Idiopathic Pulmonary Fibrosis

Treatments in Respiratory Medicine - Tập 5 - Trang 325-342 - 2012
Jeffrey C. Horowitz1, Victor J. Thannickal1
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical Center, Ann Arbor, USA

Tóm tắt

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/TH2 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.

Tài liệu tham khảo

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 KingJr 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 American 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 Coultas DB, Zumwalt RE, Black WC, et al. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med 1994; 150(4): 967–72 Lama 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 Hanson 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 Flaherty 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 Gay 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 Nadrous HF, Pellikka PA, Krowka MJ, et al. Pulmonary hypertension in patients with idiopathic pulmonary fibrosis. Chest 2005; 128(4): 2393–9 Hunninghake 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 Kazerooni 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 Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003; 58(2): 143–8 Flaherty 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 Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157 (4 Pt 1): 1301–15 King 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 Katzenstein AL. Pathogenesis of ‘fibrosis’ in interstitial pneumonia: an electron microscopic study. Hum Pathol 1985; 16(10): 1015–24 Kasper M, Haroske G. Alterations in the alveolar epithelium after injury leading to pulmonary fibrosis. Histol Histopathol 1996; 11(2): 463–83 Chilosi 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 Kuwano 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 Stewart 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 Kelly 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 Tang 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 Procop 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 Baumgartner 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 Baumgartner 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 Lawson 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 Grutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J 2005; 25(5): 915–27 Whyte 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 Pantelidis 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 Xaubet 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 Katzenstein 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 Thannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med 2004; 55: 395–417 Martinez 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 Sutinen 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 Kawanami O, Ferrans VJ, Crystal RG. Structure of alveolar epithelial cells in patients with fibrotic lung disorders. Lab Invest 1982; 46(1): 39–53 Corrin B, Dewar A, Rodriguez-Roisin R, et al. Fine structural changes in cryptogenic fibrosing alveolitis and asbestosis. J Pathol 1985; 147(2): 107–19 Coalson JJ. The ultrastructure of human fibrosing alveolitis. Virchows Arch A Pathol Anat Histol 1982; 395(2): 181–99 Xu 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 Kuwano K, Kunitake R, Kawasaki M, et al. P21Wafl/Cipl/Sdil 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 Uhal 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 Barbas-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 Maeyama 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 Plataki 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 Wang 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 Kuwano 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 Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med 2000; 342(18): 1350–8 Lee 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 Cantin AM, North SL, Fells GA, et al. Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis. J Clin Invest 1987; 79(6): 1665–73 Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 2000; 279(6): L1005–28 Thannickal 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 Thannickal 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 Waghray 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 Hagimoto 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 Kuwano 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 Aoshiba K, Yasui S, Tamaoki J, et al. The Fas/Fas-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 Uhal 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 Wang 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 Papp 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 Li 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 Otsuka 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 Shiratori 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 Inoue 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 5/6 nephrectomized mice. FASEB J 2003; 17(2): 268–70 Lazar 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 Mizuno 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 Marchand-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 Dworkin 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 Dohi 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 Taniyama 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 Nagahori T, Dohi M, Matsumoto K, et al. Interferon-gamma upregulates the c-Met/ hepatocyte growth factor receptor expression in alveolar epithelial cells. Am J Respir Cell Mol Biol 1999; 21(4): 490–7 Rubin 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 Finch 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 Deterding 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 Zhang 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 Deterding 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 Marchand-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 Christensen 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 Eitzman 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 Sisson 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 Hattori N, Degen JL, Sisson TH, et al. Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 2000; 106(11): 1341–50 Sisson 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 Chan 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 Legrand C, Polette M, Tournier JM, et al. uPA/plasmin system-mediated MMP-9 activation is implicated in bronchial epithelial cell migration. Exp Cell Res 2001; 264(2): 326–36 Bitterman 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 Lama 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 White 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 Kolodsick 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 Goldstein 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 Keerthisingam 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 Peters-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 Borok 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 Wilborn 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 Krause 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 Kotton DN, Ma BY, Cardoso WV, et al. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 2001; 128(24): 5181–8 Kotton DN, Fabian AJ, Mulligan RC. Failure of bone marrow to reconstitute lung epithelium. Am J Respir Cell Mol Biol 2005; 33(4): 328–34 Grove 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 Willis 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 Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 2005; 13(1): 7–12 Kuhn 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 Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999; 341(10): 738–46 Tomasek 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 Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 2003; 200(4): 500–3 Phan SH. The myofibroblast in pulmonary fibrosis. Chest 2002; 122 (6 Suppl.): 286S–9S Phillips 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 Moore 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 Hashimoto N, Jin H, Liu T, et al. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 2004; 113(2): 243–52 Yao HW, Xie QM, Chen JQ, et al. TGF-beta1 induces alveolar epithelial to mesenchymal transition in vitro. Life Sci 2004; 76(1): 29–37 Kasai H, Allen JT, Mason RM, et al. TGF-beta1induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res 2005; 6(1): 56 Desmouliere 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 Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331(19): 1286–92 Chapman HA. Disorders of lung matrix remodeling. J Clin Invest 2004; 113(2): 148–57 Sime 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 Kolb 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 Kolb 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 Horowitz JC, Lee DY, Waghray M, et al. Activation of the pro-survival phosphatidylinositol 3-kinase/AKT 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 Zhang HY, Phan SH. Inhibition of myofibroblast apoptosis by transforming growth factor beta (1). Am J Respir Cell Mol Biol 1999; 21(6): 658–65 Sun G, Stacey MA, Bellini A, et al. Endothelin-1 induces bronchial myofibroblast differentiation. Peptides 1997; 18(9): 1449–51 Bogatkevich 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 Morishima 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 Marshall 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 Nguyen 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 Ketteler 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 Campbell 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 Serini 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 Hinz 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 Arora 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 Zhu 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 Thannickal 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 Uhal 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 Larios 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 Phan SH, Zhang K, Zhang HY, et al. The myofibroblast as an inflammatory cell in pulmonary fibrosis. Curr Top Pathol 1999; 93: 173–82 Strieter 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 Rolfe 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 Strieter 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 Crystal 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 Mason 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 Selman 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 Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 2001; 345(7): 517–25 Zuo 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 Agostini C, Siviero M, Semenzato G. Immune effector cells in idiopathic pulmonary fibrosis. Curr Opin Pulm Med 1997; 3(5): 348–55 Kelly M, Kolb M, Bonniaud P, et al. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des 2003; 9(1): 39–49 Lukacs NW, Hogaboam C, Chensue W, et al. Type I/type 2 cytokine paradigm and the progression of pulmonary fibrosis. Chest 2001; 120 (1 Suppl.): 5S–8S Wynn TA. Fibrotic disease and the T (H)1/T (H)2 paradigm. Nat Rev Immunol 2004; 4(8): 583–94 Jakubzick 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 Cavarra 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 Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: searching for model answers. Am J Respir Cell Mol Biol 2005; 33(1): 9–13 Helene M, Lake-Bullock V, Zhu J, et al. T cell independence of bleomycin-induced pulmonary fibrosis. J Leukoc Biol 1999; 65(2): 187–95 Okazaki T, Nakao A, Nakano H, et al. Impairment of bleomycin-induced lung fibrosis in CD28-deficient mice. J Immunol 2001; 167(4): 1977–81 Jakubzick 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 Jakubzick 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 Peao 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 Turner-Warwick M. Precapillary systemic-pulmonary anastomoses. Thorax 1963; 18: 225–37 Simler NR, Brenchley PE, Horrocks AW, et al. Angiogenic cytokines in patients with idiopathic interstitial pneumonia. Thorax 2004; 59(7): 581–5 Keane 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 Keane 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 Keane 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 Keane 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 Burdick 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 Tager AM, Kradin RL, LaCamera P, et al. Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL 10. Am J Respir Cell Mol Biol 2004; 31(4): 395–404 Renzoni EA, Walsh DA, Salmon M, et al. Interstitial vascularity in fibrosing alveolitis. Am J Respir Crit Care Med 2003; 167(3): 438–43 Cosgrove 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 Sumi 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 Beer TW, Baldwin HC, Goddard JR, et al. Angiogenesis in pathological and surgical scars. Hum Pathol 1998; 29(11): 1273–8 Weitzenblum E, Ehrhart M, Rasaholinjanahary J, et al. Pulmonary hemodynamics in idiopathic pulmonary fibrosis and other interstitial pulmonary diseases. Respiration 1983; 44(2): 118–27 Agusti 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 Parambil 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 Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347(5): 322–9 Ghofrani 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 CoTherix. Inhaled iloprost in adults with abnormal pulmonary pressure and associated with idiopathic pulmonary fibrosis [online]. Available from URL: http://www.clinicaltrials.gov/ct/gui/show/NCTOO109681. [Accessed 2006 Jul 12] Douglas 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 Lynch III JP, White E, Flaherty K. Corticosteroids in idiopathic pulmonary fibrosis. Curr Opin Pulm Med 2001; 7(5): 298–308 Ryu JH, Myers JL, Capizzi SA, et al. Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 2005; 127(1): 178–84 Deheinzelin 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 Nicholson 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 Bouros 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 Dheda 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 Clark 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 Narayanan 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 Jaffe 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 Adelmann-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 Strieter 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 Hunninghake 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 Elias 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 Moseley 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 Hasegawa 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 Oldroyd SD, Thomas GL, Gabbiani G, et al. Interferon-gamma inhibits experimental renal fibrosis. Kidney Int 1999; 56(6): 2116–27 Gurujeyalakshmi 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 Weng 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 Ziesche 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 Raghu 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 InterMune 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://www.inspiretrial.com [Accessed 2006 Jul 12] Nicod LP. Pirfenidone in idiopathic pulmonary fibrosis. Lancet 1999; 354(9175): 268–9 Shihab 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 Iyer 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 Kakugawa 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 Giri 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 Misra HP, Rabideau C. Pirfenidone inhibits NADPH-dependent microsomal lipid peroxidation and scavenges hydroxyl radicals. Mol Cell Biochem 2000; 204(1-2): 119–26 Garcia L, Hernandez I, Sandoval A, et al. Pirfenidone effectively reverses experimental liver fibrosis. J Hepatol 2002; 37(6): 797–805 Suga 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 Shimizu 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 Angulo P, MacCarty RL, Sylvestre PB, et al. Pirfenidone in the treatment of primary sclerosing cholangitis. Dig Dis Sci 2002; 47(1): 157–61 Iyer 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 Kehrer JP, Margolin SB. Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice. Toxicol Lett 1997; 90(2-3): 125–32 Raghu 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 Gahl 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 Azuma 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 Charbeneau RP, Peters-Golden M. Eicosanoids: mediators and therapeutic targets in fibrotic lung disease. Clin Sci (Lond) 2005; 108(6): 479–91 Mio 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 Moore BB, Peters-Golden M, Christensen PJ, et al. Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE 2. Am J Physiol Lung Cell Mol Physiol 2003; 284(2): L342–9 Moore 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 Moore 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 US National Institutes of Health. Zileuton for the treatment of idiopathic pulmonary fibrosis [online]. Available from URL: http://www.clinicaltrials.gov/at/gui/show/NCT00262405 [Accessed 2006 Jul 12] Zhang 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 Piguet 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 Libura 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 Riha RL, Yang IA, Rabnott GC, et al. Cytokine gene polymorphisms in idiopathic pulmonary fibrosis. Intern Med J 2004; 34(3): 126–9 Miyazaki 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 Sime 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 Ortiz 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 Piguet 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 Siwik 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 Solis-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 Kahari 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 Greenwel P, Tanaka S, Penkov D, et al. Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins. Mol Cell Biol 2000; 20(3): 912–8 Han 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 Han 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 Kuroki M, Noguchi Y, Shimono M, et al. Repression of bleomycin-induced pneumopathy by TNF. J Immunol 2003; 170(1): 567–74 Fujita 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 Raghu 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 Kinnula 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 Cantin 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 Smilkstein 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 Tepel 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 Cantin AM, Larivee P, Begin RO. Extracellular glutathione suppresses human lung fibroblast proliferation. Am J Respir Cell Mol Biol 1990; 3(1): 79–85 Borok 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 Meyer 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 Meyer 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 Behr 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 Tomioka H, Kuwata Y, Imanaka K, et al. A pilot study of aerosolized N-acetylcysteine for idiopathic pulmonary fibrosis. Respirology 2005; 10(4): 449–55 Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005; 353(21): 2229–42 Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005; 353(21): 2285–7 Brewer 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 Brewer GJ. Copper control as an antiangiogenic anticancer therapy: lessons from treating Wilson’s disease. Exp Biol Med (Maywood) 2001; 226(7): 665–73 Brewer GJ. Tetrathiomolybdate anticopper therapy for Wilson’s disease inhibits angiogenesis, fibrosis and inflammation. J Cell Mol Med 2003; 7(1): 11–20 Brewer 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 US National Institutes of Health. Safety study of tetrathiomolybdate in patients with idiopathic pulmonary fibrosis [online]. Available from URL: http://www.clinicaltrials.gov/at/gui/show/NCT00189176 [Accessed 2006 Jul 12] Ehrenreich 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 Shahar 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 Goto 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 Shi-Wen X, Chen Y, Denton CP, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 2004; 15(6): 2707–19 Xu SW, Howat SL, Renzoni EA, et al. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem 2004; 279(22): 23098–103 Hocher 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 Park 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 Mutsaers 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 Giaid 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 Saleh 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 Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346(12): 896–903 BUILD program with bosentan: media release [online]. Available from URL: http://www.actelion.com/uninet/www/www_main_p.nsf/content/me+28+Nov+2005 [Accessed 2006 Jul 27] Broekelmann 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 Khalil 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 Bonniaud 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 Bonniaud 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 Chen 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 Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000; 103(2): 295–309 Goldman JM, Melo JV. Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344(14): 1084–6 Daniels 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 Aono 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 Abdollahi 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 Frisch 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 Hadden 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 Xia H, Nho RS, Kahm J, et al. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt 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 Vittal 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 Olson JM, Hallahan AR. p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med 2004; 10(3): 125–9 Yamaguchi 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 Takekawa 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 Khalil 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 Matsuoka 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 Underwood 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 Nadrous 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 Leask 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 Lasky 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 Bonniaud 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 Pan 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