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Molecular Mechanisms in the Development and Progression of Asthma: The Role of Epigenetic Regulation and the Airway Epithelium

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Molecular mechanisms and physiology of disease

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Abstract

Asthma is increasingly recognised as a heterogeneous disease, with multiple phenotypes that differ in severity, pathology, therapeutic response and long-term outcome. A combination of genetic, epigenetic and environmental factors are thought to contribute to the molecular diversity of the disease, with sensitisation (T-cell differentiation) dependent on the local microenvironment and the nature of the invading pathogen. A strong body of evidence exists associating numerous environmental and genetic components in asthma development, with multiple asthma genes involved independently (through the inheritance of polymorphisms) or through the interaction with the environment to increase risk. However, the inability to reproduce inheritance patterns and the dramatic increase in incidence over the last decade provides strong evidence that changes in the environment have activated a pre-existing susceptibility, including the alteration in epigenetic regulation, to play an important role in disease. The role of epigenetic regulation and modulation in the development of asthma and allergy has been widely speculated. Interestingly, factors known to be involved in disease susceptibility including genetic predisposition and exposure to environmental stimuli (in utero and post-natal) have been explored as factors involved in the mechanisms associated with the epigenome. Thus, it is proposed that modification of the epigenome in the regulation of important pathways, including those involved in asthma-associated gene expression and T-cell differentiation play a direct role in disease. In addition, current research focuses on the central role of the airway epithelium in asthma development and progression. Inherently defective in disease, the mechanisms associated with epithelial dysfunction, including the increased susceptibility to injury and the inability to activate normal repair processes are yet to be completely elucidated. Trefoil factor 2 (TFF2), previously shown to be upregulated in asthma and involved in airway epithelial restitution fails to protect the epithelium from pathogen-induced injury. By focusing on the role of epigenetic mechanisms, the epithelium and TFF2 in asthma pathogenesis, this chapter highlights their potential as targets in future therapeutic research.

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References

  • Abbas AK, Murphy KM, Sher A (1996) Functional diversity of helper T lymphocytes. Nature 383(6603):787–793

    CAS  PubMed  Google Scholar 

  • Adenuga D, Yao H, March TH, Seagrave J, Rahman I (2009) Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am J Respir Cell Mol Biol 40:464–473

    CAS  PubMed Central  PubMed  Google Scholar 

  • Agarwal S, Rao A (1998) Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9(6):765–775

    CAS  PubMed  Google Scholar 

  • Akimzhanov AM, Yang XO, Dong C (2007) Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 282:5969–5972

    CAS  PubMed  Google Scholar 

  • Allan RS, Zueva E, Cammas F, Schreiber HA, Masson V, Belz GT, Roche D, Maison C, Quivy J-P, Almouzni G, Amigorena S (2012) An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 487:249–253

    CAS  PubMed  Google Scholar 

  • Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Ponting C, Bhattacharyya S, Tinsley J, Zhang Y, Holt R, Jones EY, Lench N, Carey A, Jones H, Dickens N, Dimon C, Nicholls R, Baker C, Xue L, Townsend E, Kabesch M, Weiland S, Carr D, Von Mutius E, Adcock I, Barnes P, Lathrop GM, Edwards M, Moffatt M, Cookson WOCM (2003) Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 35:258–263

    CAS  PubMed  Google Scholar 

  • Amishima M et al (1998) Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. Am J Respir Crit Care Med 157(6):1907–1912

    CAS  PubMed  Google Scholar 

  • Ansel KM, Lee DU, Rao A (2003) An epigenetic view of helper T cell differentiation. Nat Immunol 4:616–623

    CAS  PubMed  Google Scholar 

  • Assem E-SK et al (2008) Effects of a selection of histone deacetylase inhibitors on mast cell activation and airway and colonic smooth muscle contraction. Int Immunopharmacol 8(13):1793–1801

    CAS  Google Scholar 

  • Ather JL et al (2011) Airway epithelial NF-kappaB activation promotes allergic sensitization to an innocuous inhaled antigen. Am J Respir Cell Mol Biol 44(5):631–638

    CAS  PubMed Central  PubMed  Google Scholar 

  • Avni O, Lee D, Macian F, Szabo S, Glimcher L, Rao A (2002) T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol 3:643–651

    CAS  PubMed  Google Scholar 

  • Baccarelli A, Rusconi F, Bollati V, Catelan D, Accetta G, Hou L, Barbone F, Bertazzi PA, Biggeri A (2012) Nasal cell DNA methylation, inflammation, lung function and wheezing in children with asthma. Epigenomics 4:91–100

    CAS  PubMed Central  PubMed  Google Scholar 

  • Banerjee A et al (2012) Trichostatin A abrogates airway constriction, but not inflammation, in murine and human asthma models. Am J Respir Cell Mol Biol 46(2):132–138

    CAS  PubMed Central  PubMed  Google Scholar 

  • Barnes PJ (2006) How corticosteroids control inflammation: quintiles prize lecture 2005. Br J Pharmacol 148(3):245–254

    CAS  PubMed Central  PubMed  Google Scholar 

  • Barnes PJ, Adcock IM (2009) Glucocorticoid resistance in inflammatory diseases. Lancet 373(9678):1905–1917

    CAS  PubMed  Google Scholar 

  • Beasley R et al (1989) Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 139(3):806–817

    CAS  PubMed  Google Scholar 

  • Berlivet S, Moussette S, Ouimet M, Verlaan D, Koka V, Al Tuwaijri A, Kwan T, Sinnett D, Pastinen T, Naumova A (2012) Interaction between genetic and epigenetic variation defines gene expression patterns at the asthma-associated locus 17q12-q21 in lymphoblastoid cell lines. Hum Genet 131:1161–1171

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bluestone JA et al (1995) TCR gamma delta cells: a specialized T-cell subset in the immune system. Annu Rev Cell Dev Biol 11:307–353

    CAS  PubMed  Google Scholar 

  • Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5(9):769–784

    CAS  PubMed  Google Scholar 

  • Bousquet J et al (2000) Asthma: from bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 161(5):1720–1745

    CAS  PubMed  Google Scholar 

  • Brand S, Teich R, Dicke T, Harb H, Yildirim AÃ, Tost JR, Schneider-Stock R, Waterland RA, Bauer U-M, Von Mutius E, Garn H, Pfefferle PI, Renz H (2011) Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. J Allergy Clin Immunol 128:618–625, e7

    CAS  PubMed  Google Scholar 

  • Breton CV, Byun H-M, Wenten M, Pan F, Yang A, Gilliland FD (2009) Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 180:462–467

    CAS  PubMed Central  PubMed  Google Scholar 

  • Breton CV, Byun H-M, Wang X, Salam MT, Siegmund K, Gilliland FD (2011) DNA methylation in the arginase-nitric oxide synthase pathway is associated with exhaled nitric oxide in children with asthma. Am J Respir Crit Care Med 184:191–197

    CAS  PubMed Central  PubMed  Google Scholar 

  • Broide DH et al (2005) Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium. Proc Natl Acad Sci USA 102(49):17723–17728

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bucchieri F et al (2002) Asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis. Am J Respir Cell Mol Biol 27(2):179–185

    CAS  PubMed  Google Scholar 

  • Cao D, Bromberg PA, Samet JM (2007) COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1. Am J Respir Cell Mol Biol 37:232–239

    CAS  PubMed  Google Scholar 

  • Cates EC et al (2004) Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism. J Immunol 173(10):6384–6392

    CAS  PubMed  Google Scholar 

  • Chang S, Collins PL, Aune TM (2008) T-bet dependent removal of Sin3A-histone deacetylase complexes at the Ifng locus drives Th1 differentiation. J Immunol 181:8372–8381

    CAS  PubMed Central  PubMed  Google Scholar 

  • Choi JH et al (2005) Trichostatin A attenuates airway inflammation in mouse asthma model. Clin Exp Allergy 35(1):89–96

    CAS  PubMed  Google Scholar 

  • Cosio BG, Mann B, Ito K, Jazrawi E, Barnes PJ, Chung KF, Adcock IM (2004) Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med 170:141–147

    PubMed  Google Scholar 

  • Crosby L, Waters C (2010) Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 298(6):L715–L731

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cui J et al (2005) TH1-mediated airway hyperresponsiveness independent of neutrophilic inflammation. J Allergy Clin Immunol 115(2):309–315

    CAS  PubMed  Google Scholar 

  • Davies D (2009) The role of the epithelium in airway remodeling in asthma. Proc Am Thorac Soc 6(8):678–682

    PubMed Central  PubMed  Google Scholar 

  • Demenais F, Chaudru V, Martinez M (2001) Detection of parent-of-origin effects for atopy by model-free and model-based linkage analyses. Genet Epidemiol 21(Suppl 1):S186–S191

    PubMed  Google Scholar 

  • Doe C, Bafadhel M, Siddiqui S, Desai D, Mistry V, Rugman P, Mccormick M, Woods J, May R, Sleeman MA, Anderson IK, Brightling CE (2010) Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest 138:1140–1147

    CAS  PubMed Central  PubMed  Google Scholar 

  • Doganci A, Eigenbrod T, Krug N, De Sanctis GT, Hausding M, Erpenbeck VJ, Haddad E-B, Schmitt E, Bopp T, Kallen K-J, Herz U, Schmitt S, Luft C, Hecht O, Hohlfeld JM, Ito H, Nishimoto N, Yoshizaki K, Kishimoto T, Rose-John S, Renz H, Neurath MF, Galle PR, Finotto S (2005) The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest 115:313–325

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ege MJ, Strachan DP, Cookson WO, Moffatt MF, Gut I, Lathrop M, Kabesch M, Genuneit J, Büchele G, Sozanska B, Boznanski A, Cullinan P, Horak E, Bieli C, Braun-Fahrländer C, Heederik D, Von Mutius E (2011) Gene-environment interaction for childhood asthma and exposure to farming in Central Europe. J Allergy Clin Immunol 127:138–144, e4

    PubMed  Google Scholar 

  • Erjeflt JS, Persson CG (1997) Airway epithelial repair: breathtakingly quick and multipotentially pathogenic. Thorax 52(11):1010–1012

    Google Scholar 

  • Evans MJ et al (1999) The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit. Am J Respir Cell Mol Biol 21(6):655–657

    CAS  PubMed  Google Scholar 

  • Fainaru O, Shseyov D, Hantisteanu S, Groner Y (2005) Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease. Proc Natl Acad Sci U S A 102:10598–10603

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fedorov IA et al (2005) Epithelial stress and structural remodelling in childhood asthma. Thorax 60(5):389–394

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fields PE, Kim ST, Flavell RA (2002) Cutting edge: changes in histone acetylation at the IL-4 and IFN-gamma loci accompany Th1/Th2 differentiation. J Immunol 169:647–650

    CAS  PubMed  Google Scholar 

  • Franic TV et al (2005) Reciprocal changes in trefoil 1 and 2 expression in stomachs of mice with gastric unit hypertrophy and inflammation. J Pathol 207(1):43–52

    CAS  PubMed  Google Scholar 

  • Grausenburger R et al (2010) Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J Immunol 185(6):3489–3497

    Google Scholar 

  • Hackett T-L (2012) Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. Curr Opin Allergy Clin Immunol 12(1):53–59

    CAS  PubMed  Google Scholar 

  • Hackett T-L, Knight DA (2007) The role of epithelial injury and repair in the origins of asthma. Curr Opin Allergy Clin Immunol 7(1):63–68

    PubMed  Google Scholar 

  • Hamilton LM et al (2001) The bronchial epithelium in asthma–much more than a passive barrier. Monaldi Arch Chest Dis 56(1):48–54

    CAS  PubMed  Google Scholar 

  • Hammad H, Lambrecht BN (2008) Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat Rev Immunol 8(3):193–204

    CAS  PubMed  Google Scholar 

  • Hew M et al (2006) Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med 174(2):134

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoffmann W (2005) Trefoil factors TFF (trefoil factor family) peptide-triggered signals promoting mucosal restitution. Cell Mol Life Sci 62(24):2932–2938

    CAS  PubMed  Google Scholar 

  • Holgate ST (1998) The inflammation-repair cycle in asthma: the pivotal role of the airway epithelium. Clin Exp Allergy 28(suppl 5):97–103

    CAS  PubMed  Google Scholar 

  • Holgate ST (2000) The bronchial epithelial origins of asthma. Chem Immunol 78:62–71

    CAS  PubMed  Google Scholar 

  • Holgate S (2007) Epithelium dysfunction in asthma. J Allergy Clin Immunol 120(6):1233–1244

    CAS  PubMed  Google Scholar 

  • Holgate ST (2008) Pathogenesis of asthma. Clin Exp Allergy 38(6):872–897

    CAS  PubMed  Google Scholar 

  • Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J, Bailey N, Potts EN, Whitehead G, Brass DM, Schwartz DA (2008) In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 118:3462–3469

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hu G-Y et al (2003) Expression of TFF2 and Helicobacter pylori infection in carcinogenesis of gastric mucosa. World J Gastroenterol 9(5):910–914

    CAS  PubMed  Google Scholar 

  • Isidoro-García M, Sanz C, García-Solaesa V, Pascual M, Pescador DB, Lorente F, Dávila I (2011) PTGDR gene in asthma: a functional, genetic, and epigenetic study. Allergy 66:1553–1562

    PubMed  Google Scholar 

  • Ito K et al (2002) Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 166(3):392–396

    PubMed  Google Scholar 

  • Ivanov II, Mckenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133

    CAS  PubMed  Google Scholar 

  • Janson PCJ, Winerdal ME, Marits P, Thörn M, Ohlsson R, Winqvist O (2008) FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS One 3:e1612

    PubMed Central  PubMed  Google Scholar 

  • Jones B, Chen J (2006) Inhibition of IFN-gamma transcription by site-specific methylation during T helper cell development. EMBO J 25(11):2443–2452

    Google Scholar 

  • Kicic A et al (2010) Decreased fibronectin production significantly contributes to dysregulated repair of asthmatic epithelium. Am J Respir Crit Care Med 181(9):889–898

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim B-S et al (2010) Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma. Proc Natl Acad Sci 107(19):8742–8747

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim S-H, Lee C-E (2011) Counter-regulation mechanism of IL-4 and IFN-α signal transduction through cytosolic retention of the pY-STAT6:pY-STAT2:p48 complex. Eur J Immunol 41:461–472

    CAS  PubMed  Google Scholar 

  • Kim H-P, Leonard WJ (2007) CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 204:1543–1551

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim ST, Fields PE, Flavell RA (2007) Demethylation of a specific hypersensitive site in the Th2 locus control region. Proc Natl Acad Sci U S A 104:17052–17057

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koh BH, Hwang SS, Kim JY, Lee W, Kang M-J, Lee CG, Park J-W, Flavell RA, Lee GR (2010) Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma. Proc Natl Acad Sci 107:10614–10619

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kuperman D et al (2005) Dissecting asthma using focused transgenic modeling and functional genomics. J Allergy Clin Immunol 116(2):305–311

    CAS  PubMed  Google Scholar 

  • Kwon N-H, Kim J-S, Lee J-Y, Oh M-J, Choi D-C (2008) DNA methylation and the expression of IL-4 and IFN-gamma promoter genes in patients with bronchial asthma. J Clin Immunol 28:139–146

    CAS  PubMed  Google Scholar 

  • Lal G, Zhang N, Van Der Touw W, Ding Y, Ju W, Bottinger EP, Reid SP, Levy DE, Bromberg JS (2009) Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol 182:259–273

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lambrecht BN, Hammad H (2009) Biology of lung dendritic cells at the origin of asthma. Immunity 31(3):412–424

    CAS  PubMed  Google Scholar 

  • Lambrecht BN, Hammad H (2012) The airway epithelium in asthma. Nat Med 18(5):684–692

    CAS  PubMed  Google Scholar 

  • Lane N et al (2010) Regulation in chronic obstructive pulmonary disease: the role of regulatory T-cells and Th17 cells. Clin Sci 119:75–86

    CAS  PubMed  Google Scholar 

  • Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan FO, Siegel R, Hennighausen L, Shevach EM, O’Shea JJ (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    CAS  PubMed  Google Scholar 

  • Le Cras T et al (2011) Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma. Am J Physiol Lung Cell Mol Physiol 300(3):L414–L421

    PubMed Central  PubMed  Google Scholar 

  • Lee DU, Agarwal S, Rao A (2002) Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity 16:649–660

    CAS  PubMed  Google Scholar 

  • Lee SL, Lam TH, Leung TH, Wong WH, Schooling M, Leung GM, Lau YL (2012) Foetal exposure to maternal passive smoking is associated with childhood asthma, allergic rhinitis, and eczema. Scientific World Journal 2012:542983

    CAS  PubMed Central  PubMed  Google Scholar 

  • Leung W et al (2002) Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. J Pathol 197(5):582–588

    CAS  PubMed  Google Scholar 

  • Liu J, Ballaney M, Al-Alem U, Quan C, Jin X, Perera F, Chen L-C, Miller RL (2008) Combined inhaled diesel exhaust particles and allergen exposure alter methylation of T helper genes and IgE production in vivo. Toxicol Sci 102:76–81

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Q, Xia Y, Zhang W, Li J, Wang P, Li H, Wei C, Gong Y (2009) A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han population. BMC Med Genet 10:59

    PubMed Central  PubMed  Google Scholar 

  • Lloyd CM, Hessel EM (2010) Functions of T cells in asthma: more than just TH2 cells. Nat Rev Immunol 10(12):838–848

    CAS  PubMed  Google Scholar 

  • Lodrup Carlsen KC, Carlsen K-H (2001) Effects of maternal and early tobacco exposure on the development of asthma and airway hyperreactivity. Curr Opin Allergy Clin Immunol 1:139–143

    CAS  PubMed  Google Scholar 

  • Lovinsky-Desir S, Miller RL (2012) Epigenetics, asthma, and allergic diseases: a review of the latest advancements. Curr Allergy Asthma Rep 12(3):211–220

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-[beta] induces development of the TH17 lineage. Nature 441:231–234

    CAS  PubMed  Google Scholar 

  • McKinley L et al (2008) TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol 181(6):4089–4097

    CAS  PubMed Central  PubMed  Google Scholar 

  • Monick MM et al (2003) Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. J Biol Chem 278(52):53035–53044

    CAS  PubMed  Google Scholar 

  • Morales E, Bustamante M, Vilahur N, Escaramis G, Montfort M, De Cid R, Garcia-Esteban R, Torrent M, Estivill X, Grimalt JO, Sunyer J (2012) DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood. Am J Respir Crit Care Med 185:937–943

    CAS  PubMed  Google Scholar 

  • Mukasa R et al (2010) Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32(5):616–627

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murata A, Ling PM (2012) Asthma diagnosis and management. Emerg Med Clin North Am 30(2):203–222

    PubMed  Google Scholar 

  • Nadeau K, Mcdonald-Hyman C, Noth EM, Pratt B, Hammond SK, Balmes J, Tager I (2010) Ambient air pollution impairs regulatory T-cell function in asthma. J Allergy Clin Immunol 126:845–852, e10

    CAS  PubMed  Google Scholar 

  • Nikolaidis N et al (2006) Allergen induced TFF2 is expressed by mucus-producing airway epithelial cells but is not a major regulator of inflammatory responses in the murine lung. Exp Lung Res 32(10):483–497

    CAS  PubMed  Google Scholar 

  • Nomura S et al (2005) Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice. Am J Physiol Gastrointest Liver Physiol 288(2):G362–G375

    CAS  PubMed  Google Scholar 

  • Ober C, Yao T-C (2011) The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev 242:10–30

    CAS  PubMed Central  PubMed  Google Scholar 

  • Oertel M et al (2001) Trefoil factor family-peptides promote migration of human bronchial epithelial cells: synergistic effect with epidermal growth factor. Am J Respir Cell Mol Biol 25(4):418–424

    CAS  PubMed  Google Scholar 

  • O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8(3):275–283

    PubMed  Google Scholar 

  • Ohta K et al (1999) Diesel exhaust particulate induces airway hyperresponsiveness in a murine model: essential role of GM-CSF. J Allergy Clin Immunol 104(5):1024–1030

    CAS  PubMed  Google Scholar 

  • Pace E et al (2008) Cigarette smoke increases Toll-like receptor 4 and modifies lipopolysaccharide-mediated responses in airway epithelial cells. Immunology 124(3):401–411

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pawankar R et al (2012) Allergic diseases and asthma: a major global health concern. Curr Opin Allergy Clin Immunol 12(1):39–41

    PubMed  Google Scholar 

  • Payne DNR et al (2003) Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med 167(1):78–82

    PubMed  Google Scholar 

  • Perera F, Tang W-Y, Herbstman J, Tang D, Levin L, Miller R, Ho S-M (2009) Relation of DNA methylation of 5′-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS One 4:e4488

    PubMed Central  PubMed  Google Scholar 

  • Perl A-K, Riethmacher D, Whitsett J (2011) Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis. Am J Respir Crit Care Med 183(4):511–521

    CAS  PubMed Central  PubMed  Google Scholar 

  • Phillips JM, Goodman JI (2009) Inhalation of cigarette smoke induces regions of altered DNA methylation (RAMs) in SENCAR mouse lung. Toxicology 260:7–15

    CAS  PubMed  Google Scholar 

  • Prescott SL (2006) The development of respiratory inflammation in children. Paediatr Respir Rev 7(2):89–96

    PubMed  Google Scholar 

  • Puddicombe SM et al (2000) Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 14(10):1362–1374

    CAS  PubMed  Google Scholar 

  • Ritz SA et al (2002) On the generation of allergic airway diseases: from GM-CSF to Kyoto. Trends Immunol 23(8):396–402

    CAS  PubMed  Google Scholar 

  • Royce S et al (2009) Effect of extracellular matrix composition on airway epithelial cell and fibroblast structure: implications for airway remodeling in asthma. Ann Allergy Asthma Immunol 102(3):238–246

    PubMed  Google Scholar 

  • Royce S et al (2011) Trefoil factor 2 regulates airway remodeling in animal models of asthma. J Asthma 48(7):653–659

    CAS  PubMed  Google Scholar 

  • Royce SG et al (2013) Trefoil factor 2 reverses airway remodeling changes in allergic airways disease. Am J Respir Cell Mol Biol 48(1):135–144

    CAS  PubMed  Google Scholar 

  • Salam MT, Byun H-M, Lurmann F, Breton CV, Wang X, Eckel SP, Gilliland FD (2012) Genetic and epigenetic variations in inducible nitric oxide synthase promoter, particulate pollution, and exhaled nitric oxide levels in children. J Allergy Clin Immunol 129:232–239, e7

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sampath D et al (1999) Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. J Clin Invest 103(9):1353–1361

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sandford AJ, Chagani T, Zhu S, Weir TD, Bai TR, Spinelli JJ, Fitzgerald JM, Behbehani NA, Tan WC, Paré PD (2000) Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 106:135–140

    CAS  PubMed  Google Scholar 

  • Santangelo S, Cousins DJ, Winkelmann NEE, Staynov DZ (2002) DNA methylation changes at human Th2 cytokine genes coincide with DNase I hypersensitive site formation during CD4+ T cell differentiation. J Immunol 169:1893–1903

    CAS  PubMed  Google Scholar 

  • Schaub B, Liu J, Höppler S, Schleich I, Huehn J, Olek S, Wieczorek G, Illi S, Von Mutius E (2009) Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J Allergy Clin Immunol 123:774–782, e5

    CAS  PubMed  Google Scholar 

  • Stämpfli MR et al (1998) GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J Clin Invest 102(9):1704

    PubMed Central  PubMed  Google Scholar 

  • Stevens PT et al (2008) Dysregulated repair in asthmatic paediatric airway epithelial cells: the role of plasminogen activator inhibitor-1. Clin Exp Allergy 38(12):1901–1910

    CAS  PubMed  Google Scholar 

  • Sunyer J, Torrent M, Muñoz-Ortiz L, Ribas-Fitó NR et al (2005) Prenatal dichlorodiphenyldichloroethylene (DDE) and asthma in children. Environ Health Perspect 113:1787–1790

    CAS  PubMed Central  PubMed  Google Scholar 

  • Suter M, Ma J, Harris AS, Patterson L, Brown KA, Shope C, Showalter L, Abramovici A, Aagaard-Tillery KM (2011) Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression. Epigenetics 6:1284–1294

    CAS  PubMed Central  PubMed  Google Scholar 

  • Trautmann A et al (2005) Apoptosis and loss of adhesion of bronchial epithelial cells in asthma. Int Arch Allergy Immunol 138(2):142–150

    CAS  PubMed  Google Scholar 

  • Tsaprouni LG, Ito K, Adcock IM, Punchard N (2007) Suppression of lipopolysaccharide- and tumour necrosis factor-α-induced interleukin (IL)-8 expression by glucocorticoids involves changes in IL-8 promoter acetylation. Clin Exp Immunol 150:151–157

    CAS  PubMed Central  PubMed  Google Scholar 

  • Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, Mckenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, Fitzgerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP (2002) Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418:426–430

    PubMed  Google Scholar 

  • van Rijt LS et al (2005) In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med 201(6):981–991

    PubMed Central  PubMed  Google Scholar 

  • Vercelli D (2008) Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 8:169–182

    CAS  PubMed  Google Scholar 

  • Vignola AM, Kips J, Bousquet J (2000) Tissue remodeling as a feature of persistent asthma. J Allergy Clin Immunol 105(6):1041–1053

    CAS  PubMed  Google Scholar 

  • Wan H et al (2000) Quantitative structural and biochemical analyses of tight junction dynamics following exposure of epithelial cells to house dust mite allergen Der p 1. Clin Exp Allergy 30(5):685–698

    CAS  PubMed  Google Scholar 

  • Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z, Cui K, Kanno Y, Roh T-Y, Watford WT, Schones DE, Peng W, Sun H-W, Paul WE, O’shea JJ, Zhao K (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30:155–167

    PubMed Central  PubMed  Google Scholar 

  • Weinberg EG (2011) The WAO white book on allergy 2011-2012: review article. Curr Allergy Clin Immunol 24(3):156–157

    Google Scholar 

  • White SR (2001) Trefoil peptides in airway epithelium: an important addition to the plethora of peptides. Am J Respir Cell Mol Biol 25(4):401–404

    CAS  PubMed  Google Scholar 

  • White GP, Hollams EM, Yerkovich ST, Bosco A, Holt BJ, Bassami MR, Kusel M, Sly PD, Holt PG (2006) CpG methylation patterns in the IFNγ promoter in naive T cells: variations during Th1 and Th2 differentiation and between atopics and non-atopics. Pediatr Allergy Immunol 17:557–564

    PubMed  Google Scholar 

  • Wills Karp M et al (2012) Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med 209(3):607–622

    CAS  PubMed Central  PubMed  Google Scholar 

  • Woodruff PG et al (2009) T-helper type 2–driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 180(5):388

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wright NA (1993) Trefoil peptides and the gut. Gut 34(5):577–579

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xepapadaki P, Manios Y, Liarigkovinos T, Grammatikaki E, Douladiris N, Kortsalioudaki C, Papadopoulos NG (2009) Association of passive exposure of pregnant women to environmental tobacco smoke with asthma symptoms in children. Pediatr Allergy Immunol 20:423–429

    PubMed  Google Scholar 

  • Xiao C et al (2011) Defective epithelial barrier function in asthma. J Allergy Clin Immunol 128(3):549–556, e1

    CAS  PubMed  Google Scholar 

  • Yang IV, Schwartz DA (2011) Epigenetic control of gene expression in the lung. Am J Respir Crit Care Med 183(10):1295

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang M, Kumar RK, Foster PS (2009) Pathogenesis of steroid-resistant airway hyperresponsiveness: interaction between IFN-gamma and TLR4/MyD88 pathways. J Immunol 182(8):5107–5115

    CAS  PubMed  Google Scholar 

  • Yang L et al (1998) Essential role of nuclear factor kB in the induction of eosinophilia in allergic airway inflammation. J Exp Med 188(9):1739–1750

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang S-R, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I (2006) Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol 291:L46–L57

    CAS  PubMed  Google Scholar 

  • Yang Y, Haitchi HM, Cakebread J, Sammut D, Harvey A, Powell RM, Holloway JW, Howarth P, Holgate ST, Davies DE (2008) Epigenetic mechanisms silence a disintegrin and metalloprotease 33 expression in bronchial epithelial cells. J Allergy Clin Immunol 121:1393–1399, e14

    CAS  PubMed  Google Scholar 

  • Yuyama N et al (2002) Analysis of novel disease-related genes in bronchial asthma. Cytokine 19(6):287–296

    CAS  PubMed  Google Scholar 

  • Zahm JM, Chevillard M, Puchelle E (1991) Wound repair of human surface respiratory epithelium. Am J Respir Cell Mol Biol 5(3):242–248

    CAS  PubMed  Google Scholar 

  • Zhang Y, Moffatt M, Cookson WOC (2012) Genetic and genomic approaches to asthma: new insights for the origins. Curr Opin Pulm Med 18:6–13

    PubMed  Google Scholar 

  • Zhou C et al (2011) Epithelial apoptosis and loss in airways of children with asthma. J Asthma 48(4):358–365

    PubMed  Google Scholar 

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Acknowledgements

The support of the Australian Institute of Nuclear Science and Engineering is acknowledged. TCK was the recipient of AINSE awards. TCK is a Future Fellow and Epigenomic Medicine Laboratory is supported by the Australian Research Council. Supported in part by the Victorian Government’s Operational Infrastructure Support Program.

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    Authors and Affiliations

    1. Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, 75 Commercial Road, Melbourne, VIC, Australia

      Stephanie Tortorella, Simon G. Royce & Tom C. Karagiannis

    2. Department of Pathology, The University of Melbourne, Parkville, VIC, Australia

      Simon G. Royce & Tom C. Karagiannis

    3. Allergy and Immune Disorders, Murdoch Children’s Research Institute, Parkville, VIC, Australia

      Simon G. Royce

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    Correspondence to Stephanie Tortorella .

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    1. Department of Surgery Molecular cardiology and Angiogenesis, University of Connecticut School of Medicine, Farmington, Connecticut, USA

      Nilanjana Maulik

    2. Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia

      Tom Karagiannis

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    Tortorella, S., Royce, S.G., Karagiannis, T.C. (2014). Molecular Mechanisms in the Development and Progression of Asthma: The Role of Epigenetic Regulation and the Airway Epithelium. In: Maulik, N., Karagiannis, T. (eds) Molecular mechanisms and physiology of disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0706-9_9

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