Budhiraja R, Fanburg BL, et al. Oxidative protein cross-linking reactions involving L-tyrosine in transforming growth factor-beta1-stimulated fibroblasts. J Biol Chem 2001; 276(20): 17437–41\nPhan SH, Zhang K, Zhang HY, et al. The myofibroblast as an inflammatory cell in pulmonary fibrosis. Curr Top Pathol 1999; 93: 173–82\nStrieter RM, Wiggins R, Phan SH, et al. Monocyte chemotactic protein gene expression by cytokine-treated human fibroblasts and endothelial cells. Biochem Biophys Res Commun 1989; 162(2): 694–700\nRolfe MW, Kunkel SL, Standiford TJ, et al. Pulmonary fibroblast expression of interleukin-8: a model for alveolar macrophage-derived cytokine networking. Am J Respir Cell Mol Biol 1991; 5(5): 493–501\nStrieter RM. Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest 2005; 128 (5 Suppl. 1): 526S–32S\nCrystal RG, Fulmer JD, Roberts WC, et al. Idiopathic pulmonary fibrosis: clinical, histologic, radiographic, physiologic, scintigraphic, cytologie, and biochemical aspects. Ann Intern Med 1976; 85(6): 769–88\nMason RJ, Schwarz MI, Hunninghake W, et al. NHLBI Workshop Summary. Pharmacological therapy for idiopathic pulmonary fibrosis: past, present, and future. Am J Respir Crit Care Med 1999; 160 (5 Pt 1): 1771–7\nSelman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134(2): 136–51\nGross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001; 345(7): 517–25\nZuo F, Kaminski N, Eugui E, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A 2002; 99(9): 6292–7\nAgostini C, Siviero M, Semenzato G. Immune effector cells in idiopathic pulmonary fibrosis. Curr Opin Pulm Med 1997; 3(5): 348–55\nKelly M, Kolb M, Bonniaud P, et al. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des 2003; 9(1): 39–49\nLukacs NW, Hogaboam C, Chensue W, et al. Type I\u002Ftype 2 cytokine paradigm and the progression of pulmonary fibrosis. Chest 2001; 120 (1 Suppl.): 5S–8S\nWynn TA. Fibrotic disease and the T (H)1\u002FT (H)2 paradigm. Nat Rev Immunol 2004; 4(8): 583–94\nJakubzick C, Choi ES, Joshi BH, et al. Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells. J Immunol 2003; 171(5): 2684–93\nCavarra E, Carraro F, Fineschi S, et al. Early response to bleomycin is characterized by different cytokine and cytokine receptor profiles in lungs. Am J Physiol Lung Cell Mol Physiol 2004; 287(6): L1186–92\nChua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: searching for model answers. Am J Respir Cell Mol Biol 2005; 33(1): 9–13\nHelene M, Lake-Bullock V, Zhu J, et al. T cell independence of bleomycin-induced pulmonary fibrosis. J Leukoc Biol 1999; 65(2): 187–95\nOkazaki T, Nakao A, Nakano H, et al. Impairment of bleomycin-induced lung fibrosis in CD28-deficient mice. J Immunol 2001; 167(4): 1977–81\nJakubzick C, Choi ES, Kunkel SL, et al. Augmented pulmonary IL-4 and IL-13 receptor subunit expression in idiopathic interstitial pneumonia. J Clin Pathol 2004; 57(5): 477–86\nJakubzick C, Choi ES, Carpenter KJ, et al. Human pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression in idiopathic interstitial pneumonia. Am J Pathol 2004; 164(6): 1989–2001\nPeao MN, Aguas AP, de Sa CM, et al. Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin. Anat Rec 1994; 238(1): 57–67\nTurner-Warwick M. Precapillary systemic-pulmonary anastomoses. Thorax 1963; 18: 225–37\nSimler NR, Brenchley PE, Horrocks AW, et al. Angiogenic cytokines in patients with idiopathic interstitial pneumonia. Thorax 2004; 59(7): 581–5\nKeane MP, Arenberg DA, Lynch III JP, et al. The CXC chemokines, IL-8 and IP-10, regulate angiogenic activity in idiopathic pulmonary fibrosis. J Immunol 1997; 159(3): 1437–43\nKeane MP, Belperio JA, Burdick MD, et al. ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001; 164(12): 2239–42\nKeane MP, Belperio JA, Arenberg DA, et al. IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis. J Immunol 1999; 163(10): 5686–92\nKeane MP, Belperio JA, Burdick MD, et al. IL-12 attenuates bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2001; 281(1): L92–7\nBurdick MD, Murray LA, Keane MP, et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med 2005; 171(3): 261–8\nTager AM, Kradin RL, LaCamera P, et al. Inhibition of pulmonary fibrosis by the chemokine IP-10\u002FCXCL 10. Am J Respir Cell Mol Biol 2004; 31(4): 395–404\nRenzoni EA, Walsh DA, Salmon M, et al. Interstitial vascularity in fibrosing alveolitis. Am J Respir Crit Care Med 2003; 167(3): 438–43\nCosgrove GP, Brown KK, Schiemann WP, et al. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis. Am J Respir Crit Care Med 2004; 170(3): 242–51\nSumi M, Satoh H, Kagohashi K, et al. Increased serum levels of endostatin in patients with idiopathic pulmonary fibrosis. J Clin Lab Anal 2005; 19(4): 146–9\nBeer TW, Baldwin HC, Goddard JR, et al. Angiogenesis in pathological and surgical scars. Hum Pathol 1998; 29(11): 1273–8\nWeitzenblum E, Ehrhart M, Rasaholinjanahary J, et al. Pulmonary hemodynamics in idiopathic pulmonary fibrosis and other interstitial pulmonary diseases. Respiration 1983; 44(2): 118–27\nAgusti AG, Roca J, Gea J, et al. Mechanisms of gas-exchange impairment in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1991; 143(2): 219–25\nParambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest 2005; 128(5): 3310–5\nOlschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347(5): 322–9\nGhofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360(9337): 895–900\nCoTherix. Inhaled iloprost in adults with abnormal pulmonary pressure and associated with idiopathic pulmonary fibrosis [online]. Available from URL: http:\u002F\u002Fwww.clinicaltrials.gov\u002Fct\u002Fgui\u002Fshow\u002FNCTOO109681. [Accessed 2006 Jul 12]\nDouglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary fibrosis: impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 2000; 161 (4 Pt 1): 1172–8\nLynch III JP, White E, Flaherty K. Corticosteroids in idiopathic pulmonary fibrosis. Curr Opin Pulm Med 2001; 7(5): 298–308\nRyu JH, Myers JL, Capizzi SA, et al. Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 2005; 127(1): 178–84\nDeheinzelin D, Capelozzi VL, Kairalla RA, et al. Interstitial lung disease in primary Sjogren’s syndrome: clinical-pathological evaluation and response to treatment. Am J Respir Crit Care Med 1996; 154 (3 Pt 1): 794–9\nNicholson AG, Colby TV, du Bois RM, et al. The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 2000; 162(6): 2213–7\nBouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002; 165(12): 1581–6\nDheda K, Lalloo UG, Cassim B, et al. Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 2004; 23(4): 306–9\nClark JG, Dedon TF, Wayner EA, et al. Effects of interferon-gamma on expression of cell surface receptors for collagen and deposition of newly synthesized collagen by cultured human lung fibroblasts. J Clin Invest 1989; 83(5): 1505–11\nNarayanan AS, Whithey J, Souza A, et al. Effect of gamma-interferon on collagen synthesis by normal and fibrotic human lung fibroblasts. Chest 1992; 101(5): 1326–31\nJaffe HA, Gao Z, Mori Y, et al. Selective inhibition of collagen gene expression in fibroblasts by an interferon-gamma transgene. Exp Lung Res 1999; 25(3): 199–215\nAdelmann-Grill BC, Hein R, Wach F, et al. Inhibition of fibroblast chemotaxis by recombinant human interferon gamma and interferon alpha. J Cell Physiol 1987; 130(2): 270–5\nStrieter RM, Belperio JA, Keane MP. CXC chemokines in vascular remodeling related to pulmonary fibrosis. Am J Respir Cell Mol Biol 2003; 29 (3 Suppl.): S67–9\nHunninghake GW, Hemken C, Brady M, et al. Immune interferon is a growth factor for human lung fibroblasts. Am Rev Respir Dis 1986; 134(5): 1025–8\nElias JA, Jimenez SA, Freundlich B. Recombinant gamma, alpha, and beta interferon regulation of human lung fibroblast proliferation. Am Rev Respir Dis 1987; 135(1): 62–5\nMoseley PL, Hemken C, Monick M, et al. Interferon and growth factor activity for human lung fibroblasts: release from bronchoalveolar cells from patients with active sarcoidosis. Chest 1986; 89(5): 657–62\nHasegawa T, Nakao A, Sumiyoshi K, et al. IFN-gamma fails to antagonize fibrotic effect of TGF-beta on keloid-derived dermal fibroblasts. J Dermatol Sci 2003; 32(1): 19–24\nOldroyd SD, Thomas GL, Gabbiani G, et al. Interferon-gamma inhibits experimental renal fibrosis. Kidney Int 1999; 56(6): 2116–27\nGurujeyalakshmi G, Giri SN. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Exp Lung Res 1995; 21(5): 791–808\nWeng HL, Cai WM, Liu RH. Animal experiment and clinical study of effect of gamma-interferon on hepatic fibrosis. World J Gastroenterol 2001; 7(1): 42–8\nZiesche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999; 341(17): 1264–9\nRaghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 2004; 350(2): 125–33\nInterMune Inc. INSPIRE: international study of survival outcomes in idiopathic pulmonary fibrosis (IPF) with interferon gamma-1b (IFN-γ1b) — early intervention [online]. Available from URL: http:\u002F\u002Fwww.inspiretrial.com [Accessed 2006 Jul 12]\nNicod LP. Pirfenidone in idiopathic pulmonary fibrosis. Lancet 1999; 354(9175): 268–9\nShihab FS, Bennett WM, Yi H, et al. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Am J Transplant 2002; 2(2): 111–9\nIyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999; 289(1): 211–8\nKakugawa T, Mukae H, Hayashi T, et al. Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J 2004; 24(1): 57–65\nGiri SN, Leonard S, Shi X, et al. Effects of pirfenidone on the generation of reactive oxygen species in vitro. J Environ Pathol Toxicol Oncol 1999; 18(3): 169–77\nMisra HP, Rabideau C. Pirfenidone inhibits NADPH-dependent microsomal lipid peroxidation and scavenges hydroxyl radicals. Mol Cell Biochem 2000; 204(1-2): 119–26\nGarcia L, Hernandez I, Sandoval A, et al. Pirfenidone effectively reverses experimental liver fibrosis. J Hepatol 2002; 37(6): 797–805\nSuga H, Teraoka S, Ota K, et al. Preventive effect of pirfenidone against experimental sclerosing peritonitis in rats. Exp Toxicol Pathol 1995; 47(4): 287–91\nShimizu T, Fukagawa M, Kuroda T, et al. Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partial nephrectomy. Kidney Int Suppl 1997; 63: S239–43\nAngulo P, MacCarty RL, Sylvestre PB, et al. Pirfenidone in the treatment of primary sclerosing cholangitis. Dig Dis Sci 2002; 47(1): 157–61\nIyer SN, Margolin SB, Hyde DM, et al. Lung fibrosis is ameliorated by pirfenidone fed in diet after the second dose in a three-dose bleomycin-hamster model. Exp Lung Res 1998; 24(1): 119–32\nKehrer JP, Margolin SB. Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice. Toxicol Lett 1997; 90(2-3): 125–32\nRaghu G, Johnson WC, Lockhart D, et al. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. Am J Respir Crit Care Med 1999; 159 (4 Pt 1): 1061–9\nGahl WA, Brantly M, Troendle J, et al. Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome. Mol Genet Metab 2002; 76(3): 234–42\nAzuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171(9): 1040–7\nCharbeneau RP, Peters-Golden M. Eicosanoids: mediators and therapeutic targets in fibrotic lung disease. Clin Sci (Lond) 2005; 108(6): 479–91\nMio T, Nagai S, Kitaichi M, et al. Proliferative characteristics of fibroblast lines derived from open lung biopsy specimens of patients with IPF (UIP). Chest 1992; 102(3): 832–7\nMoore BB, Peters-Golden M, Christensen PJ, et al. Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1\u002FCCR2 and mediated by PGE 2. Am J Physiol Lung Cell Mol Physiol 2003; 284(2): L342–9\nMoore BB, Paine III R, Christensen PJ, et al. Protection from pulmonary fibrosis in the absence of CCR2 signaling. J Immunol 2001; 167(8): 4368–77\nMoore BB, Coffey MJ, Christensen P, et al. GM-CSF regulates bleomycin-induced pulmonary fibrosis via a prostaglandin-dependent mechanism. J Immunol 2000; 165(7): 4032–9\nUS National Institutes of Health. Zileuton for the treatment of idiopathic pulmonary fibrosis [online]. Available from URL: http:\u002F\u002Fwww.clinicaltrials.gov\u002Fat\u002Fgui\u002Fshow\u002FNCT00262405 [Accessed 2006 Jul 12]\nZhang Y, Lee TC, Guillemin B, et al. Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol 1993; 150(9): 4188–96\nPiguet PF, Ribaux C, Karpuz V, et al. Expression and localization of tumor necrosis factor-alpha and its mRNA in idiopathic pulmonary fibrosis. Am J Pathol 1993; 143(3): 651–5\nLibura J, Bettens F, Radkowski A, et al. Risk of chemotherapy-induced pulmonary fibrosis is associated with polymorphic tumour necrosis factor-a2 gene. Eur Respir J 2002; 19(5): 912–8\nRiha RL, Yang IA, Rabnott GC, et al. Cytokine gene polymorphisms in idiopathic pulmonary fibrosis. Intern Med J 2004; 34(3): 126–9\nMiyazaki Y, Araki K, Vesin C, et al. Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis: a mouse model of progressive pulmonary fibrosis. J Clin Invest 1995; 96(1): 250–9\nSime PJ, Marr RA, Gauldie D, et al. Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts. Am J Pathol 1998; 153(3): 825–32\nOrtiz LA, Lasky J, Hamilton Jr RF, et al. Expression of TNF and the necessity of TNF receptors in bleomycin-induced lung injury in mice. Exp Lung Res 1998; 24(6): 721–43\nPiguet PF, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J 1994; 7(3): 515–8\nSiwik DA, Chang DL, Colucci WS. Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res 2000; 86(12): 1259–65\nSolis-Herruzo JA, Brenner DA, Chojkier M. Tumor necrosis factor alpha inhibits collagen gene transcription and collagen synthesis in cultured human fibroblasts. J Biol Chem 1988; 263(12): 5841–5\nKahari VM, Chen YQ, Su MW, et al. Tumor necrosis factor-alpha and interferongamma suppress the activation of human type I collagen gene expression by transforming growth factor-beta 1: evidence for two distinct mechanisms of inhibition at the transcriptional and posttranscriptional levels. J Clin Invest 1990; 86(5): 1489–95\nGreenwel P, Tanaka S, Penkov D, et al. Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT\u002Fenhancer-binding proteins. Mol Cell Biol 2000; 20(3): 912–8\nHan YP, Tuan TL, Hughes M, et al. Transforming growth factor-beta- and tumor necrosis factor-alpha-mediated induction and proteolytic activation of MMP-9 in human skin. J Biol Chem 2001; 276(25): 22341–50\nHan YP, Tuan TL, Wu H, et al. TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1 -MMP. J Cell Sci 2001; 114 (Pt 1): 131–9\nKuroki M, Noguchi Y, Shimono M, et al. Repression of bleomycin-induced pneumopathy by TNF. J Immunol 2003; 170(1): 567–74\nFujita M, Shannon JM, Morikawa O, et al. Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta. Am J Respir Cell Mol Biol 2003; 29(6): 669–76\nRaghu G, Lasky JA, Costabel U, et al. A randomized placebo controlled trial assessing the efficacy and safety of etanercept in patients with idiopathic pulmonary fibrosis (IPF). Chest 2005; 128(4): 496S-a\nKinnula VL, Fattman CL, Tan RJ, et al. Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am J Respir Crit Care Med 2005; 172(4): 417–22\nCantin AM, Hubbard RC, Crystal RG. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1989; 139(2): 370–2\nSmilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med 1991; 20(10): 1058–63\nTepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343(3): 180–4\nCantin AM, Larivee P, Begin RO. Extracellular glutathione suppresses human lung fibroblast proliferation. Am J Respir Cell Mol Biol 1990; 3(1): 79–85\nBorok Z, Buhl R, Grimes GJ, et al. Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis. Lancet 1991; 338(8761): 215–6\nMeyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis. Eur Respir J 1994; 7(3): 431–6\nMeyer A, Buhl R, Kampf S, et al. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respir Crit Care Med 1995; 152(3): 1055–60\nBehr J, Maier K, Degenkolb B, et al. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis: adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med 1997; 156(6): 1897–901\nTomioka H, Kuwata Y, Imanaka K, et al. A pilot study of aerosolized N-acetylcysteine for idiopathic pulmonary fibrosis. Respirology 2005; 10(4): 449–55\nDemedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353(21): 2229–42\nHunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005; 353(21): 2285–7\nBrewer GJ, Ullenbruch MR, Dick R, et al. Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice. J Lab Clin Med 2003; 141(3): 210–6\nBrewer GJ. Copper control as an antiangiogenic anticancer therapy: lessons from treating Wilson’s disease. Exp Biol Med (Maywood) 2001; 226(7): 665–73\nBrewer GJ. Tetrathiomolybdate anticopper therapy for Wilson’s disease inhibits angiogenesis, fibrosis and inflammation. J Cell Mol Med 2003; 7(1): 11–20\nBrewer GJ, Dick R, Ullenbruch MR, et al. Inhibition of key cytokines by tetrathiomolybdate in the bleomycin model of pulmonary fibrosis. J Inorg Biochem 2004; 98(12): 2160–7\nUS National Institutes of Health. Safety study of tetrathiomolybdate in patients with idiopathic pulmonary fibrosis [online]. Available from URL: http:\u002F\u002Fwww.clinicaltrials.gov\u002Fat\u002Fgui\u002Fshow\u002FNCT00189176 [Accessed 2006 Jul 12]\nEhrenreich H, Anderson RW, Fox CH, et al. Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 1990; 172(6): 1741–8\nShahar I, Fireman E, Topilsky M, et al. Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases. Int J Immunopharmacol 1999; 21(11): 759–75\nGoto T, Yanaga F, Ohtsuki I. Studies on the endothelin-1-induced contraction of rat granulation tissue pouch mediated by myofibroblasts. Biochim Biophys Acta 1998; 1405(1-3): 55–66\nShi-Wen X, Chen Y, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac\u002Fphosphoinositide 3-kinase\u002FAkt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 2004; 15(6): 2707–19\nXu SW, Howat SL, Renzoni EA, et al. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK\u002FERK. J Biol Chem 2004; 279(22): 23098–103\nHocher B, Schwarz A, Fagan KA, et al. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol 2000; 23(1): 19–26\nPark SH, Saleh D, Giaid A, et al. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997; 156 (2 Pt 1): 600–8\nMutsaers SE, Marshall RP, Goldsack NR, et al. Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Pulm Pharmacol Ther 1998; 11(2-3): 221–5\nGiaid A, Michel RP, Stewart DJ, et al. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet 1993; 341(8860): 1550–4\nSaleh D, Furukawa K, Tsao MS, et al. Elevated expression of endothelin-1 and endothelin-converting enzyme-1 in idiopathic pulmonary fibrosis: possible involvement of proinflammatory cytokines. Am J Respir Cell Mol Biol 1997; 16(2): 187–93\nRubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346(12): 896–903\nBUILD program with bosentan: media release [online]. Available from URL: http:\u002F\u002Fwww.actelion.com\u002Funinet\u002Fwww\u002Fwww_main_p.nsf\u002Fcontent\u002Fme+28+Nov+2005 [Accessed 2006 Jul 27]\nBroekelmann TJ, Limper AH, Colby TV, et al. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci U S A 1991; 88(15): 6642–6\nKhalil N, O’Connor RN, Unruh HW, et al. Increased production and immunohis-tochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 1991; 5(2): 155–62\nBonniaud P, Margetts PJ, Kolb M, et al. Progressive transforming growth factor ta 1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor. Am J Respir Crit Care Med 2005; 171(8): 889–98\nBonniaud P, Kolb M, Galt T, et al. Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis. J Immunol 2004; 173(3): 2099–108\nChen H, Sun J, Buckley S, et al. Abnormal mouse lung alveolarization caused by Smad3 deficiency is a developmental antecedent of centrilobular emphysema. Am J Physiol Lung Cell Mol Physiol 2005; 288(4): L683–91\nMassague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000; 103(2): 295–309\nGoldman JM, Melo JV. Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344(14): 1084–6\nDaniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004; 114(9): 1308–16\nAono Y, Nishioka Y, Inayama M, et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2005; 171(11): 1279–85\nAbdollahi A, Li M, Ping G, et al. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med 2005; 201(6): 925–35\nFrisch SM, Vuori K, Ruoslahti E, et al. Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 1996; 134(3): 793–9\nHadden HL, Henke CA. Induction of lung fibroblast apoptosis by soluble fibronectin peptides. Am J Respir Crit Care Med 2000; 162 (4 Pt 1): 1553–60\nXia H, Nho RS, Kahm J, et al. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase\u002FAkt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem 2004; 279(31): 33024–34\nVittal R, Horowitz JC, Moore BB, et al. Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury. Am J Pathol 2005; 166(2): 367–75\nOlson JM, Hallahan AR. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med 2004; 10(3): 125–9\nYamaguchi K, Shirakabe K, Shibuya H, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 1995; 270(5244): 2008–11\nTakekawa M, Tatebayashi K, Itoh F, et al. Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta. EMBO J 2002; 21(23): 6473–82\nKhalil N, Xu YD, O’Connor R, et al. Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK. J Biol Chem 2005; 280(52): 43000–9\nMatsuoka H, Arai T, Mori M, et al. A p38 MAPK inhibitor, FR-167653, ameliorates murine bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2002; 283(1): L103–12\nUnderwood DC, Osborn RR, Bochnowicz S, et al. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 2000; 279(5): L895–902\nNadrous HF, Ryu JH, Douglas WW, et al. Impact of angiotensin-converting enzyme inhibitors and statins on survival in idiopathic pulmonary fibrosis. Chest 2004; 126(2): 438–46\nLeask A, Holmes A, Black CM, et al. Connective tissue growth factor gene regulation. Requirements for its induction by transforming growth factor-beta 2 in fibroblasts. J Biol Chem 2003; 278(15): 13008–15\nLasky JA, Ortiz LA, Tonthat B, et al. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis. Am J Physiol 1998; 275 (2 Pt 1): L365–71\nBonniaud P, Margetts PJ, Kolb M, et al. Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis. Am J Respir Crit Care Med 2003; 168(7): 770–8\nPan LH, Yamauchi K, Uzuki M, et al. Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF. Eur Respir J 2001; 17(6): 1220–7",{"VOID":496},"10.2165\u002F00151829-200605050-00004","http:\u002F\u002Flink.springer.com\u002F10.2165\u002F00151829-200605050-00004",[499,514],{"id":500,"sortIndex":19,"researcher":18,"roles":501,"affiliations":502,"properties":511,"displayName":513,"givenName":18,"familyName":18},"555c58ce-d85b-4248-8a10-1349a859d1f3",[86],[503],{"id":504,"sortIndex":19,"affiliation":505,"properties":18},"2b87dc06-06ba-45e5-8a3f-0693357a9972",{"id":504,"createTime":18,"updateTime":18,"relativeEntities":506,"slug":18,"properties":507,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":510,"statistic":18},[],{"title":508},{"VI":509},"Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, USA",[],{"title":512},{"VI":513},"Jeffrey C. 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Sinha",{"url":563,"publisher":581,"properties":600},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":582,"slug":10,"properties":583,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":586,"manageAffiliations":587,"indexDatabases":588,"url":38,"thumbnailPath":18,"statistic":595,"gsStatistic":18,"type":58,"analyzePriority":18},[],{"issn":584,"title":585},{"VOID":13},{"EN":15},[],[],[589],{"id":24,"indexDatabase":590,"url":35,"indexYears":36,"academicFieldIds":18,"indexDatabaseRanking":37},{"id":26,"createTime":18,"updateTime":18,"relativeEntities":591,"label":592,"description":593,"key":32,"publicationTags":594,"standard":18},[],{"EN":29,"VI":29},{"EN":29,"VI":31},[34],{"impactFactor":19,"impactFactorByYear":596,"i10Index":41,"i10IndexLast5Year":19,"totalPublication":42,"totalPublicationByYear":597,"totalCitation":47,"totalCitationByYear":598,"totalCitationPerPublication":52,"totalCitationPerPublicationByYear":599,"hindexLast5Year":57,"hindex":57},{},{"2004":44,"2005":44,"2006":45,"2012":46},{"2004":49,"2005":50,"2006":51},{"2004":54,"2005":55,"2006":56},{"pages":601,"volume":603},{"VOID":602},"146-146",{"VOID":299},[],{"id":606,"createTime":607,"updateTime":608,"relativeEntities":609,"slug":610,"properties":611,"entityType":78,"verifyStatus":79,"verifyTime":620,"verifyNote":80,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":621,"fullTextUrl":18,"authors":622,"publicationType":187,"publisherRelationship":651,"citationCount":18,"citationInfo":18,"publishDate":213,"publishYear":214,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":676,"openAccess":18,"references":18,"isForceReanalyzing":216},"8fa50f79-3caa-4fb9-af7a-d1c663b6388b","2024-01-24T10:40:34.230+00:00","2025-02-17T08:41:52.512+00:00",[],"Tiotropium-Bromide",{"abstract":612,"title":614,"references":616,"doi":618},{"EN":613},"Tiotropium bromide (Spiriva®) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. The active moiety is the tiotropium cation (tiotropium); tiotropium bromide 22.5µg is equivalent to 18µg of tiotropium cation. Greater improvements in lung function from baseline (primary endpoint mean trough FEV1) were observed with inhaled tiotropium 18µg once daily than with placebo in 6-month and 1-year randomized, double-blind trials in patients with COPD. Tiotropium improved lung function (trough FEV1 response) more effectively than ipratropium bromide (ipratropium) 40µg four times daily in 1-year clinical trials, and was at least as effective as salmeterol 50µg 12-hourly in 6-month trials. Preliminary data suggest that tiotropium alone or in combination with once-daily formoterol has a greater bronchodilator effect than twice-daily formoterol in patients with COPD. Improvements in patients’ perception of health-related quality of life (HR-QOL) or dyspnea were greater with tiotropium than with placebo or ipratropium, and were similar to those with salmeterol. Reductions in the frequency and severity of acute exacerbations and in the use of rescue medication were also greater with tiotropium than with ipratropium or placebo. There was no evidence of tachyphylaxis with tiotropium during 1-year clinical trials. Inhaled tiotropium was generally well tolerated in clinical trials. Apart from dry mouth, the type and incidence of adverse events with tiotropium were similar to those with ipratropium, salmeterol or placebo in patients with COPD. In conclusion, inhaled tiotropium 18µg once daily improved lung function, dyspnea, and HR-QOL, and decreased the incidence of acute COPD exacerbations and the use of rescue medication relative to placebo or ipratropium in clinical trials in patients with COPD. Tiotropium was at least as effective as salmeterol in terms of bronchodilator efficacy and improvements in dyspnea or HR-QOL. With the exception of dry mouth, the tolerability profile of tiotropium was similar to that with placebo, ipratropium, or salmeterol. Consequently, inhaled tiotropium is likely to be a valuable option for first-line, long-term maintenance therapy in the management of bronchoconstriction in patients with symptomatic COPD. Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilator; the active moiety is the tiotropium cation (tiotropium). A 22.5µg dose of tiotropium bromide provides 18µg of tiotropium. Orally inhaled tiotropium bromide antagonizes the muscarinic M1, M2, and M3 receptors located in airway smooth muscle, reversing vagally mediated bronchoconstriction. Receptor binding assays and in vitro tests indicate that tiotropium bromide is kinetically selective for M1 and M3 receptors over the M2 receptor, unlike ipratropium bromide, which is nonselective. Animal and in vitro studies showed that tiotropium bromide was more potent (≈20-fold) than ipratropium bromide in displacing [3H]N-methylscopolamine (NMS) from muscarinic receptors, and had a more sustained protective effect (>70% inhibition) against NMS binding. Tiotropium bromide was a more potent inhibitor of bronchial contraction than atropine (≈ 23-fold), and had a slower onset and markedly longer duration of action than atropine or an equipotent dose of ipratropium bromide. Aerosol particle penetration is improved with tiotropium, without delaying mucus clearance from the lungs. Tiotropium 4.5–36µg once daily for 4 weeks increased mean trough and average FEV1 and FVC and mean PEFR values from baseline compared with placebo, with no evidence of tachyphylaxis. Improvements in trough FEV1 from baseline with tiotropium 4.5–36µg were not dose dependent. Based on a lack of dose response, the optimal once-daily tiotropium dosage is 18µg. Steady-state trough FEV1 values are achieved within 48 hours of commencing tiotropium. Sustained bronchodilation (for ≥24 hours) and an attenuation of the nocturnal decline in FEV1 that were unaffected by timing of the daily tiotropium dose were seen in randomized, double-blind, placebo-controlled studies in patients with stable COPD. The drug improved static and dynamic lung hyperinflation (evidenced by reduced trapped air volume and increased tidal volume and end-of-exercise inspiratory capacity), and improved exertional dyspnea (during activities of daily living and exertion) and exercise tolerance compared with placebo in randomized, double-blind studies. In patients with stable COPD, improved sleep-related oxygen desaturation that was unaffected by the timing of the daily dose was seen with tiotropium but not with placebo. Clinically significant treatment-related disorders of conduction or rhythm, or changes in heart rate were not observed with tiotropium in this patient group. Mean maximal plasma concentrations (Cmax) were observed within 5 minutes of inhalation of a single dose of tiotropium 18µg in patients with COPD. Plasma drug levels declined to minimum concentrations (Cmin) within 1 hour of treatment in healthy volunteers. Mean steady-state Cmax concentrations (16 ng\u002FL) were achieved after 2–3 weeks of once-daily inhaled tiotropium 18µg in elderly patients with COPD; tiotropium does not appear to accumulate once steady-state has been achieved. The estimated absolute bioavailability of tiotropium at steady state in healthy volunteers was approximately 20–25%, and approximately 72% of the drug is bound to plasma proteins. Excretion of tiotropium is predominantly renal (through active secretion by the kidneys), although in vitro studies suggest that cytochrome P450 (CYP) oxidation (possibly involving CYP2D6 and CYP3A4 enzymes) may have a minor role. In patients with COPD, renal excretion of the unchanged drug at 24 hours (Ae24) was approximately 7%. The mean plasma elimination half-life after single or multiple doses in healthy volunteers and elderly patients with COPD was approximately 5–6 days. The renal clearance and urinary excretion of tiotropium decrease with increasing age; however, these changes are not considered to be clinically significant. Because of altered steady-state Cmax, Cmin, area under the concentration-time curve, and Ae24 values, caution is required with tiotropium administration in patients with moderate-to-severe renal impairment. The pharmacokinetics of tiotropium in patients with severe renal or hepatic impairment have not been studied. Tiotropium does not interact with drugs such as cimetidine or ranitidine, which are also eliminated by active renal secretion. Orally inhaled tiotropium bromide has been evaluated as a bronchodilator for the management of patients with COPD in randomized, double-blind 6-month and 1-year trials, and in several shorter studies. In clinical trials, COPD was diagnosed according to the American Thoracic Society guidelines. The bronchodilator effect was expressed as the trough FEV1 response (the mean change in FEV1 from baseline measured 1 hour prior to and immediately before a scheduled dose), and was the primary endpoint in all but two clinical trials. The bronchodilator effect with tiotropium 18µg once daily was superior to that with placebo in several well designed trials in patients with COPD. Moreover, greater improvements in mean peak and average FEV1 responses occurred with tiotropium but not with placebo. Mean trough, peak, and average FVC responses, and weekly mean morning and evening PEFR values were also improved to a greater extent with tiotropium than with placebo. Tiotropium demonstrated a greater bronchodilator effect than ipratropium bromide (hereafter referred to as ipratropium when used at approved dosages) 40µg four times daily in two 1-year trials in patients with COPD. Mean peak and average FEV1, mean trough FVC responses, and weekly mean morning and evening PEFR values were also increased to a greater extent with tiotropium than with ipratropium. In one of the two 6-month trials that compared the efficacy of tiotropium with that of inhaled salmeterol 50µg twice daily, greater improvements from baseline in mean trough, peak, and average FEV1 and FVC responses were seen with tiotropium than with salmeterol. Increases in weekly mean evening, but not morning, PEFR values were generally greater with tiotropium than salmeterol. In the second trial, improvement in the primary endpoint (mean trough FEV1 response from baseline) with tiotropium or salmeterol was similar, although peak and average responses were superior with tiotropium. Preliminary results from a 6-week crossover study in patients with COPD suggested that tiotropium alone or in combination with once-daily formoterol improved mean trough and average FEV1 and trough FVC values from baseline to a greater extent than twice-daily formoterol. More patients achieved a clinically important improvement (increase of ≥1 unit) in the transitional dyspnea index focal score (a measure of dyspnea-related impairment) with tiotropium than with placebo in the 1-year trials. Tiotropium was superior to ipratropium in 1-year trials, and was at least as effective as salmeterol in 6-month trials, in achieving a clinically important improvement in focal scores. Tiotropium recipients experienced fewer COPD exacerbations than placebo or ipratropium recipients and had fewer and shorter COPD-related hospitalizations compared with placebo recipients. Unlike salmeterol, tiotropium lengthened the time to onset of the first exacerbation and decreased the number of exacerbations compared with placebo in two 6-month trials. Similar proportions of tiotropium, salmeterol, and placebo recipients required COPD-related hospitalizations. According to the St George’s Respiratory Questionnaire, more patients achieved a clinically meaningful improvement (a reduction of ≥4 units from baseline) in heath-related quality of life with tiotropium than with placebo, ipratropium, or salmeterol in 6-month or 1-year trials. Results from the Short Form 36 questionnaire confirmed that greater improvements in physical domains occurred with tiotropium than with placebo or ipratropium. The need for rescue treatment with albuterol (salbutamol) was reduced with tiotropium compared with placebo or ipratropium, but was similar to that with salmeterol. The increased cost of treatment with tiotropium over 1 year compared with ipratropium in patients with COPD was €180 per patient per year. The higher acquisition cost of tiotropium was partially offset by reduced healthcare utilization costs. Inhaled tiotropium was generally well tolerated in all clinical trials. Similar percentages of tiotropium, ipratropium, salmeterol, or placebo recipients reported at least one adverse event in studies of up to 1 year. Apart from dry mouth, tiotropium appears to have a similar tolerability profile to that of placebo, ipratropium, or salmeterol. Dry mouth (an event likely to be related to the pharmacologic activity of tiotropium) occurred more frequently with tiotropium than with placebo (6-fold increase; p \u003C 0.05), ipratropium (2-fold increase; p = 0.03) or salmeterol (4-fold increase; p-value not reported). Dry mouth, constipation, and urinary tract infections were reported more frequently with increasing age with tiotropium than with ipratropium in 1-year trials. Similar percentages of tiotropium, ipratropium, or placebo recipients experienced serious adverse events or adverse events leading to withdrawal in the 1-year trials. However, significantly (p \u003C 0.01) fewer tiotropium than salmeterol or placebo recipients withdrew because of adverse events in the 6-month trials. Tiotropium was not associated with any clinically significant changes in ECG recordings, vital signs or laboratory values in 6-month and 1-year trials. Heart rate or rhythm disorders were uncommon with tiotropium (4%), placebo (2%) or ipratropium (5%) in 1-year trials. Inhaled tiotropium bromide is a bronchodilator indicated for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD. It is approved in >40 countries worldwide, including the US and those in the EU. The recommended dosage is a once-daily inhalation of tiotropium 18µg via a dry powder capsule inhaler, the HandiHaler®, at the same time each day. Tiotropium should not be used as an initial treatment for episodes of acute bronchospasm.",{"EN":615},"Tiotropium Bromide",{"VOID":617},"Burrows B, Fletcher CM, Heard BE, et al. The emphysematous and bronchial types of chronic airways obstruction: a clinicopathological study of patients in London and Chicago. Lancet 1966 Apr 16; 1(7442): 830–5\nNational Institutes of Health: National Heart Lung and Blood Institute. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease updated 2003. Executive summary [online]. Available from URL: http:\u002F\u002Fwww.goldcopd.com [Accessed 2003 Aug 20]\nHogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004 Jun 24; 350(26): 2645–53\nSutherland ER, Cherniak RM. Management of chronic obstructive pulmonary disease. N Engl J Med 2004 Jun 24; 350(26): 2689–97\nBarnes PJ. Muscarinic receptor subtypes in airways. Life Sci 1993; 52(5–6): 521–7\nEglen RM, Hegde SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996 Dec; 48(4): 531–65\nBarnes PJ. The pharmacological properties of tiotropium. Chest 2000 Feb; 117 (2 Suppl.): 63S–6S\nVan Noord JA. Tiotropium bromide: a viewpoint by JA van Noord. Drugs 2002; 62(8): 1204–5\nHaddad EB, Mak JCW, Barnes J. Characterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: radioligand binding and autoradiographic mapping. Mol Pharmacol 1994 May; 45: 899–907\nHvizdos KM, Goa KL. Tiotropium bromide. Drugs 2002; 62(8): 1195–203\nDisse B, Reichl R, Speck G, et al. BA 679 BR, a novel long-acting anticholinergic bronchodilator. Life Sci 1993; 52(5–6): 537–44\nTakahashi T, Belvisi MG, Patel H, et al. Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways. Am J Respir Crit Care Med 1994 Dec; 150 (6 Pt 1): 1640–5\nMaesen FPV, Smeets JJ, Sledsens TJH, et al. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group. Eur Respir J 1995 Sep; 8(9): 1506–13\nCalverley PM, Lee A, Towse L, et al. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease. Thorax 2003 Oct; 58(10): 855–60\nLittner MR, Ilowite JS, Tashkin DP, et al. Long-acting bronchodilation with oncedaily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000 Apr; 161 (4 Pt 1): 1136–42\nO’Donnell DE, Magnussen H, Aguilaniu B, et al. Spiriva (tiotropium) improves exercise tolerance in COPD [abstract]. Am J Respir Crit Care Med 2002 Apr; 165 (8 Suppl. Pt 2): A227\nO’Donnell DE, Magnussen H, Aguilaniu B, et al. Spiriva (tiotropium) reduces exertional dyspnea in COPD [abstract]. Am J Respir Crit Care Med 2002 Apr; 165 (8 Suppl. Pt 2): A265\nMagnussen H, O’Donnell DE, Casaburi R, et al. Spiriva® (tiotropium) reduces lung hyperinflation in COPD [abstract]. Am J Respir Crit Care Med 2002 Apr; 165 (8 Suppl. Pt 2): A227\nvan Noord JA, Smeets JJ, Custers FL, et al. Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J 2002 Apr; 19(4): 639–44\nMcNicholas WT, Calverley PMA, Edwards C, et al. Effects of anticholinergic therapy (tiotropium) on REM-related desaturation (SaO2) and sleep quality in patients with COPD [abstract]. Am J Respir Crit Care Med 2001 Apr; 163 (5 Suppl. Pt 2): A280\nO’Donnell DE, Magnussen H, Gerken F, et al. Mechanisms of improved exercise tolerance in COPD in response to tiotropium [abstract no. P1826]. Eur Respir J 2002 Sep; 20Suppl. 38: 288s\nLangley S, Towse L, Kesten S, et al. Heart rate and rhythm analysis from Holter monitoring in COPD patients receiving tiotropium [abstract]. Am J Respir Crit Care Med 2002; 165 (8 Suppl. Pt 2): A592\nHasani A, Toms N, Agnew JE, et al. The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD. Chest 2004 May; 125(5): 1726–34\nO’Donnell D, Marcinuik D, Hernandez P, et al. Spiriva (tiotropium) reduces lung hyperinflation at rest and during exercise [abstract plus poster]. Am J Respir Crit Care Med 2004 Apr; 169(7): A772\nO’Donnell D, Maltais F, Sciurba F, et al. Spiriva (tiotropium) improves symptom-limited exercise tolerance in COPD patients [abstract plus poster]. Am J Respir Crit Care Med 2004 Apr; 169(7): A771\nCasaburi R, Kukafka D, Cooper CB, et al. Improvement in exercise endurance with the combination of tiotropium and rehabilitative exercise training in COPD patients [abstract]. Am J Respir Crit Care Med 2004 Apr; 169(7): A756\nCooper B, Kukafka D, Casaburi R, et al. Tiotropium augments improvements in dyspnea and health-related quality of life following pulmonary rehabilitation in COPD patients [abstract plus poster]. Am J Respir Crit Care Med 2004 Apr; 169(7): A518\nBriggs Jr D, Covelli H, Lapidus R, et al. Improved daytime spirometric efficacy of tiotropium compared to salmeterol in COPD patients [abstract plus poster]. Am J Respir Crit Care Med 2004 Apr; 169(7): A518\nFood and Drug Administration. Clinical pharmacology and biopharmaceutics briefing document [online]. Available from URL: http:\u002F\u002Fwww.fda.gov\u002Fohrms\u002Fdockets\u002Fac\u002F02\u002Fbriefing\u002F3890Bl_06_Pharmacology-Biopharmaceutics.pdf [Accessed 2002 Sep 18]\nCasaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002 Feb; 19(2): 217–24\nVincken W, van Noord JA, Greefhorst APM, et al. Improved health outcomes in patients with COPD during 1 year’s treatment with tiotropium. The Dutch\u002FBelgian Tiotropium Study Group. Eur Respir J 2002 Feb; 19(2): 209–16\nCollege Ter Beoordeling Van Geneesmiddelen Medicines Evaluation Board. Public assessment report: Spiriva 18µg, inhalation powder in hard capsules RVG 26191 [online]. Available from URL: http:\u002F\u002Fwww.cbg-meb.nl\u002Fnl\u002Fdocs\u002Fgnsmiddl\u002Fpar-spiriva.pdf [Accessed 2002 Jul 23]\nDonohue JF, Van Noord A, Bateman ED, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002 Jul; 122(1): 47–55\nVan Noord JA, Aumann J, Janssens E, et al. Comparison of once daily tiotropium, twice daily formoterol and the free combination, once daily, in patients with COPD [abstract no. BO24]. 99th International Conference of the American Thoracic Society; 2003 May 16–21; Seattle, (WA), A320\nHuchon G, Verkindre C, Bart F, et al. Improvements with tiotropium on endurance measured by the shuttle walking test (SWT) and on health related quality of life (HRQoL) in COPD patients [abstract no. P1825]. Eur Respir J 2002; 20Suppl. 38: 287s\nO’Donnell DE, Magnussen H, Gerken F, et al. Cardiovascular evaluation of tiotropium during constant-work rate exercise in COPD [abstract no. P430]. Eur Resp J 2003; 22Suppl. 45: 49s\nVan Noord J, Aumann J, Jannsens E. Relation between acute response to salbutamol and long-term FEV1 responses to tiotropium (TIO), formoterol (FORM) and its combination (T+F) in COPS patients [abstract no. 153]. Eur Resp J 2003 Sep; 22Suppl. 45: 4s\nCelli BR, ZuWallack RL, Wang S, et al. Improvements in inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 2003; 124(5): 1743–8\nMahler DA, Weinberg DH, Wells CK, et al. The measurement of dyspnea. Contents, interobserver agreement and physiologic correlates of two new clinical indexes. Chest 1984 Jun; 85(6): 751–8\nDisse B, Rominger K, Serby CW, et al. The pharmacokinetic (PK) profile of tiotropium during long-term treatment in stable COPD [abstract]. Am J Respir Crit Care Med 1999 Mar; 159 (3 Suppl. Pt 2): A524\nBoehringer Ingelheim. Samenvatting van de productkenmerken [online]. Available from URL: http:\u002F\u002Fwww.cbg-meb.nl\u002FIB-teksten\u002F26191.PDF [Accessed 2002 Jul 24]\nDisse B, Speck GA, Rominger KL, et al. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci 1999; 64(6–7): 457–64\nFood and Drug Administration. Spiriva (tiotropium bromide inhalation powder) NDA 21-395 Boehringer Ingelheim Pharmaceuticals, Inc [online]. Available from URL: http:\u002F\u002Fwww.fda.gov\u002Fohrms\u002Fdockets\u002Fac\u002F02\u002Fbriefing\u002F3890Bl_l_Boehringer%20Ingelheim.pdf [Accessed 2002 Sep 18]\nTiirck D, Weber W, Sigmund R, et al. Pharmacokinetics of intravenous, single-dose tiotropium in subjects with different degrees of renal impairment. J Clin Pharmacol 2004; 44: 163–72\nWanner A, ZuWallack R, Elias D, et al. Efficacy of once daily tiotropium (TIO) in stable COPD [abstract no. P3406]. 9th Annual Congress of the European Respiratory Society; 1999 Oct 9–13; Madrid, (abstracts-on-disk)\nSan Pedro G, Elias DJ, Serby CW, et al. Tiotropium (Spiriva): one year bronchodilator efficacy established with once daily dosing in COPD patients [abstract]. Am J Respir Crit Care Med 2000 Mar; 161 (3 Suppl. Pt 2): A749\nZu Wallack R, Jones PW, Kotch A, et al. Tiotropium (Spiriva) improves health status in patients with COPD [abstract]. Am J Respir Crit Care Med 2000 Mar; 161 (3 Suppl. Pt 2): A892\nMahler DA, Montner P, Brazinsky SA, et al. Tiotropium (Spiriva), a new long-acting anticholinergic bronchodilator, improves dyspnea in patients with COPD [abstract]. Am J Respir Crit Care Med 2000 Mar; 161 (3 Suppl. Pt 2): A892\nCasaburi R, Briggs Jr DD, Donohue JF, et al. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Chest 2000 Nov; 118(5): 1294–302\nTashkin D, Kesten S. Long-term treatment benefits with tiotropium in COPD patients with and without short-term bronchodilator responses. Chest 2003 May; 123(5): 1441–9\nDonohue JF, Menjoge S, Kesten S. Tolerance to bronchodilating effects of salmeterol in COPD. Respir Med 2003 Sep; 97(9): 1014–20\nBriggs Jr DD, Witek TJ, Menjoge SS, et al. Evaluating the efficacy of chronic therapy with tiotropium in COPD through discontinuation of treatment [abstract no. P1589]. Eur Respir J 2002 Sep; 20Suppl. 38: 245s\nHodder RV, White RJ, Menjoge SS, et al. Effectiveness of tiotropium or salmeterol in COPD patients receiving inhaled steroids [abstract]. Am J Respir Crit Care Med 2002 Apr; 165 (8 Suppl. Pt 2): A228\nFriedman M, Korducki L, Kesten S. Recovery of PEFR in COPD exacerbations in one year clinical trials [abstract]. Am J Respir Crit Care Med 2002 Apr; 165 (8 Part 2): A270\nSpencer S, Jones PW. Decline in health status over one year is eliminated by tiotropium. Tiotropium study group [abstract]. Am J Respir Crit Care Med 2002 Apr; 165 (8 Suppl. Pt 2): A228\nBeeh KM, Beier J, Buhl R, et al. Efficacy of tiotropium in patients with mild to moderate COPD [abstract plus poster]. Am J Respir Crit Care Med 2004 Apr; 169(7): A519\nNiewoehner D, Rice K, Cote C, et al. Reduced COPD exacerbations and associated health care utilization with once-daily tiotropium (TIO) in the VA medical system [abstract]. Am J Respir Crit Care Med 2004 Apr; 169(7): A207\nFriedman M, Menjoge SS, Anton S, et al. Healthcare costs with tiotropium plus usual care versus usual care alone following 1 year of treatment in patients with chronic obstructive pulmonary disorder (COPD). Pharmacoeconomics 2004; 22(No. 11): 741–9\nBrusasco V, Hodder R, Miravitlles M, et al. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003 May; 58(5): 399–404\nVan Noord JA, Bantje TA, Eland ME, et al. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax 2000 Apr; 55(4): 289–94\nVincken W, Greefhorst APM, Westbroek J, et al. Once-daily tiotropium (TIO) is more efficacious than Q.I.D. ipratropium (IB) as maintenance treatment of COPD [abstract no. P3407]. 9th Annual Congress of the European Respiratory Society; 1999 Oct 9–13; Madrid, (abstracts-on-disk)\nde Guia T, Punzal P, Canizares L, et al. Evaluation of the response of Filipino patients to tiotropium (EVEREST Study) [abstract]. Am J Respir Crit Care Med 2004 Apr; 169(7): A611\nFood and Drug Administration. Clinical briefing document NDA 21-395 Spiriva (tiotropium bromide) inhalation powder for COPD [online]. Available from URL: http:\u002F\u002Fwww.fda.gov\u002Fohrms\u002Fdockets\u002Fac\u002F02\u002Fbriefing\u002F3890Bl_05_Clinical%20Briefing-%20Part%201.pdf; http:\u002F\u002Fwww.fda.gov\u002Fohrms\u002Fdockets\u002Fac\u002F02\u002Fbriefing\u002F3890Bl_05_Clinical%20Briefing-%20Part%202.pdf [Accessed 2002 Sep 18]\nWitek Jr TJ, Mahler DA. Meaningful effect size and patterns of response of the transition dyspnea index. J Clin Epidemiol 2003 Mar; 56(3): 248–55\nKesten S, Flanders S, Menjoge SS, et al. Improvements in COPD following treatment with tiotropium in elderly patients. Chest 2001 Oct; 120(4 Suppl.): 163S–4S\nWeisman I, Menjoge SS, Serby CW, et al. Influence of gender on outcomes in large COPD clinical trials [abstract]. Am J Respir Crit Care Med 2001 Apr; 163 (5 Suppl. Pt 2): A281\nAmerican Thoracic Society. Standardisation of spirometry: 1994 update. Am J Respir Crit Care Med 1995 Sep; 152(3): 1107–36\nVincken WG, Vermiere P, Menjoge SS, et al. Maintenance of bronchodilation following tiotropium in patients with mild, moderate and severe COPD in one year clinical trials [abstract]. Eur Respir J 2001 Sep; 18Suppl. 33: 331s\nJones PW, Quirk FH, Baveystock CM. The St. George’s Respiratory Questionnaire. Respir Med 1991; 85Suppl B: 25–31\nJones PW, Quirk FH, Baveystock CM, et al. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis 1992 Jun; 145(6): 1321–7\nMahler DA. How should health-related quality of life be assessed in patients with COPD? Chest 2000 Feb; 117(2 Suppl.): 54S–7S\nWare Jr JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). 1. Conceptual framework and item selection. Med Care 1992 Jun; 30(6): 473–83\nKesten S, Flanders J, Serby CW, et al. Compliance with tiotropium, a once daily dry powder inhaled bronchodilator, in one year COPD trials. Chest 2000 Oct; 118(4 Suppl.): 191S–2S\nOostenbrink JB, Rutten-van Mölken MPMH, Al J, et al. One-year cost-effectiveness of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease. Eur Respir J 2004; 23: 241–9\nBoehringer Ingelheim International GmbH. Summary of product characteristics: Spiriva. Boehringer Ingelheim International GmbH, 2002\nBoehringer Ingelheim, Pfizer Inc. Prescribing information: Spiriva® Handihaler® (tiotropium bromide inhalation powder) [online]. Available from URL: http:\u002F\u002Fwww.spiriva.com [Accessed 2004 Mar 12]\nBoehringer Ingelheim, Pfizer Inc. FDA approves Spiriva Handihaler for the treatment of COPD [media release]. 2004\nMurray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997 May; 349(9064): 1498–504\nNational Institutes of Health: National Heart Lung and Blood Institute. Morbidity and Mortality: 2002 chart book on cardiovascular, lung, and blood diseases [online]. Available from URL: http:\u002F\u002Fwww.nhlbi.nih.gov\u002Fresources\u002Fdocs\u002F02_chtbk.pdf [Accessed 2002 Aug 21]\nNational Center for Health Statistics. Births, marriages, divorces, and deaths for 1997. Mon Vital Stat Rep 1998 Jul 28; 46(12): 1–18\nNational Heart Lung and Blood Institute. Data fact sheet: chronic obstructive pulmonary disease (COPD) [online]. Available from URL: http:\u002F\u002Fwww.nhlbi.nih.gov [Accessed 2002 Jul 15]\nHoyert DL, Arias E, Smith BL, et al. Deaths: final data for 1999. Natl Vital Stat Rep 2001 Sep 21; 49(8): 1–113\nNational Institute for Clinical Excellence. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care [online]. Available from URL: http:\u002F\u002Fwww.nice.org.uk [Accessed 2004 Mar 16]\nBarnes PJ. Chronic obstructive pulmonary disease. N Eng J Med 2000 Jul 27; 343(4): 269–80\nPauwels RA. National and international guidelines for COPD: the need for evidence. Chest 2000 Feb; 117(2 Suppl.): 20S–2S\nBarnes PJ. Tiotropium bromide. Expert Opin Investig Drugs 2001 Apr; 10(4): 733–40\nClaxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001 Aug; 23(8): 1296–310\nLipson DA. Redefining treatment in COPD: new directions in bronchodilator therapy. Treat Respir Med 2004; 3(2): 89–95\nRedelmeier DA, Goldstein RS, Min ST, et al. Spirometry and dyspnea in patients with COPD: when small differences mean little. Chest 1996 May; 109(5): 1163–8\nBauerle O, Chrusch CA, Younes M. Mechanisms by which COPD affects exercise tolerance. Am J Respir Crit Care Med 1998 Jan; 157(1): 57–68\nMahler DA, Jones PW. Measurement of dyspnea and quality of life in advanced lung disease. Clin Chest Med 1997 Sep; 18(3): 457–69\nJarvis B, Markham A. Inhaled salmeterol: a review of its efficacy in chronic obstructive pulmonary disease. Drugs Aging 2001; 18(6): 441–72\nCheer SM, Scott LJ. Formoterol: a review of its use in chronic obstructive pulmonary disease. Am J Respir Med 2002; 1(4): 285–300\nBoehringer Ingelheim, Pfizer Inc. 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2000, Natl Vital Stat Rep, 48, 1",{},{"id":18,"text":782,"url":18,"identifiers":783},"Strassels, 2001, Chest, 119, 344, 10.1378\u002Fchest.119.2.344",{"doi":784},"10.1378\u002Fchest.119.2.344",{"id":18,"text":786,"url":18,"identifiers":787},"Seemungal, 2000, Am J Respir Crit Care Med, 161, 1608, 10.1164\u002Fajrccm.161.5.9908022",{"doi":788},"10.1164\u002Fajrccm.161.5.9908022",{"id":18,"text":790,"url":18,"identifiers":791},"Seemungal, 1998, Am J Respir Crit Care Med, 157, 1418, 10.1164\u002Fajrccm.157.5.9709032",{"doi":792},"10.1164\u002Fajrccm.157.5.9709032",{"id":18,"text":794,"url":18,"identifiers":795},"Connors Jr, 1996, Am J Respir Crit Care Med, 154, 959, 10.1164\u002Fajrccm.154.4.8887592",{"doi":796},"10.1164\u002Fajrccm.154.4.8887592",{"id":18,"text":798,"url":18,"identifiers":799},"Mushlin, 1991, JAMA, 266, 80, 10.1001\u002Fjama.1991.03470010084035",{"doi":800},"10.1001\u002Fjama.1991.03470010084035",{"id":18,"text":802,"url":18,"identifiers":803},"Afessa, 2002, Crit Care Med, 30, 1610, 10.1097\u002F00003246-200207000-00035",{"doi":804},"10.1097\u002F00003246-200207000-00035",{"id":18,"text":806,"url":18,"identifiers":807},"Charlson, 1987, J Chronic Dis, 40, 373, 10.1016\u002F0021-9681(87)90171-8",{"doi":808},"10.1016\u002F0021-9681(87)90171-8",{"id":18,"text":810,"url":18,"identifiers":811},"Romano, 1993, J Clin Epidemiol, 46, 1075, 10.1016\u002F0895-4356(93)90103-8",{"doi":812},"10.1016\u002F0895-4356(93)90103-8",{"id":18,"text":814,"url":18,"identifiers":815},"Duan, 1983, J Am Stat Assoc, 78, 605, 10.1080\u002F01621459.1983.10478017",{"doi":816},"10.1080\u002F01621459.1983.10478017",{"id":18,"text":818,"url":18,"identifiers":819},"Mannino, 2002, Respir Care, 47, 1184",{},{"id":18,"text":821,"url":18,"identifiers":822},"Garcia-Aymerich, 2003, Thorax, 58, 100, 10.1136\u002Fthorax.58.2.100",{"doi":823},"10.1136\u002Fthorax.58.2.100",{"id":825,"createTime":826,"updateTime":827,"relativeEntities":828,"slug":829,"properties":830,"entityType":78,"verifyStatus":79,"verifyTime":827,"verifyNote":80,"languages":18,"translateLanguages":18,"viewCount":46,"primaryUrl":839,"fullTextUrl":18,"authors":840,"publicationType":187,"publisherRelationship":856,"citationCount":18,"citationInfo":18,"publishDate":213,"publishYear":214,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":880,"openAccess":18,"references":18,"isForceReanalyzing":216},"c354ff46-646d-4d6d-ad49-4b08e7807b6f","2024-01-26T10:08:19.875+00:00","2025-02-13T16:17:11.236+00:00",[],"Asthma-Management-Issues-in-Infancy-and-Childhood",{"abstract":831,"title":833,"references":835,"doi":837},{"EN":832},"The prevalence of asthma has been increasing worldwide over the past 2 decades, especially the prevalence of childhood asthma. Currently, the prevalence of childhood asthma is around 3–20% in different countries based on the report from the International Study of Asthma and Allergies in Children (ISAAC). Asthma in childhood is predominantly an extrinsic asthma. In general, countries in the coastal, temperate, and subtropical zones have the highest prevalence of mite- and cockroach-sensitive asthma. Countries in the sub-arctic or semi-arid areas have a lower prevalence of childhood asthma, mostly associated with sensitization to pet dander, moulds, and pollens. Many genes have been linked to asthma in different ethnic populations. A global consensus for the management of asthma in adults and children >5 years of age has been made possible in the Global Initiative for Asthma (GINA) guidelines, where a step-wise management program using inhaled medication with and without oral anti-inflammatory drugs is recommended. The management of asthma in children \u003C5 years of age remains inconclusive. Recent studies suggest that inherited susceptibility associated with risk factors from the prenatal and postnatal environment is likely to promote allergic sensitization and development of asthma. Consequently, early prevention of prenatal sensitization in utero and environmental control of early life exposure to various allergens may decrease the incidence of childhood asthma. In the management of moderate persistent asthma in infants and young children \u003C5 years of age, airway resistance tests (FEV1 or PEF) are not of significance, but assessment of respiratory rate and skin pulse oximeter measurements of arterial oxygen saturation are helpful. Moreover, recent advances in pharmacogenetics and pharmacogenomics may provide better individualized care for early pharmacological prevention of childhood asthma via selective modulation of airway remodeling.",{"EN":834},"Asthma Management Issues in Infancy and Childhood",{"VOID":836},"Global Initiative for Asthma (GINA): pocket guide for asthma management and prevention — updated 2004 [online]. Available from URL: http:\u002F\u002Fwww.ginasthma.org [Accessed 2005 Jan 17]\nNational Asthma Education and Prevention Program (NAEPP) Expert Panel Report-2: guidelines for the diagnosis and management of asthma. Bethesda (MD): National Heart, Lung, and Blood Institute, NIH, US Department of Health And Human Services, 1997: 1–147. NIH Publication No. 97-4051\nStein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999; 354: 541–5\nStein RT, Holberg CJ, Morgan WJ, et al. Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax 1997; 52: 946–52\nWeiss ST, Van Natta ML, Zeiger RS. Relationship between increased airway responsiveness and asthma severity in the Childhood Asthma Management Program. Am J Respir Crit Care Med 2000; 162: 50–6\nNelson HS, Szefler SJ, Jacobs J, et al. The relationships among environmental allergen sensitization, allergen exposure, pulmonary function, and bronchial hyperresponsiveness in the Childhood Asthma Management Program. J Allergy Clin Immunol 1999; 104: 775–85\nSigurs N, Bjarnason R, Sigurbergsson F, et al. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 1995; 95: 500–5\nWorldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: the International Study of Asthma and Allergies in Childhood (ISAAC) steering committee. Lancet 1998; 351: 1225–32\nYang KD. Aspects of global environment, genetics and management. Chang Gung Med J 2000; 23: 641–61\nHsieh KH, Shen JJ. Prevalence of childhood asthma in Taipei, Taiwan, and other Asian Pacific countries. J Asthma 1988; 25: 73–82\nPearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999; 54: 268–72\nIngram JM, Sporik R, Rose G, et al. Quantitative assessment of exposure to dog (Can f1) and cat (Fel d1) allergens: relation to sensitization and asthma among children living in Los Alamos, New Mexico. J Allergy Clin Immunol 1995; 96: 449–56\nChan-Yeung M, Becker A, Lam J, et al. House dust mite allergen levels in two cities in Canada: effects of season, humidity, city and home characteristics. Clin Exp Allergy 1995; 25: 240–6\nBeaumont F, Kauffman HE, Sluiter HJ, et al. A volumetric-aerobiologic study of seasonal fungus prevalence inside and outside dwellings of asthmatic patients living in northeast Netherlands. Ann Allergy 1984; 53: 486–92\nEzeamuzie CI, Al-Ali S, Khan M, et al. IgE-mediated sensitization to mould allergens among patients with allergic respiratory diseases in a desert environment. Int Arch Allergy Immunol 2000; 121: 300–7\nCelenza A, Fothergill J, Kupek E, et al. Thunderstorm associated asthma: a detailed analysis of environmental factors. BMJ 1996; 312(7031): 604–7\nLubs MLE. Empiric risks for genetic counseling in families with allergy. J Pediatr 1972; 80: 26–31\nOwnby DR. Environmental factors versus genetic determinants of childhood inhalant allergies. J Allergy Clin Immunol 1990; 86: 279–87\nCookson WO, Moffatt MF. Genetics of asthma and allergic disease. Hum Mol Gene 2000; 9: 2359–64\nKoppelman GH, Reijmerink NE, Colin Stine O, et al. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 2001; 163: 965–9\nD’amato M, Vitiani LR, Petrelli G, et al. Association of persistent bronchial hyperresponsiveness with beta2-adrenoceptor (ADRB2) haplotypes: a population study. Am J Respir Crit Care Med 1998; 158: 1968–73\nVan Eerdewegh P, Little RD, Dupuis J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 2002; 418: 426–30\nPanhuysen CIM, Bleecker ER, Koeter GH, et al. Dutch approach to the genetics of asthma. Clin Exp Allergy 1995; 25Suppl. 2: 35–8\nSears MR, Herbison GP, Holdaway MD, et al. The relative risks of sensitivity to grass pollen, house dust mite, and cat dander in the development of childhood asthma. Clin Exp Allergy 1989; 19: 419–24\nSears MR, Burrfows B, Flannery EM, et al. Atopy in childhood. I: gender and allergen related risks for development of hay fever and asthma. Clin Exp Allergy 1993; 23: 826–31\nJaakkola JJ, Nafstad P, Magnus P. Environmental tobacco smoke, parental atopy, and childhood. Environ Health Perspect 2001; 109: 579–82\nRonchetti R, Bonci E, Cutera R, et al. Enhanced allergic sensitization related to parental smoking. Arch Dis Child 1992; 67: 496–500\nRonchetti R, Macri F, Ciofetta G, et al. Increased serum immunoglobulin E and increased prevalence of eosinophilia in nine year old children of smoking parents. J Allergy Clin Immunol 1990; 86: 400–7\nBarrios C, Brawand P, Berney M, et al. Neonatal and early life immune responses to various forms of vaccine antigens qualitatively differ from adult responses: predominance of a Th2-biased pattern which persists after adult boosting. Eur J Immunol 1996; 26: 1489–96\nJohnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9 to 11 year old children. BMJ 1995; 310: 1225–9\nHorwitz RJ, Busse WW. Inflammation and asthma. Clin Chest Med 1995; 16: 583–602\nRoche WR. Fibroblasts and asthma. Clin Exp Allergy 1991; 21: 545–8\nHart PH. Regulation of the inflammatory response in asthma by mast cell products. Immunol Cell Biol 2001; 79: 149–53\nKam KL, Hsieh KH. Comparison of three in vitro assays for serum IgE with skin testing in asthmatic children. Ann Allergy 1994; 73: 329–36\nBurrows B, Martinez FD, Halonen M, et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989; 320: 271–7\nHuss K, Adkinson NF, Eggleston PA, et al. House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program. J Allergy Clin Immunol 2001; 107: 48–54\nSly PD. Peak expiratory flow monitoring in pediatric asthma: is there a role? J Asthma 1996; 33: 277–87\nTing S. Multicolored simplified asthma guideline reminder (MSAGR) for better adherence to national\u002Fglobal asthma guidelines. Ann Allergy Asthma Immunol 2002; 88: 326–30\nModl M, Eber E, Steinbrugger B, et al. Comparing methods for assessing bronchial responsiveness in children: single step cold air challenge, multiple step cold air challenge, and histamine provocation. Eur Respir J 1995; 8: 1742–7\nHopp RJ, Bewtra AK, Nair NM, et al. Specificity and sensitivity of methacholine inhalation challenge in normal and asthmatic children. J Allergy Clin Immunol 1984; 74: 154–8\nWarner JA, Jones AC, Miles EA, et al. Materofetal interaction and allergy. Allergy 1996; 51: 447–51\nJohnson CC, Ownby DR, Peterson EL. Parental history of atopic disease and concentration of cord blood IgE. Clin Exp Allergy 1996; 26: 624–9\nTariq SM. Allergen avoidance in the primary prevention of atopy. Br J Clin Pract 1996; 50: 99–102\nLiu CA, Wang CL, Chuang H, et al. Prenatal prediction of infant atopy by maternal but not paternal total IgE levels. J Allergy Clin Immunol 2003: 112: 899–904\nBjerke T, Hedegaard M, Henriksen TB, et al. Several genetic and environmental factors influence cord blood IgE concentration. Pediatr Allergy Immunol 1994; 5: 88–94\nKalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial. Lancet 2001; 357: 1076–9\nGehring U, Bolte G, Borte M, et al. Exposure to endotoxin decreases the risk of atopic eczema in infancy: a cohort study. LISA study group: Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood. J Allergy Clin Immunol 2001; 108: 847–54\nMcKeever TM, Lewis SA, Smith C, et al. Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database. J Allergy Clin Immunol 2002; 109: 43–50\nShaheen SO, Aaby P, Hall AJ, et al. Measles and atopy in Guinea-Bissau. Lancet 1996; 347: 1792–6\nShearer GM, Chougnet C, Shearer MS. Atopic disease and immunologic response. Science 1997; 276: 17–8\nZeiger RS, Dawson C, Weiss S. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 1999; 103: 376–87\nLong-term effects of budesonide or nedocromil in children with asthma: the Childhood Asthma Management Program Research Group. N Engl J Med 2000; 343: 1054–63\nBisgaard H. Use of inhaled corticosteroids in pediatric asthma. Pediatr Pulmonol 1997; 15: 27S–33S\nBustos GJ, Bustos D, Bustos GJ, et al. Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study. Clin Exp Allergy 1995; 25: 568–73\nKnorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001; 108: E48\nBibi H, Khvolis E, Shoseyov D, et al. The prevalence of gastroesophageal reflux in children with tracheomalacia and laryngomalacia. Chest 2001; 119(2): 409–13\nAvital A, Uwyyed K, Berkman N, et al. Exhaled nitric oxide and asthma in young children. Pediatr Pulmonol 2001; 32: 308–13\nKlinnert MD, Nelson HS, Price MR, et al. Onset and persistence of childhood asthma: predictors from infancy. Pediatrics 2001; 108: E69\nBisgaard H, Munck SL, Nielsen JP, et al. Inhaled budesonide for treatment of recurrent wheezing in early childhood. Lancet 1990; 336: 649–51\nBerger I, Argaman Z, Schwartz SB, et al. Efficacy of corticosteroids in acute bronchiolitis: short-term and long-term follow-up. Pediatr Pulmonol 1998; 26: 162–6\nSpringer C, Bar-Yishay E, Uwayyed K, et al. Corticosteroids do not affect the clinical or physiological status of infants with bronchiolitis. Pediatr Pulmonol 1990; 9: 181–5\nBisgaard H. Leukotriene modifiers in pediatric asthma management. Pediatrics 2001; 107: 381–90\nPalmqvist M, Arvdsson P, Beckman O, et al. Onset of bronchodilation of budesonide\u002Fformoterol vs. salmeterol\u002Ffluticasone in single inhalers. Pulm Pharmacol Ther 2001; 14: 29–34\nAgertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994; 88: 373–81\nPedersen S, Hansen OR. Budesonide treatment of moderate and severe asthma in children: a dose-response study. J Allergy Clin Immunol 1995; 95: 29–33\nLaitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol 1992; 90: 32–42\nBarnes PJ. Inhaled glucocorticoid for asthma. N Engl J Med 1995; 332: 868–75\nWelch MJ. Inhaled steroids and severe viral infections. J Asthma 1994; 31: 43–50\nNewacheck PW, Halfon N. Prevalence, impact, and trends in childhood disability due to asthma. Arch Pediatr Adolesc Med 2000; 154: 287–93\nBarnes PJ. Scientific rationale for inhaled combination theory with long-acting β-agonists and corticosteroids. Eur Respir J 2002; 19: 182–91\nSharek PJ, Bergman DA. The effect of inhaled steroids on the linear growth of children with asthma: a meta-analysis. Pediatrics 2000; 106: E8\nDoull IJM, Campbell MJ, Holgate ST. The growth suppressive effects of regular inhaled corticosteroids are relatively short term. Arch Dis Child 1998; 78: 172–3\nRubin BK, Albers GM. Use of anticholinergic bronchodilation in children. Am J Med 1996; 100: 49S–53S\nKajosaari M, Syvanen P, Forars M, et al. Inhaled corticosteroids during and after respiratory syncytial virus-bronchiolitis may decrease subsequent asthma. Pediatr Allergy Immunol 2000; 11: 198–202\nTsai YG, Lee MY, Yang KD, et al. A single dose of nebulized budesonide decreases exhaled nitric oxide in children with acute asthma. J Pediatr 2001; 139: 433–7\nSafdar B, Cone DC, Pham KT. Subcutaneous epinephrine in the prehospital setting. Prehosp Emerg Care 2001; 5: 200–7\nMalling HJ, Weeks B. EAACI Immunotherapy position paper. Allergy 1993; 48: 9–35\nAdkinson NF, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for children in allergic asthma. N Engl J Med 1997; 336: 324–31\nDempsey OJ, Wilson AM, Sims EJ, et al. Additive bronchoprotective and bronchodilator defects with single doses of salmeterol and montelukast in asthmatic patients receiving inhaled corticosteroids. Chest 2000; 117: 950–3\nRadielovic P, Morley J, Hansel TT, et al. Zaditen SRO permits once-daily dosing with superior efficacy in the prophylaxis of asthma. J Asthma 1995; 32: 105–15\nInternational Consensus Report on diagnosis and management of asthma. Eur Respir J 1992; 5: 601–41\nD’Ambrosio FP, Ricciardi L, Isola S, et al. Rush sublingual immunotherapy in Parietaria allergic patients. Allergol Immunopathol (Madr) 1996; 24: 146–51\nMungan D, Misirligil Z, Gurbuz L. Comparison of the efficacy of subcutaneous and sublingual immunotherapy in mite-sensitive patients with rhinitis and asthma: a placebo controlled study. Ann Allergy Asthma Immunol 1999; 82: 485–90\nDry J. Effect of a fish oil diet on asthma: results of a 1-year double-blind study. Int Arch Allergy Appl Immunol 1991; 95: 156–7\nMedici TC, Schmid AZ, Hacki M. Are asthmatics salt-sensitive? A preliminary controlled study. Chest 1993; 104: 1138–43\nAnah CO, Jarike L, Baig H. High dose ascorbic acid in Nigerian asthmatics. Trop Geogr Med 1980; 32: 132–7\nCollipp PJ, Goldzier S, Weiss N, et al. Pyridoxine treatment of childhood bronchial asthma. Ann Allergy 1975; 35: 93–7\nSchwarz J. Caffeine intake and asthma symptoms. Ann Epidemiol 1992; 2: 627–35\nKong XT, Fang HT, Jiang GQ, et al. Treatment of acute bronchiolitis with Chinese herbs. Arch Dis Child 1993; 68: 468–71\nSchachter EN, Doyle CA, Beck GJ. A prospective study of asthma in a rural community. Chest 1984; 85: 623–30\nSchwartz J, Gold D, Dockery DW, et al. Predictors of asthma and persistent wheeze in a national sample of children in the United States. Am Rev Respir Dis 1990; 142: 555–62\nFoucard T, Sjoberg O. A prospective 12-year follow-up study of children with wheezy bronchitis. Acta Paediatr Scand 1984; 73: 577–83\nLarsson ML, Frisk M, Hallstrom J, et al. Environmental tobacco smoke exposure during childhood is associated with increased prevalence of asthma in adults. Chest 2001; 120: 711–7\nSaga R, Mochizuki H, Tokuyama K, et al. Relationship between bronchial hyperresponsiveness and development of asthma in wheezy infants. Chest 2001; 119: 685–90\nHopes E, McDougall C, Christie G, et al. Association of glutamine 27 polymorphism of beta 2 adrenoceptor with reported childhood asthma: population based study. BMJ 1998; 316: 664\nDrazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999; 22: 168–70\nRusnak JM, Kisabeth RM, Herbert DP, et al. Pharmacogenomics: a clinician’s primer on emerging technologies for improved patient care. Mayo Clinic Proc 2001; 76: 299–309",{"VOID":838},"10.2165\u002F00151829-200504010-00002","https:\u002F\u002Flink.springer.com\u002Farticle\u002F10.2165\u002F00151829-200504010-00002",[841],{"id":842,"sortIndex":19,"researcher":18,"roles":843,"affiliations":844,"properties":853,"displayName":855,"givenName":18,"familyName":18},"a4c61c18-5bb0-427e-8361-befe9e7aebac",[86],[845],{"id":846,"sortIndex":19,"affiliation":847,"properties":18},"6075a6d5-8e15-46d3-83c1-1395693b9f54",{"id":846,"createTime":18,"updateTime":18,"relativeEntities":848,"slug":18,"properties":849,"entityType":18,"verifyStatus":18,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":18,"url":18,"parentIds":852,"statistic":18},[],{"title":850},{"VI":851},"Chang Gung Children’s Hospital at Kaohsiung, Niao-Sung, Kaohsiung, Taiwan",[],{"title":854},{"VI":855},"Kuender D. Yang",{"url":839,"publisher":857,"properties":876},{"id":6,"createTime":7,"updateTime":8,"relativeEntities":858,"slug":10,"properties":859,"entityType":16,"verifyStatus":17,"verifyTime":18,"verifyNote":18,"languages":18,"translateLanguages":18,"viewCount":19,"subjectFields":862,"manageAffiliations":863,"indexDatabases":864,"url":38,"thumbnailPath":18,"statistic":871,"gsStatistic":18,"type":58,"analyzePriority":18},[],{"issn":860,"title":861},{"VOID":13},{"EN":15},[],[],[865],{"id":24,"indexDatabase":866,"url":35,"indexYears":36,"academicFieldIds":18,"indexDatabaseRanking":37},{"id":26,"createTime":18,"updateTime":18,"relativeEntities":867,"label":868,"description":869,"key":32,"publicationTags":870,"standard":18},[],{"EN":29,"VI":29},{"EN":29,"VI":31},[34],{"impactFactor":19,"impactFactorByYear":872,"i10Index":41,"i10IndexLast5Year":19,"totalPublication":42,"totalPublicationByYear":873,"totalCitation":47,"totalCitationByYear":874,"totalCitationPerPublication":52,"totalCitationPerPublicationByYear":875,"hindexLast5Year":57,"hindex":57},{},{"2004":44,"2005":44,"2006":45,"2012":46},{"2004":49,"2005":50,"2006":51},{"2004":54,"2005":55,"2006":56},{"pages":877,"volume":879},{"VOID":878},"9-20",{"VOID":299},[],{"id":882,"createTime":883,"updateTime":884,"relativeEntities":885,"slug":886,"properties":887,"entityType":78,"verifyStatus":79,"verifyTime":884,"verifyNote":80,"languages":18,"translateLanguages":18,"viewCount":19,"primaryUrl":896,"fullTextUrl":18,"authors":897,"publicationType":187,"publisherRelationship":913,"citationCount":18,"citationInfo":18,"publishDate":213,"publishYear":214,"citationAnalyzeStatus":17,"lastCitationAnalyze":18,"indexDatabases":937,"openAccess":18,"references":18,"isForceReanalyzing":216},"22a5038b-f901-4aec-ad06-961d44be1b7b","2024-01-19T05:04:22.383+00:00","2025-02-13T09:18:10.525+00:00",[],"Selectin-Antagonists",{"abstract":888,"title":890,"references":892,"doi":894},{"EN":889},"Asthma and COPD are chronic inflammatory conditions that affect hundreds of millions of patients worldwide. New therapeutics are desperately needed, especially those that target the underlying causes and prevent disease progression. Although asthma and COPD have distinct etiologies, both are associated with reduced airflow caused by excess infiltration of inflammatory cells into healthy lung tissues. As selectin-mediated adhesion of leukocytes to the vascular endothelium is a key early event in the initiation of the inflammatory response, selectin inhibition is thought to be a good target for therapeutic intervention. Three known selectins are expressed in distinct subsets of cells: P-selectin is presented on the surface of activated platelets and endothelial cells, L-selectin is constitutively expressed on leukocytes, and E-selectin synthesis is upregulated in activated endothelial cells. They mediate cell-cell adhesion in the shear flow of the bloodstream via specialized interactions with clusters of oligosaccharides presented on cell surface glycopeptide ligands. The role of selectin-ligand interactions in the inflammatory response has been demonstrated in various animal models, prompting considerable attention from the pharmaceutical industry. Drug discovery efforts have yielded many different classes of selectin inhibitors, including soluble protein ligands, antibodies, oligosaccharides and small molecules. Although many selectin inhibitors have shown activity in preclinical models, clinical progress of selectin-directed therapies has been slow. Early approaches employed carbohydrate-based inhibitors to mimic the natural ligand sialyl Lewis X; however, these compounds proved challenging to develop. Cytel’s CY 1503, a complex oligosaccharide, progressed to phase II\u002FIII trials for reperfusion injury, but further development was halted when it failed to demonstrate clinical efficacy. Two protein-based selectin inhibitors have reached phase II development. These included Wyeth’s recombinant soluble P-selectin ligand, TSI (PSGL-1), which was discontinued after disappointing results in myocardial infarction trials and Protein Design Labs’ humanized anti-L-selectin monoclonal antibody, which is currently in development for trauma. Bimosiamose, discovered by Encysive Pharmaceutical and presently being developed by Revotar Biopharmaceuticals, is an 863 g\u002Fmol molecular weight dimer with minimal carbohydrate content and is, to date, the leading selectin inhibitor in clinical development. This compound has shown promise in a phase Ha ‘proof of concept’ trial in patients with asthma, reducing airway recruitment of eosinophils after intravenous administration. Further clinical development of an inhaled formulation is underway. Despite a significant need for new therapeutics, selectin inhibitors have not yet been explored for the treatment of COPD. Bimosiamose represents an important proof of principle, and hopefully continued success will spark renewed interest in selectin-directed therapeutics for respiratory diseases.",{"EN":891},"Selectin Antagonists",{"VOID":893},"World Health Organization. World Health Report 1998. Life in the 21st century: a vision for all. Geneva: World Health Organization, 1998\nNews and commentary: fighting for breathing space in the respiratory market [news article]. Curr Drug Disc 2002 Jul: 10–l\nSchleimer RP, Bochner BS. The role of adhesion molecules in allergic inflammation and their suitability as targets of antiallergic therapy. Clin Exp Allergy 1998; 28Suppl. 3: 15–23\nVanderslice P, Biediger RJ, Woodside DG, et al. Development of cell adhesion molecule antabonists as therapeutics for asthma and COPD. Pulm Pharmacol Ther 2004; 17(1): 1–10\nAlbelda SM, Smith CW, Ward PA. Adhesion molecules and inflammatory injury. FASEB J 1994; 8: 504–12\nRomano SJ, Slee DH. Targeting selectins for the treatment of respiratory diseases. Curr Opin Investig Drugs 2001; 2(7): 907–13\nVestweber D, Blanks J. Mechanisms that regulate the function of the selectins and their ligands. Physiol Rev 1999; 79(1): 181–213\nLowe JB, Ward PA. Therapeutic inhibition of carbohydrate-protein interactions in vivo. J Clin Invest 1997; 99(5): 822–6\nMcEver R. Selectins. Curr Opin Immunol 1994; 6(1): 75–84\nMcEver RP, Moore KL, Cummings RD. Leukocyte trafficking mediated by selectin-carbohydrate interactions. J Biol Chem 1995; 270(19): 11025–8\nTedder TF, Steeber DA, Chen A, et al. The selectins: vascular adhesion molecules. FASEB J 1995; 9(10): 866–73\nRosen SD, Bertozzi CR. The selectins and their ligands. Curr Opin Cell Biol 1994; 6(5): 663–73\nLasky L, Presta L, Erbe D. Structure-function aspects of selectin-carbohydrate interactions. In: Metcalf B, Dalton B, Poste G, editors. Cellular adhesion: molecular definition to therapeutic potential. New York: Plenum Press, 1994: 37–53\nBertozzi C. Cracking the carbohydrate code for selectin recognition. Chem Biol 1995; 2(11): 703–8\nAigner S, Sthoeger Z, Fogel M, et al. CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood 1997; 89(9): 3385–95\nLawrence M. Selectin-carbohydrate interactions in shear flow. Curr Opin Chem Biol 1999; 3(6): 659–64\nLawrence MB, Kansas GS, Kunkel EJ, et al. Threshold levels of fluid shear promote leukocyte adhesion through selectins (CD62L,P,E). J Cell Biol 1997; 136(3): 717–27\nSlee D, Romano S, Yu J, et al. The development of potent non-carbohydrate imidazole-based small molecule selectin inhibitors with anti-inflammatory activity. J Med Chem 2001; 44(13): 2094–107\nOhmoto H, Nakamura K, Inoue T, et al. Studies on selectin blocker 1. structure-activity relationships of sialyl Lewis X analogs. J Med Chem 1996; 39(6): 1339–43\nFoxall C, Watson SR, Dowbenko D, et al. The three members of the selectin receptor family recognize a common carbohydrate epitope, the sialyl Lewis X oligosaccharide. J Cell Biol 1992; 117(4): 895–902\nKogan TP, Dupre B, Bui H, et al. Novel synthetic inhibitors of selectin-mediated cell adhesion: synthesis of 1,6-bis[3- (3-carboxymethylphenyl)-4- (2-cc-D-mannopyranosyloxy)phenyl]hexane (TBC1269). J Med Chem 1998; 41: 1099–111\nJenison R, Jennings S, Walker D, et al. Oligonucleotide inhibitors of P-selectin-dependent neutrophil-platelet adhesion. Antisense Nucleic Acid Drug Dev 1998; 8(4): 265–79\nSanders W, Gordon E, Dwir O, et al. Inhibition of L-selectin-mediated leukocyte rolling by synthetic glycoprotein mimics. J Biol Chem 1999; 274(9): 5271–8\nReinhardt P, Kubes P. Differential leukocyte recruitment from whole blood via endothelial adhesion molecules under shear conditions. Blood 1998; 92(12): 4691–9\nSriramarao P, Anderson W, Wolitzky B, et al. Mouse bone marrow-derived mast cells roll on P-selectin under conditions of flow in vivo. Lab Invest 1996; 74(3): 634–43\nLawrence M, Springer T. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell 1991; 65(5): 859–73\nWhelan J. Selectin synthesis and inflammation. Trends Biochem Sci 1996; 21(2): 65–9\nFrenette P, Wagner D. Insights into selectin function from knockout mice. Thromb Haemost 1997; 78(1): 60–4\nEtzioni A, Tonetti M. Leukocyte adhesion deficiency II-from A to almost Z. Immunol Rev 2000; 178: 138–47\nEtzioni A, Doerschuk C, Harlan J. Of man and mouse: leukocyte and endothelial adhesion molecule deficiencies. Blood 1999; 94(10): 3281–8\nvon-Andrian U, Berger E, Ramezani L, et al. In vivo behavior of neutrophils from two patients with distinct inherited leukocyte adhesion deficiency syndromes. J Clin Invest 1993; 91(6): 2893–7\nPrice T, Ochs H, Gershoni-Baruch R, et al. In vivo neutrophil and lymphocyte function studies in a patient with leukocyte adhesion deficiency type II. Blood 1994; 84(5): 1635–9\nFrenette P, Mayadas T, Rayburn H, et al. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell 1996; 84(4): 563–74\nMunoz F, Hawkins E, Bullard D, et al. Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E\u002FP-selectin deficient mice. J Clin Invest 1997; 100(8): 2099–106\nMaly P, Thall A, Petryniak B, et al. The α (l,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell 1996; 86: 643–53\nBerens K, Vanderslice P, Dupre B, et al. Selectin antagonists: therapeutics for airway inflammation. In: Hansel T, Barnes P, editors. New drugs for asthma, allergy and COPD. Vol. 31. Basel: Karger, 2001: 306–9\nWard P, Mulligan M, Vaporciyan A, et al. Adhesion molecules in experimental lung inflammatory injury. In: Ward P, Fantone J, editors. Adhesion molecules and the lung. Vol. 89. New York: Dekker, 1996: 159–76\nWard P, Mulligan M. Adhesion molecules in inflammatory lung injury. In: Paul L, Issekutz T, editors. Adhesion molecules in health and disease. New York: Dekker, 1997: 523–37\nDe Sanctis GT, Wolyniec WW, Green FHY, et al. Reduction of allergic airway responses in P-selectin-deficient mice. J Appl Physiol 1997; 83(3): 681–7\nBroide D, Sullivan S, Gifford T, et al. Inhibition of pulmonary eosinophilia in P-selectin and ICAM-1-deficient mice. Am J Respir Cell Mol Biol 1998; 18(2): 218–25\nFiscus L, Herpen JV, Steeber D, et al. L-Selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma. J Allergy Clin Immunol 2001; 107(6): 1019–24\nTang M, Fiscus L. Important roles for L-selectin and ICAM-1 in the development of allergic airway inflammation in asthma. Pulm Pharmacol Ther 2001; 14(3): 203–10\nAbraham W, Ahmed A, Sabater J, et al. Selectin blockade prevents antigen-induced late bronchial responses and airway hyperresponsiveness in allergic sheep. Am J Respir Crit Care Med 1999; 159(4): 1205–14\nGundel RH, Wegner CD, Torcellini CA, et al. Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase obstruction in monkeys. J Clin Invest 1991; 88(4): 1407–11\nDasgupta F. Selectin antagonists. In: Kahn M, editor. High throughput screening for novel anti-inflammatories. Basel: Birkhauser Verlag, 2000: 123–44\nRomano S, Slee D. Targeting selectins for the treatment of respiratory diseases. Curr Opin Investig Drugs 2001; 2(7): 907–13\nStewart A, Bhatia P, McCarty C, et al. Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells: 1. Selective inhibition of ICAM-1 and E-selectin expression. J Med Chem 2001; 44(6): 988–1002\nBennett F, Condon T, Grimm S, et al. Inhibition of endothelial cell adhesion molecule expression with antisense oligonucleotides. J Immunol 1994; 152(7): 3530–40\nHafezi-Moghadam A, Thomas K, Prorock A, et al. L-Selectin shedding regulates leukocyte recruitment. J Exp Med 2001; 193(7): 863–72\nDiaz-Gonzales F, Gonzales-Alvaro I, Campanero MR, et al. Prevention of in vitro neutrophil-endothelial attachment through shedding of L-selectin by non-ster-oidal antiinflammatory drugs. J Clin Invest 1995; 95(4): 1756–65\nTilton R, Berens K. Functional role for selectins in the pathogenesis of cerebral ischemia. Drug News Perspect 2002; 15(6): 351–7\nAydt E, Wolff G. Development of synthetic pan-selectin antagonists: a new treatment strategy for chronic inflammation in asthma. Pathobiol 2003; 70: 297–301\nSchlag G, Redl H, Till G, et al. Anti-L-selectin antibody treatment of hemorrhagic- traumatic shock in baboons. Crit Care Med 1999; 27(9): 1900–7\nKumar A, Villani M, Patel U, et al. Recombinant soluble form of PSGL-1 accelerates thrombolysis and prevents reocclusion in a porcine model. Circulation 1999; 99(10): 1363–9\nRidings P, Holloway S, Bloomfield G, et al. Protective role of synthetic sialylated oligosaccharide in sepsis-induced acute lung injury. J Appl Physiol 1997; 82(2): 644–51\nPark I, Lee D, Song M, et al. Cylexin: a P-selectin inhibitor prolongs heart allograft survival in hypersensitized rat recipients. Transplant Proc 1998; 30(7): 2927–8\nAlper J. Searching for medicine’s sweet spot. Science 2001; 291: 2338–43\nCytel Corporation halts clinical trial of Cylexin [company press release]. San Diego, 1999\nService R. After the fall. Science 2001; 291: 2340–1\nSeekamp A, van Griensven M, Dhondt E, et al. The effect of anti-L-selectin (aseulizumab) in multiple traumatized patients: results of a phase II clinical trial. Crit Care Med 2004; 32(10): 2021–8\nLorenz HM, Kalden JR. Perspectives for TNF-a-targeting therapies. Arthritis Res 2002; 4Suppl. 3: S17–24\nGraves BJ, Crowther RL, Chandran C, et al. Insight into E-selectin\u002Fligand interaction from the crystal structure and mutagenesis of the Lec\u002FEGF domains. Nature 1994; 367(6463): 532–8\nSomers W, Tang J, Shaw G, et al. Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P- and E-selectin bound to sLex and PSGL-1. Cell 2000; 103(3): 467–79\nPoppe L, Brown G, Philo J, et al. Conformation of sLex tetrasaccharide, free in solution and bound to E-, P-, and L-selectin. J Am Chem Soc 1997; 119: 1727–36\nNorman K, Anderson G, Kolb HC, et al. Sialyl Lewis X (sLex) and an sLex mimetic, CGP69669A, disrupt E-selectin-dependent leukocyte rolling in vivo. Blood 1998; 91(2): 475–83\nTodderud G, Nair X, Lee D, et al. BMS-190394, a selectin inhibitor, prevents rat cutaneous inflammatory reactions. J Pharmacol Exp Ther 1997; 282(3): 1298–304\nTsukida T, Moriyama H, Kurokawa K, et al. Studies on selectin blockers. 7. Structure-activity relationships of sialyl Lewis X mimetics based on modified Ser-Glu dipeptides. J Med Chem 1998; 41(22): 4279–87\nPradella L. TBC-1269: Texas Biotechnology Group. Curr Opin Anti-Inflamm Immunomod Invest Drugs 1999; 1(1): 56–60\nBeeh K-M, Beier J, Buhl R, et al. Influence of inhaled bimosiamose (TBC 1269) a synthetic pan-selectin antagonist, on the allergen-induced late asthmatic response (LAR) in patients with mild allergic asthma [abstract]. Am J Resp Crit Care Med 2004; 167(7): A321\nSlee D, Romano S, Yu J, et al. Development of potent non-carbohydrate small molecule selectin inhibitors. American Chemical Society 221 st National Meeting; 2001 Apr 1–5; San Diego\nRomano SJ, Slee DH, John JK, et al. OC 229-648, A novel, non-carbohydrate small molecule selectin inhibitor with anti-inflammatory activity [abstract]. Inflamm Res 2000; 49Suppl. 2: S90\nDouwes J, Gibson P, Pekkanen J, et al. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002; 57(7): 643–8\nGiembycz M. Are eosinophils out of asthma? Trends Pharmacol Sci 2001; 22(2): 61–2\nRogers D, Giembycz M. Asthma therapy for the 21st century. Trends Pharmacol Sci 1998; 19(5): 160–4\nAdcock I, Matthews J. New drugs for asthma. Drug Discov Today 1998; 3(9): 395–9\nLiebermann P. 57th AAAAI: novel drugs. IDrugs 2001; 4(6): 639–42\nPaterson D. Asthma: new drug targets and innovative therapeutics. SMi Conference. IDrugs 2001; 4(6): 646–9\nHenderson WJ, Chi E, Albert R, et al. Blockade of CD49d (α4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. J Clin Invest 1997; 100(12): 3083–92\nTexas Biotechnology Corp. Annual report. Houston (TX): Texas Biotechnology Corp., 1999\nHoyert D, Arias E, Smith B, et al. Deaths: final data for 1999. Natl Vital Stat Rep 2001; 49(8): 1–114\nVyas B. Severe asthma and COPD: the good, the bad and the ugly. IDrugs 2001; 4(9): 1002–4\nChavannes N, Schayck CV. Developments in the treatment of chronic obstructive pulmonary disease: the clinical picture. Curr Opin Investig Drugs 2000; 1(1): 75–8\nBarnes P. New treatments for COPD. Nat Rev Drug Discov 2002; 1(6): 437–46\nBarnes P. Mechanisms in COPD: differences from asthma. Chest 2000; 117 (2 Suppl.): 10S–4S\nMulligan M, Paulson J, DeFrees S, et al. Protective effects of oligosaccharides in P-selectin-dependent lung injury. Nature 1993; 364(6433): 149–51\nMulligan M, Watson S, Fennie C, et al. Protective effects of selectin chimeras in neutrophil-mediated lung injury. J Immunol 1993; 151(11): 6410–7\nDiStefano A, Maestrelli P, Roggeri A, et al. Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med 1994; 149 (3 Pt 1): 803–10\nWitt C, Schumacher A, Liebers U, et al. Comparative analysis of P-selectin glycoprotein ligand-1 (PSGL-1) expression on leukocytes from patients with allergic asthma, COPD, and smokers [abstract]. Am J Resp Crit Care Med 2004; 169(7): A840\nDavenpeck K, Berens K, Dixon R, et al. Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewis antagonist TBC1269: preferential activity against neutrophil adhesion in vitro. J Allergy Clin Immunol 2000; 105(4): 769–75\nEverts M, Kok R, Asgeirsdottir S, et al. Selective intracellular delivery of dexamethasone into activated endothelial cells using an E-selectin-directed immunoconjugate. 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