Airway remodelling in asthma: from benchside to clinical practice

Céline Bergeron, Meri K Tulic, Qutayba Hamid, Céline Bergeron, Meri K Tulic, Qutayba Hamid

Abstract

Airway remodelling refers to the structural changes that occur in both large and small airways relevant to miscellaneous diseases including asthma. In asthma, airway structural changes include subepithelial fibrosis, increased smooth muscle mass, gland enlargement, neovascularization and epithelial alterations. Although controversial, airway remodelling is commonly attributed to an underlying chronic inflammatory process. These remodelling changes contribute to thickening of airway walls and, consequently, lead to airway narrowing, bronchial hyper-responsiveness, airway edema and mucous hypersecretion. Airway remodelling is associated with poor clinical outcomes among asthmatic patients. Early diagnosis and prevention of airway remodelling has the potential to decrease disease severity, improve control and prevent disease expression. The relationship between structural changes and clinical and functional abnormalities clearly deserves further investigation. The present review briefly describes the characteristic features of airway remodelling observed in asthma, its clinical consequences and relevance for physicians, and its modulation by therapeutic approaches used in the treatment of asthmatic patients.

Figures

Figure 1)
Figure 1)
A Hematoxylin and eosin-stained endobronchial biopsy sample from an asthmatic subject showing goblet cell hyperplasia (original magnification ×40). B Hematoxylin and eosin-stained endobronchial biopsy sample from an asthmatic subject showing extensive total subepithelial fibrosis and increased smooth muscle mass (original magnification ×200). C Lung biopsy sample of a small airway from an asthmatic subject showing increased smooth muscle mass and submucosal fibrosis (original magnification ×200)
Figure 2)
Figure 2)
Main airway remodelling features observed in endobronchial biopsies from a severe asthmatic subject. Clinical consequences of each remodelling feature are reported. AHR Airway hyper-responsiveness; BC Bronchoconstriction
Figure 3)
Figure 3)
Transforming growth factor (TGF)-beta messenger RNA (mRNA) expression and subepithelial fibrosis increase with asthma severity. TGF-beta expression is correlated with subepithelial fibrosis. Subepithelial fibrosis was measured by collagen I and III expression levels. Airway biopsies were used to detect TGF-beta and collagen expression. BM Basement membrane. Modified from Minshall et al (132)

References

    1. Redington AE, Howarth PH. Airway wall remodelling in asthma. Thorax. 1997;52:310–2.
    1. James AL, Maxwell PS, Pearce-Pinto G, Elliot JG, Carroll NG. The relationship of reticular basement membrane thickness to airway wall remodeling in asthma. Am J Respir Crit Care Med. 2002;166:1590–5.
    1. Naylor B. The shedding of the mucosa of the bronchial tree in asthma. Thorax. 1962;17:69–72.
    1. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet. 1989;1:520–4.
    1. Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodeling in asthma. J Clin Investig. 1999;104:1001–6.
    1. Carroll N, Elliot J, Morton A, James A. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis. 1993;147:405–10.
    1. Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima T. Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. Chest. 1992;101:916–21.
    1. Haraguchi M, Shimura S, Shirato K. Morphometric analysis of bronchial cartilage in chronic obstructive pulmonary disease and bronchial asthma. Am J Respir Crit Care Med. 1999;159:1005–13.
    1. Li X, Wilson JW. Increased vascularity of the bronchial mucosa in mild asthma. Am J Respir Crit Care Med. 1997;156:229–33.
    1. Tanaka H, Yamada G, Saikai T, et al. Increased airway vascularity in newly diagnosed asthma using a high-magnification bronchovideoscope. Am J Respir Crit Care Med. 2003;168:1495–9.
    1. Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev. 1997;77:1033–79.
    1. Kroegel C, Virchow JC, Jr, Luttmann W, Walker C, Warner JA. Pulmonary immune cells in health and disease: The eosinophil leucocyte (Part I) Eur Respir J. 1994;7:519–43.
    1. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–57.
    1. Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990;172:921–9.
    1. Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990;145:3796–806.
    1. Zeiger RS, Dawson C, Weiss S. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP) J Allergy Clin Immunol. 1999;103:376–87.
    1. Boulet LP, Laviolette M, Turcotte H, et al. Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine. Chest. 1997;112:45–52.
    1. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis. 1985;131:599–606.
    1. Montefort S, Roberts JA, Beasley R, Holgate ST, Roche WR. The site of disruption of the bronchial epithelium in asthmatic and non-asthmatic subjects. Thorax. 1992;47:499–503.
    1. Ordonez C, Ferrando R, Hyde DM, Wong HH, Fahy JV. Epithelial desquamation in asthma: Artifact or pathology? Am J Respir Crit Care Med. 2000;162:2324–9.
    1. Shebani E, Shahana S, Janson C, Roomans GM. Attachment of columnar airway epithelial cells in asthma. Tissue Cell. 2005;37:145–52.
    1. Hackett TL, Knight DA. The role of epithelial injury and repair in the origins of asthma. Curr Opin Allergy Clin Immunol. 2007;7:63–8.
    1. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis. 1989;140:1745–53.
    1. Chakir J, Laviolette M, Boutet M, Laliberte R, Dube J, Boulet LP. Lower airways remodeling in nonasthmatic subjects with allergic rhinitis. Lab Invest. 1996;75:735–44.
    1. Milanese M, Crimi E, Scordamaglia A, et al. On the functional consequences of bronchial basement membrane thickening. J Appl Physiol. 2001;91:1035–40.
    1. Payne DN, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med. 2003;167:78–82.
    1. Jenkins HA, Cool C, Szefler SJ, et al. Histopathology of severe childhood asthma: A case series. Chest. 2003;124:32–41.
    1. Huang J, Olivenstein R, Taha R, Hamid Q, Ludwig M. Enhanced proteoglycan deposition in the airway wall of atopic asthmatics. Am J Respir Crit Care Med. 1999;160:725–9.
    1. Laitinen A, Altraja A, Kampe M, Linden M, Virtanen I, Laitinen LA. Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med. 1997;156:951–8.
    1. Wilson JW, Li X. The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin Exp Allergy. 1997;27:363–71.
    1. Karjalainen EM, Lindqvist A, Laitinen LA, et al. Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma. Respir Med. 2003;97:1045–51.
    1. Bergeron C, Page N, Joubert P, Barbeau B, Hamid Q, Chakir J. Regulation of procollagen I (alpha1) by interleukin-4 in human bronchial fibroblasts: A possible role in airway remodelling in asthma. Clin Exp Allergy. 2003;33:1389–97.
    1. Minshall E, Chakir J, Laviolette M, et al. IL-11 expression is increased in severe asthma: Association with epithelial cells and eosinophils. J Allergy Clin Immunol. 2000;105:232–8.
    1. Hoshino M, Nakamura Y, Sim JJ. Expression of growth factors and remodelling of the airway wall in bronchial asthma. Thorax. 1998;53:21–7.
    1. Chetta A, Foresi A, Del Donno M, Bertorelli G, Pesci A, Olivieri D. Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest. 1997;111:852–7.
    1. Little SA, Sproule MW, Cowan MD, et al. High-resolution computed tomographic assessment of airway wall thickness in chronic asthma: Reproducibility and relationship with lung function and severity. Thorax. 2002;57:247–53.
    1. Westergren-Thorsson G, Chakir J, Lafreniere-Allard MJ, Boulet LP, Tremblay GM. Correlation between airway responsiveness and proteoglycan production by bronchial fibroblasts from normal and asthmatic subjects. Int J Biochem Cell Biol. 2002;34:1256–67.
    1. Lemjabbar H, Gosset P, Lamblin C, et al. Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Am J Respir Crit Care Med. 1999;159(4 Pt 1):1298–307.
    1. Prikk K, Maisi P, Pirila E, et al. Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma. Lab Invest. 2002;82:1535–45.
    1. Vignola AM, Riccobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med. 1998;158:1945–50.
    1. Suzuki R, Kato T, Miyazaki Y, et al. Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in sputum from patients with bronchial asthma. J Asthma. 2001;38:477–84.
    1. Wenzel SE, Balzar S, Cundall M, Chu HW. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: Association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol. 2003;111:1345–52.
    1. Johnson C, Sung HJ, Lessner SM, Fini ME, Galis ZS. Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues. Potential role in capillary branching. Circ Res. 2004;94:262–8.
    1. Johnson C, Galis ZS. Matrix metalloproteinase-2 and -9 differentially regulate smooth muscle cell migration and cell-mediated collagen organization. Arterioscler Thromb Vasc Biol. 2004;24:54–60.
    1. Johnson S, Knox A. Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation. Am J Physiol. 1999;277(6 Pt 1):L1109–17.
    1. Cataldo DD, Bettiol J, Noel A, Bartsch P, Foidart JM, Louis R. Matrix metalloproteinase-9, but not tissue inhibitor of matrix metalloproteinase-1, increases in the sputum from allergic asthmatic patients after allergen challenge. Chest. 2002;122:1553–9.
    1. Johnson PR, Burgess JK. Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep. 2004;4:102–8.
    1. Joubert P, Lajoie-Kadoch S, Labonte I, et al. CCR3 expression and function in asthmatic airway smooth muscle cells. J Immunol. 2005;175:2702–8.
    1. Panettieri RA., Jr Airway smooth muscle: An immunomodulatory cell. J Allergy Clin Immunol. 2002;110(Suppl 6):S269–74.
    1. Hakonarson H, Maskeri N, Carter C, Grunstein MM. Regulation of TH1- and TH2-type cytokine expression and action in atopic asthmatic sensitized airway smooth muscle. J Clin Invest. 1999;103:1077–87.
    1. Johnson PR. Role of human airway smooth muscle in altered extracellular matrix production in asthma. Clin Exp Pharmacol Physiol. 2001;28:233–6.
    1. Benayoun L, Druilhe A, Dombret MC, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003;167:1360–8.
    1. Hoshino M, Takahashi M, Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J Allergy Clin Immunol. 2001;107:295–301.
    1. Noble PB, Turner DJ, Mitchell HW. Relationship of airway narrowing, compliance, and cartilage in isolated bronchial segments. J Appl Physiol. 2002;92:1119–24.
    1. Sont JK, Han J, van Krieken JM, et al. Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids. Thorax. 1996;51:496–502.
    1. Molet S, Hamid Q, Davoine F, et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001;108:430–8.
    1. Chakir J, Shannon J, Molet S, et al. Airway remodeling-associated mediators in moderate to severe asthma: Effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol. 2003;111:1293–8.
    1. Kunzmann S, Schmidt-Weber C, Zingg JM, et al. Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: Potential role of histamine in airway remodeling. J Allergy Clin Immunol. 2007;119:1398–407.
    1. Bergeron C, Tulic MK, Hamid Q. Tools used to measure airway remodelling in research. Eur Respir J. 2007;29:596–604.
    1. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339:1194–200.
    1. Settipane RJ, Hagy GW, Settipane GA. Long-term risk factors for developing asthma and allergic rhinitis: A 23-year follow-up study of college students. Allergy Proc. 1994;15:21–5.
    1. Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol. 2002;109:419–25.
    1. Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects. Results from the European Community Respiratory Health Survey. J Allergy Clin Immunol. 1999;104(2 Pt 1):301–4.
    1. Laprise C, Laviolette M, Boutet M, Boulet LP. Asymptomatic airway hyperresponsiveness: Relationships with airway inflammation and remodelling. Eur Respir J. 1999;14:63–73.
    1. Laprise C, Boulet LP. Airway responsiveness and atopy in families of patients with asthma. Clin Invest Med. 1996;19:461–9.
    1. Watson WT, Becker AB, Simons FE. Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: Effect on lower airway responsiveness. J Allergy Clin Immunol. 1993;91(1 Pt 1):97–101.
    1. Corren J, Adinoff AD, Buchmeier AD, Irvin CG. Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma. J Allergy Clin Immunol. 1992;90:250–6.
    1. Wilson AM, Orr LC, Sims EJ, Lipworth BJ. Effects of monotherapy with intra-nasal corticosteroid or combined oral histamine and leukotriene receptor antagonists in seasonal allergic rhinitis. Clin Exp Allergy. 2001;31:61–8.
    1. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol. 2001;108(Suppl 5):S147–334.
    1. Walker SM, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy for seasonal rhinitis and asthma: A randomized, controlled trial. J Allergy Clin Immunol. 2001;107:87–93.
    1. Haahtela T, Jarvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med. 1994;331:700–5.
    1. Levine SJ, Larivee P, Logun C, Angus CW, Shelhamer JH. Corticosteroids differentially regulate secretion of IL-6, IL-8, and G-CSF by a human bronchial epithelial cell line. Am J Physiol. 1993;265(4 Pt 1):L360–8.
    1. Dorscheid DR, Wojcik KR, Sun S, Marroquin B, White SR. Apoptosis of airway epithelial cells induced by corticosteroids. Am J Respir Crit Care Med. 2001;164(10 Pt 1):1939–47.
    1. Sabatini F, Silvestri M, Sale R, et al. Concentration-dependent effects of mometasone furoate and dexamethasone on foetal lung fibroblast functions involved in airway inflammation and remodeling. Pulm Pharmacol Ther. 2003;16:287–97.
    1. Descalzi D, Folli C, Nicolini G, et al. Anti-proliferative and anti-remodelling effect of beclomethasone dipropionate, formoterol and salbutamol alone or in combination in primary human bronchial fibroblasts. Allergy. 2008;63:432–7.
    1. Young PG, Skinner SJ, Black PN. Effects of glucocorticoids and beta-adrenoceptor agonists on the proliferation of airway smooth muscle. Eur J Pharmacol. 1995;273:137–43.
    1. Schramm CM, Grunstein MM. Corticosteroid modulation of Na(+)-K+ pump-mediated relaxation in maturing airway smooth muscle. Br J Pharmacol. 1996;119:807–12.
    1. Stewart AG, Fernandes D, Tomlinson PR. The effect of glucocorticoids on proliferation of human cultured airway smooth muscle. Br J Pharmacol. 1995;116:3219–26.
    1. Laitinen LA, Laitinen A. Inhaled corticosteroid treatment for asthma. Allergy Proc. 1995;16:63–6.
    1. Jeffery PK. Pathology of asthma. Br Med Bull. 1992;48:23–39.
    1. Boulet LP, Turcotte H, Laviolette M, et al. Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids. Am J Respir Crit Care Med. 2000;162:1308–13.
    1. Olivieri D, Chetta A, Del Donno M, et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: A placebo-controlled study. Am J Respir Crit Care Med. 1997;155:1864–71.
    1. Trigg CJ, Manolitsas ND, Wang J, et al. Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med. 1994;150:17–22.
    1. Hoshino M, Takahashi M, Takai Y, Sim J. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma. J Allergy Clin Immunol. 1999;104:356–63.
    1. Ward C, Pais M, Bish R, et al. Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma. Thorax. 2002;57:309–16.
    1. Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med. 1999;159(4 Pt 1):1043–51.
    1. Mattos W, Lim S, Russell R, Jatakanon A, Chung KF, Barnes PJ. Matrix metalloproteinase-9 expression in asthma: Effect of asthma severity, allergen challenge, and inhaled corticosteroids. Chest. 2002;122:1543–52.
    1. Mautino G, Oliver N, Chanez P, Bousquet J, Capony F. Increased release of matrix metalloproteinase-9 in bronchoalveolar lavage fluid and by alveolar macrophages of asthmatics. Am J Respir Cell Mol Biol. 1997;17:583–91.
    1. Djukanovic R, Wilson JW, Britten KM, et al. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992;145:669–74.
    1. Laitinen LA, Laitinen A, Heino M, Haahtela T. Eosinophilic airway inflammation during exacerbation of asthma and its treatment with inhaled corticosteroid. Am Rev Respir Dis. 1991;143:423–7.
    1. Bentley AM, Hamid Q, Robinson DS, et al. Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med. 1996;153:551–6.
    1. Lemiere C, Bai T, Balter M, et al. Adult Asthma Consensus Guidelines Update 2003. Can Respir J. 2004;11(Suppl A):9A–18A.
    1. Dompeling E, van Schayck CP, Molema J, Folgering H, van Grunsven PM, van Weel C. Inhaled beclomethasone improves the course of asthma and COPD. Eur Respir J. 1992;5:945–52.
    1. Grol MH, Gerritsen J, Vonk JM, et al. Risk factors for growth and decline of lung function in asthmatic individuals up to age 42 years. A 30-year follow-up study. Am J Respir Crit Care Med. 1999;160:1830–7.
    1. Selroos O, Pietinalho A, Lofroos AB, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest. 1995;108:1228–34.
    1. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343:1054–63.
    1. Ragab S, Parikh A, Darby YC, Scadding GK. An open audit of montelukast, a leukotriene receptor antagonist, in nasal polyposis associated with asthma. Clin Exp Allergy. 2001;31:1385–91.
    1. Leigh R, Vethanayagam D, Yoshida M, et al. Effects of montelukast and budesonide on airway responses and airway inflammation in asthma. Am J Respir Crit Care Med. 2002;166:1212–7.
    1. Henderson WR, Jr, Tang LO, Chu SJ, et al. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med. 2002;165:108–16.
    1. Muz MH, Deveci F, Bulut Y, Ilhan N, Yekeler H, Turgut T. The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model. Exp Mol Med. 2006;38:109–18.
    1. Kelly MM, Chakir J, Vethanayagam D, et al. Montelukast treatment attenuates the increase in myofibroblasts following low-dose allergen challenge. Chest. 2006;130:741–53.
    1. Milgrom H, Fick RB, Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med. 1999;341:1966–73.
    1. Djukanovic R, Wilson SJ, Kraft M, et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170:583–93.
    1. Noga O, Hanf G, Kunkel G. Immunological and clinical changes in allergic asthmatics following treatment with omalizumab. Int Arch Allergy Immunol. 2003;131:46–52.
    1. Orsida BE, Ward C, Li X, et al. Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma. Am J Respir Crit Care Med. 2001;164:117–21.
    1. Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med. 1995;151:1907–14.
    1. Serebrisky D, Teper AA, Huang CK, et al. CpG oligodeoxynucleotides can reverse Th2-associated allergic airway responses and alter the B7.1/B7.2 expression in a murine model of asthma. J Immunol. 2000;165:5906–12.
    1. Flood-Page P, Menzies-Gow A, Phipps S, et al. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest. 2003;112:1029–36.
    1. Billington CK, Joseph SK, Swan C, Scott MG, Jobson TM, Hall IP. Modulation of human airway smooth muscle proliferation by type 3 phosphodiesterase inhibition. Am J Physiol. 1999;276:L412–L9.
    1. Cox GMJ, McWilliams A, Fitzgerald M, Lam S. Bronchial thermoplasty: One-year update. Am J Respir Crit Care Med. 2004:A313.
    1. Cox G. New interventions in asthma including bronchial thermoplasty. Curr Opin Pulm Med. 2008;14:77–81.
    1. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356:1327–37.
    1. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185–91.
    1. Borish LC, Nelson HS, Lanz MJ, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999;160:1816–23.
    1. Henderson WR, Jr, Chi EY, Maliszewski CR. Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma. J Immunol. 2000;164:1086–95.
    1. Tomkinson A, Duez C, Cieslewicz G, et al. A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J Immunol. 2001;166:5792–800.
    1. Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet. 2000;356:2144–8.
    1. Blyth DI, Wharton TF, Pedrick MS, Savage TJ, Sanjar S. Airway subepithelial fibrosis in a murine model of atopic asthma: Suppression by dexamethasone or anti-interleukin-5 antibody. Am J Respir Cell Mol Biol. 2000;23:241–6.
    1. Tulic MK, Fiset PO, Christodoulopoulos P, et al. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol. 2004;113:235–41.
    1. Kline JN, Waldschmidt TJ, Businga TR, et al. Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. J Immunol. 1998;160:2555–9.
    1. Jain VV, Kitagaki K, Businga T, et al. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J Allergy Clin Immunol. 2002;110:867–72.
    1. Fanucchi MV EM, Baker GL, et al. Immunostimulatory DNA Sequence (ISS) inhibition of airways remodeling in young adult rhesus monkey. Am J Respir Crit Care Med. 2003;167:A955.
    1. Campos HS, Xisto DG, Oliveira MB, et al. Protective effects of phosphodiesterase inhibitors on lung function and remodeling in a murine model of chronic asthma. Braz J Med Biol Res. 2006;39:283–7.
    1. Kumar RK, Herbert C, Thomas PS, et al. Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma. J Pharmacol Exp Ther. 2003;307:349–55.
    1. Fujitani Y, Trifilieff A. In vivo and in vitro effects of SAR 943, a rapamycin analogue, on airway inflammation and remodeling. Am J Respir Crit Care Med. 2003;167:193–8.
    1. Bradley BL, Azzawi M, Jacobson M, et al. Eosinophils, T-lymphocytes, mast cells, neutrophils, and macrophages in bronchial biopsy specimens from atopic subjects with asthma: Comparison with biopsy specimens from atopic subjects without asthma and normal control subjects and relationship to bronchial hyperresponsiveness. J Allergy Clin Immunol. 1991;88:661–74.
    1. Varga EM, Jacobson MR, Till SJ, et al. Cellular infiltration and cytokine mRNA expression in perennial allergic rhinitis. Allergy. 1999;54:338–45.
    1. KleinJan A, Dijkstra MD, Boks SS, Severijnen LA, Mulder PG, Fokkens WJ. Increase in IL-8, IL-10, IL-13, and RANTES mRNA levels (in situ hybridization) in the nasal mucosa after nasal allergen provocation. J Allergy Clin Immunol. 1999;103(3 Pt 1):441–50.
    1. Nag S, Lamkhioued B, Renzi PM. Interleukin-2-induced increased airway responsiveness and lung Th2 cytokine expression occur after antigen challenge through the leukotriene pathway. Am J Respir Crit Care Med. 2002;165:1540–5.
    1. Bousquet J, Jacquot W, Vignola AM, Bachert C, Van Cauwenberge P. Allergic rhinitis: A disease remodeling the upper airways? J Allergy Clin Immunol. 2004;113:43–9.
    1. Toda M, Leung DY, Molet S, et al. Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. J Allergy Clin Immunol. 2003;111:875–81.
    1. Minshall EM, Leung DY, Martin RJ, et al. Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol. 1997;17:326–33.

Source: PubMed

3
Se inscrever