NF-kappaB Signaling in Chronic Inflammatory Airway Disease

Biomolecules - Tập 5 Số 3 - Trang 1266-1283
Michael Schuliga1
1Lung Health Research Centre (LHRC), Department Pharmacology and Therapeutics, University of Melbourne, Grattan St., Parkville 3010, Victoria, Australia.

Tóm tắt

Asthma and chronic obstructive pulmonary disease (COPD) are obstructive airway disorders which differ in their underlying causes and phenotypes but overlap in patterns of pharmacological treatments. In both asthma and COPD, oxidative stress contributes to airway inflammation by inducing inflammatory gene expression. The redox-sensitive transcription factor, nuclear factor (NF)-kappaB (NF-κB), is an important participant in a broad spectrum of inflammatory networks that regulate cytokine activity in airway pathology. The anti-inflammatory actions of glucocorticoids (GCs), a mainstay treatment for asthma, involve inhibition of NF-κB induced gene transcription. Ligand bound GC receptors (GRs) bind NF-κB to suppress the transcription of NF-κB responsive genes (i.e., transrepression). However, in severe asthma and COPD, the transrepression of NF-κB by GCs is negated as a consequence of post-translational changes to GR and histones involved in chromatin remodeling. Therapeutics which target NF-κB activation, including inhibitors of IκB kinases (IKKs) are potential treatments for asthma and COPD. Furthermore, reversing GR/histone acetylation shows promise as a strategy to treat steroid refractory airway disease by augmenting NF-κB transrepression. This review examines NF-κB signaling in airway inflammation and its potential as target for treatment of asthma and COPD.

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Tài liệu tham khảo

WHO (2007). Global Surveillance, Prevention and Control of Chronic Respiratory Diseases: A Comprehensive Approach, WHO.

Decramer, 2012, Chronic obstructive pulmonary disease, Lancet, 379, 1341, 10.1016/S0140-6736(11)60968-9

Ambrosino, 2012, The management of asthma and chronic obstructive pulmonary disease: Current status and future perspectives, Expert Rev. Respir. Med., 6, 117, 10.1586/ers.12.2

Tetley, 2005, Inflammatory cells and chronic obstructive pulmonary disease, Curr. Drug Targets Inflamm. Allergy, 4, 607, 10.2174/156801005774912824

Tubby, 2011, Immunological basis of reversible and fixed airways disease, Clin. Sci., 121, 285, 10.1042/CS20110062

Papiris, S.A., Kollintza, A., Karatza, M., Manali, E.D., Sotiropoulou, C., Milic-Emili, J., Roussos, C., and Daniil, Z. (2007). CD8+ T lymphocytes in bronchoalveolar lavage in idiopathic pulmonary fibrosis. J. Inflamm.

Durham, 2011, Steroid resistance in severe asthma: Current mechanisms and future treatment, Curr. Pharm. Des., 17, 674, 10.2174/138161211795428984

Salter, 2007, Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease, Am. J. Physiol. Lung Cell. Mol. Physiol., 293, L660, 10.1152/ajplung.00108.2007

Ghosh, 1998, NF-κB and Rel proteins: Evolutionarily conserved mediators of immune responses, Annu. Rev. Immunol., 16, 225, 10.1146/annurev.immunol.16.1.225

Hinz, 2014, The IκB kinase complex in NF-κB regulation and beyond, EMBO Rep., 15, 46, 10.1002/embr.201337983

Panettieri, 2011, Airway smooth muscle and immunomodulation in acute exacerbations of airway disease, Immunol. Rev., 242, 178, 10.1111/j.1600-065X.2011.01022.x

Ward, 2008, Proliferation is not increased in airway myofibroblasts isolated from asthmatics, Eur. Respir. J., 32, 362, 10.1183/09031936.00119307

Flavell, 2008, Fibroblasts as novel therapeutic targets in chronic inflammation, Br. J. Pharmacol., 153, S241, 10.1038/sj.bjp.0707487

Li, 2011, Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension, J. Immunol., 187, 2711, 10.4049/jimmunol.1100479

Edwards, 2009, Targeting the NF-κB pathway in asthma and chronic obstructive pulmonary disease, Pharmacol. Ther., 121, 1, 10.1016/j.pharmthera.2008.09.003

Rajendrasozhan, 2008, Deacetylases and NF-κB in redox regulation of cigarette smoke-induced lung inflammation: Epigenetics in pathogenesis of COPD, Antioxid. Redox Signal., 10, 799, 10.1089/ars.2007.1938

Barnes, 1998, Anti-inflammatory actions of glucocorticoids: Molecular mechanisms, Clin. Sci., 94, 557, 10.1042/cs0940557

Kagoshima, 2003, Glucocorticoid suppression of nuclear factor-κB: A role for histone modifications, Biochem. Soc. Trans., 31, 60, 10.1042/bst0310060

Adcock, 2005, Histone deacetylation: An important mechanism in inflammatory lung diseases, COPD, 2, 445, 10.1080/15412550500346683

To, T., Stanojevic, S., Moores, G., Gershon, A.S., Bateman, E.D., Cruz, A.A., and Boulet, L.P. (2012). Global asthma prevalence in adults: Findings from the cross-sectional world health survey. BMC Public Health.

Buist, 2007, International variation in the prevalence of COPD (the BOLD Study): A population-based prevalence study, Lancet, 370, 741, 10.1016/S0140-6736(07)61377-4

Brusselle, 2014, Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease, Ann. Am. Thorac. Soc., 11, S322, 10.1513/AnnalsATS.201403-118AW

Hart, 1998, Activation and localization of transcription factor, nuclear factor-κB, in asthma, Am. J. Respir. Crit. Care Med., 158, 1585, 10.1164/ajrccm.158.5.9706116

Gagliardo, 2003, Persistent activation of nuclear factor-κB signaling pathway in severe uncontrolled asthma, Am. J. Respir. Crit. Care Med., 168, 1190, 10.1164/rccm.200205-479OC

Tully, 2013, Epithelial NF-κB orchestrates house dust mite-induced airway inflammation, hyperresponsiveness, and fibrotic remodeling, J. Immunol., 191, 5811, 10.4049/jimmunol.1301329

Poynter, 2004, NF-κB activation in airways modulates allergic inflammation but not hyperresponsiveness, J. Immunol., 173, 7003, 10.4049/jimmunol.173.11.7003

Poynter, 2002, Rapid activation of nuclear factor-κB in airway epithelium in a murine model of allergic airway inflammation, Am. J. Pathol., 160, 1325, 10.1016/S0002-9440(10)62559-X

Poynter, 2003, A prominent role for airway epithelial NF-κB activation in lipopolysaccharide-induced airway inflammation, J. Immunol., 170, 6257, 10.4049/jimmunol.170.12.6257

Quinton, 2007, Functions and regulation of NF-κB RelA during pneumococcal pneumonia, J. Immunol., 178, 1896, 10.4049/jimmunol.178.3.1896

Donovan, 1999, NF-κB/Rel transcription factors: c-Rel Promotes airway hyperresponsiveness and allergic pulmonary inflammation, J. Immunol., 163, 6827, 10.4049/jimmunol.163.12.6827

Li, 2014, Ovalbumin-induced experimental allergic asthma is Toll-like receptor 2 dependent, Allergy Asthma Proc., 35, e15, 10.2500/aap.2014.35.3735

Lam, 2008, Airway house dust extract exposures modify allergen-induced airway hypersensitivity responses by TLR4-dependent and independent pathways, J. Immunol., 181, 2925, 10.4049/jimmunol.181.4.2925

Wilson, 2001, Effects of budesonide and formoterol on NF-κB, adhesion molecules, and cytokines in asthma, Am. J. Respir. Crit. Care Med., 164, 1047, 10.1164/ajrccm.164.6.2010045

Hancox, 1999, Effects of inhaled beta agonist and corticosteroid treatment on nuclear transcription factors in bronchial mucosa in asthma, Thorax, 54, 488, 10.1136/thx.54.6.488

Hart, 2000, Effects of inhaled corticosteroid therapy on expression and DNA-binding activity of nuclear factor kappaB in asthma, Am. J. Respir. Crit. Care Med., 161, 224, 10.1164/ajrccm.161.1.9809019

Caramori, 2002, Increased expression of nuclear factor-κB in bronchial biopsies from smokers and patients with COPD, Eur. Respir. J., 20, 556, 10.1183/09031936.02.00272002

Caramori, 2003, Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations, Thorax, 58, 348, 10.1136/thorax.58.4.348

Szulakowski, 2006, The effect of smoking on the transcriptional regulation of lung inflammation in patients with chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care Med., 174, 41, 10.1164/rccm.200505-725OC

Gagliardo, 2011, IκB kinase-driven nuclear factor-κB activation in patients with asthma and chronic obstructive pulmonary disease, J. Allergy Clin. Immunol., 128, 635.e2, 10.1016/j.jaci.2011.03.045

Brown, V., Elborn, J.S., Bradley, J., and Ennis, M. (2009). Dysregulated apoptosis and NFκB expression in COPD subjects. Respir. Res.

Yang, 2009, RelB is differentially regulated by IκB Kinase-α in B cells and mouse lung by cigarette smoke, Am. J. Respir. Cell Mol. Biol., 40, 147, 10.1165/rcmb.2008-0207OC

Li, Y.T., He, B., Wang, Y.Z., and Wang, J. (2009). Effects of intratracheal administration of nuclear factor-κB decoy oligodeoxynucleotides on long-term cigarette smoke-induced lung inflammation and pathology in mice. Respir. Res.

Rajendrasozhan, 2010, Anti-inflammatory effect of a selective IκB kinase-beta inhibitor in rat lung in response to LPS and cigarette smoke, Pulm. Pharmacol. Ther., 23, 172, 10.1016/j.pupt.2010.01.002

Rastrick, 2013, Cigarette smoke induced airway inflammation is independent of NF-κB signalling, PLoS ONE, 8, e54128, 10.1371/journal.pone.0054128

Yao, 2008, Cigarette smoke-mediated inflammatory and oxidative responses are strain-dependent in mice, Am. J. Physiol. Lung Cell. Mol. Physiol., 294, L1174, 10.1152/ajplung.00439.2007

Das, 2001, A critical role for NF-κB in GATA3 expression and TH2 differentiation in allergic airway inflammation, Nat. Immunol., 2, 45, 10.1038/83158

Coward, 2004, Allergen activates peripheral blood eosinophil nuclear factor-κB to generate granulocyte macrophage-colony stimulating factor, tumour necrosis factor-α and interleukin-8, Clin. Exp. Allergy, 34, 1071, 10.1111/j.1365-2222.2004.02003.x

Wong, 2006, Induction of adhesion molecules upon the interaction between eosinophils and bronchial epithelial cells: Involvement of p38 MAPK and NF-κB, Int. Immunopharmacol., 6, 1859, 10.1016/j.intimp.2006.08.003

Langereis, 2010, Abrogation of NF-κB signaling in human neutrophils induces neutrophil survival through sustained p38-MAPK activation, J. Leukoc. Biol., 88, 655, 10.1189/jlb.0809544

Murugan, 2009, Signal transduction pathways linking the activation of alveolar macrophages with the recruitment of neutrophils to lungs in chronic obstructive pulmonary disease, Exp. Lung Res., 35, 439, 10.1080/01902140902759290

Yang, 2006, Cigarette smoke induces proinflammatory cytokine release by activation of NF-κB and posttranslational modifications of histone deacetylase in macrophages, Am. J. Physiol. Lung Cell. Mol. Physiol., 291, L46, 10.1152/ajplung.00241.2005

Lee, 2007, Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFκB, Proc. Natl. Acad. Sci. USA, 104, 914, 10.1073/pnas.0607305104

Newton, 2007, Repression of inflammatory gene expression in human pulmonary epithelial cells by small-molecule IκB kinase inhibitors, J. Pharmacol. Exp. Ther., 321, 734, 10.1124/jpet.106.118125

Shimizu, 2012, Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-κB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma, Clin. Exp. Allergy, 42, 1273, 10.1111/j.1365-2222.2012.04007.x

Cao, 2011, Bronchial epithelial cells release IL-6, CXCL1 and CXCL8 upon mast cell interaction, Cytokine, 56, 823, 10.1016/j.cyto.2011.09.016

Redhu, 2011, Essential role of NF-κB and AP-1 transcription factors in TNF-α-induced TSLP expression in human airway smooth muscle cells, Am. J. Physiol. Lung Cell. Mol. Physiol., 300, L479, 10.1152/ajplung.00301.2009

Tirumurugaan, K.G., Kang, B.N., Panettieri, R.A., Foster, D.N., Walseth, T.F., and Kannan, M.S. (2008). Regulation of the CD38 promoter in human airway smooth muscle cells by TNF-α and dexamethasone. Respir. Res.

Lee, 2006, Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in human tracheal smooth muscle cells: Involvement of MAPKs, NF-κB, p300, and histone acetylation, J. Cell. Physiol., 207, 174, 10.1002/jcp.20549

Catley, 2006, Validation of the anti-inflammatory properties of small-molecule IκB Kinase (IKK)-2 inhibitors by comparison with adenoviral-mediated delivery of dominant-negative IKK1 and IKK2 in human airways smooth muscle, Mol. Pharmacol., 70, 697, 10.1124/mol.106.023150

John, 2009, Human airway smooth muscle cells from asthmatic individuals have CXCL8 hypersecretion due to increased NF-κB p65, C/EBP β, and RNA polymerase II binding to the CXCL8 promoter, J. Immunol., 183, 4682, 10.4049/jimmunol.0803832

Alrashdan, 2012, Asthmatic airway smooth muscle CXCL10 production: Mitogen-activated protein kinase JNK involvement, Am. J. Physiol. Lung Cell. Mol. Physiol., 302, L1118, 10.1152/ajplung.00232.2011

Gras, 2013, Bronchial epithelium as a target for innovative treatments in asthma, Pharmacol. Ther., 140, 290, 10.1016/j.pharmthera.2013.07.008

Clarke, 2010, TNFα and IFNγ synergistically enhance transcriptional activation of CXCL10 in human airway smooth muscle cells via STAT-1, NF-κB, and the transcriptional coactivator CREB-binding protein, J. Biol. Chem., 285, 29101, 10.1074/jbc.M109.099952

Pelaia, G., Vatrella, A., Busceti, M.T., Gallelli, L., Calabrese, C., Terracciano, R., and Maselli, R. (2015). Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediat. Inflamm.

Brusselle, 2013, Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma, Nat. Med., 19, 977, 10.1038/nm.3300

Chien, 2013, Increased IL-17A secreting CD4+ T cells, serum IL-17 levels and exhaled nitric oxide are correlated with childhood asthma severity, Clin. Exp. Allergy, 43, 1018, 10.1111/cea.12119

Chesne, 2014, IL-17 in severe asthma. Where do we stand?, Am. J. Respir. Crit. Care Med., 190, 1094, 10.1164/rccm.201405-0859PP

Fujisawa, 2011, NF-κB mediates IL-1β- and IL-17A-induced MUC5B expression in airway epithelial cells, Am. J. Respir. Cell Mol. Biol., 45, 246, 10.1165/rcmb.2009-0313OC

Dragon, 2014, IL-17A mediates a selective gene expression profile in asthmatic human airway smooth muscle cells, Am. J. Respir. Cell Mol. Biol., 50, 1053, 10.1165/rcmb.2012-0267OC

Chang, 2012, Th17-associated cytokines promote human airway smooth muscle cell proliferation, FASEB J., 26, 5152, 10.1096/fj.12-208033

Kankaanranta, 2014, Tumour necrosis factor-α regulates human eosinophil apoptosis via ligation of TNF-receptor 1 and balance between NF-κB and AP-1, PLoS ONE, 9, e90298, 10.1371/journal.pone.0090298

Ordonez, 2000, Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance, Am. J. Respir. Crit. Care Med., 161, 1185, 10.1164/ajrccm.161.4.9812061

Nakagome, 2012, Neutrophilic inflammation in severe asthma, Int. Arch. Allergy Immunol., 158, 96, 10.1159/000337801

Pappas, 2013, The role of macrophages in obstructive airways disease: Chronic obstructive pulmonary disease and asthma, Cytokine, 64, 613, 10.1016/j.cyto.2013.09.010

Cundall, 2003, Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids, J. Allergy Clin. Immunol., 112, 1064, 10.1016/j.jaci.2003.08.013

Wang, 2005, Induction of IL-6 in co-culture of bronchial epithelial cells and eosinophils is regulated by p38 MAPK and NF-κB, Allergy, 60, 1378, 10.1111/j.1398-9995.2005.00884.x

Kang, 2015, S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC5AC via extracellular signal-regulated kinase and nuclear factor-κB pathways, Immunology, 144, 79, 10.1111/imm.12352

James, 2007, Clinical relevance of airway remodelling in airway diseases, Eur. Respir. J., 30, 134, 10.1183/09031936.00146905

Amin, 2000, Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group, Am. J. Respir. Crit. Care Med., 162, 2295, 10.1164/ajrccm.162.6.9912001

Gosselink, 2010, Differential expression of tissue repair genes in the pathogenesis of chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care Med., 181, 1329, 10.1164/rccm.200812-1902OC

Xia, 2013, Pro-inflammatory and immunomodulatory functions of airway smooth muscle: Emerging concepts, Pulm. Pharmacol. Ther., 26, 64, 10.1016/j.pupt.2012.05.006

Tran, 2005, Stimulus-dependent glucocorticoid-resistance of GM-CSF production in human cultured airway smooth muscle, Br. J. Pharmacol., 145, 123, 10.1038/sj.bjp.0706174

Keenan, 2012, Glucocorticoid-resistant asthma and novel anti-inflammatory drugs, Drug Discov. Today, 17, 1031, 10.1016/j.drudis.2012.05.011

Salem, 2012, Transforming growth factor-β impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line, Br. J. Pharmacol., 166, 2036, 10.1111/j.1476-5381.2012.01885.x

Langenbach, 2007, Resistance of fibrogenic responses to glucocorticoid and 2-methoxyestradiol in bleomycin-induced lung fibrosis in mice, Can. J. Physiol. Pharmacol., 85, 727, 10.1139/Y07-065

Bonacci, 2006, Collagen impairs glucocorticoid actions in airway smooth muscle through integrin signalling, Br. J. Pharmacol., 149, 365, 10.1038/sj.bjp.0706881

Barnes, 2013, Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease, J. Allergy Clin. Immunol., 131, 636, 10.1016/j.jaci.2012.12.1564

Adcock, 2005, Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response, Antioxid. Redox Signal., 7, 144, 10.1089/ars.2005.7.144

Kagoshima, 2001, Glucocorticoid-mediated transrepression is regulated by histone acetylation and DNA methylation, Eur. J. Pharmacol., 429, 327, 10.1016/S0014-2999(01)01332-2

Ito, 2006, Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression, J. Exp. Med., 203, 7, 10.1084/jem.20050466

Rajendrasozhan, 2008, SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care Med., 177, 861, 10.1164/rccm.200708-1269OC

Chen, 2014, SIRT4 inhibits cigarette smoke extracts-induced mononuclear cell adhesion to human pulmonary microvascular endothelial cells via regulating NF-κB activity, Toxicol. Lett., 226, 320, 10.1016/j.toxlet.2014.02.022

Keenan, 2015, Pro-inflammatory mediators increase levels of the noncoding RNA GAS5 in airway smooth muscle and epithelial cells, Can. J. Physiol. Pharmacol., 93, 203, 10.1139/cjpp-2014-0391

Eddleston, 2007, The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells, J. Allergy Clin. Immunol., 119, 115, 10.1016/j.jaci.2006.08.027

Ayroldi, 2001, Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor κB, Blood, 98, 743, 10.1182/blood.V98.3.743

Che, 2012, Sphingosine 1-phosphate induces MKP-1 expression via p38 MAPK- and CREB-mediated pathways in airway smooth muscle cells, Biochim. Biophys. Acta, 1823, 1658, 10.1016/j.bbamcr.2012.06.011

Manetsch, 2012, MKP-1: A negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells, Cell Signal., 24, 907, 10.1016/j.cellsig.2011.12.013

King, 2009, Inhibition of NF-κB-dependent transcription by MKP-1: Transcriptional repression by glucocorticoids occurring via p38 MAPK, J. Biol. Chem., 284, 26803, 10.1074/jbc.M109.028381

Ziegelbauer, 2005, A selective novel low-molecular-weight inhibitor of IκB kinase-β (IKK-β) prevents pulmonary inflammation and shows broad anti-inflammatory activity, Br. J. Pharmacol., 145, 178, 10.1038/sj.bjp.0706176

Sugita, 2009, Antiallergic and anti-inflammatory effects of a novel IκB kinase beta inhibitor, IMD-0354, in a mouse model of allergic inflammation, Int. Arch. Allergy Immunol., 148, 186, 10.1159/000161579

Ogawa, 2011, IκB kinase beta inhibitor IMD-0354 suppresses airway remodelling in a Dermatophagoides pteronyssinus-sensitized mouse model of chronic asthma, Clin. Exp. Allergy, 41, 104, 10.1111/j.1365-2222.2010.03564.x

Sommers, 2009, Novel tight-binding inhibitory factor-κB kinase (IKK-2) inhibitors demonstrate target-specific anti-inflammatory activities in cellular assays and following oral and local delivery in an in vivo model of airway inflammation, J. Pharmacol. Exp. Ther., 330, 377, 10.1124/jpet.108.147538

Kobayashi, 2013, A novel macrolide/fluoroketolide, solithromycin (CEM-101), reverses corticosteroid insensitivity via phosphoinositide 3-kinase pathway inhibition, Br. J. Pharmacol., 169, 1024, 10.1111/bph.12187

To, 2010, Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care Med., 182, 897, 10.1164/rccm.200906-0937OC

Mercado, 2011, Nortriptyline reverses corticosteroid insensitivity by inhibition of phosphoinositide-3-kinase-delta, J. Pharmacol. Exp. Ther., 337, 465, 10.1124/jpet.110.175950

Rossios, 2012, Corticosteroid insensitivity is reversed by formoterol via phosphoinositide-3-kinase inhibition, Br. J. Pharmacol., 167, 775, 10.1111/j.1476-5381.2012.01864.x

Kobayashi, 2013, A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-κB inhibition, J. Pharmacol. Exp. Ther., 345, 76, 10.1124/jpet.112.200733

Li, 2012, Effect of erythromycin on cigarette-induced histone deacetylase protein expression and nuclear factor-κB activity in human macrophages in vitro, Int. Immunopharmacol., 12, 643, 10.1016/j.intimp.2011.12.022

Lee, 2006, Phosphoinositide 3-kinase-delta inhibitor reduces vascular permeability in a murine model of asthma, J. Allergy Clin. Immunol., 118, 403, 10.1016/j.jaci.2006.04.041

Collison, 2013, Inhibiting AKT phosphorylation employing non-cytotoxic anthraquinones ameliorates TH2 mediated allergic airways disease and rhinovirus exacerbation, PLoS ONE, 8, e79565, 10.1371/journal.pone.0079565

Choi, 2013, Inhibition of protein kinase C delta attenuates allergic airway inflammation through suppression of PI3K/Akt/mTOR/HIF-1 alpha/VEGF pathway, PLoS ONE, 8, e81773, 10.1371/journal.pone.0081773

Kim, 2010, Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease, J. Allergy Clin. Immunol., 125, 449.e14, 10.1016/j.jaci.2009.08.009

Chen, 2015, Therapeutic effects of resveratrol in a mouse model of HDM-induced allergic asthma, Int. Immunopharmacol., 25, 43, 10.1016/j.intimp.2015.01.013

Ichikawa, 2013, Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma, Respirology, 18, 332, 10.1111/j.1440-1843.2012.02284.x

Royce, S.G., Dang, W., Yuan, G., Tran, J., el Osta, A., Karagiannis, T.C., and Tang, M.L. (2011). Resveratrol has protective effects against airway remodeling and airway hyperreactivity in a murine model of allergic airways disease. Pathobiol. Aging Age Relat. Dis.

Lee, 2009, Anti-inflammatory and anti-asthmatic effects of resveratrol, a polyphenolic stilbene, in a mouse model of allergic asthma, Int. Immunopharmacol., 9, 418, 10.1016/j.intimp.2009.01.005

Yao, 2012, SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice, J. Clin. Invest., 122, 2032, 10.1172/JCI60132

Yao, 2014, SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism, Am. J. Physiol. Lung Cell. Mol. Physiol., 306, L816, 10.1152/ajplung.00323.2013