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What effect does asthma treatment have on airway remodeling? Current perspectives

2011; Elsevier BV; Volume: 128; Issue: 3 Linguagem: Inglês

10.1016/j.jaci.2011.06.002

1097-6825

Sheharyar R. Durrani, Ravi Viswanathan, William W. Busse,

IL-33, ST2, and ILC Pathways

Airway remodeling, or structural changes of the airway wall arising from injury and repair, plays an important role in the pathophysiology of asthma. Remodeling is characterized as structural changes involving the composition, content, and organization of many of the cellular and molecular constituents of the bronchial wall. These structural changes can include epithelial injury, subepithelial thickening/fibrosis, airway smooth muscle hyperplasia, goblet cell hypertrophy and hyperplasia, and angiogenesis. Historically, these changes are considered a consequence of long-standing airway inflammation. Recent infant and child studies, however, suggest that remodeling occurs in parallel with inflammation in asthmatic subjects. Despite advancements in the recognition of key cellular and molecular mechanisms involved in remodeling, there remains a paucity of information about which treatments or interactions are most likely to regulate these processes. Furthermore, it is unclear as to when is the best time to initiate treatments to modify remodeling, which components to target, and how best to monitor interventions on remodeling. Indeed, inhaled corticosteroids, which are generally considered to have limited influence on remodeling, have been shown to be beneficial in studies in which the dose and duration of treatment were increased and prolonged, respectively. Moreover, several studies have identified the need to identify novel asthma indices and phenotypes that correlate with remodeling and, as a consequence, might specifically respond to new therapies, such as anti-IgE, anti–IL-5, and anti–TNF-α mAbs. Our review will evaluate the development of remodeling in asthmatic subjects and the effects of treatment on these processes. Airway remodeling, or structural changes of the airway wall arising from injury and repair, plays an important role in the pathophysiology of asthma. Remodeling is characterized as structural changes involving the composition, content, and organization of many of the cellular and molecular constituents of the bronchial wall. These structural changes can include epithelial injury, subepithelial thickening/fibrosis, airway smooth muscle hyperplasia, goblet cell hypertrophy and hyperplasia, and angiogenesis. Historically, these changes are considered a consequence of long-standing airway inflammation. Recent infant and child studies, however, suggest that remodeling occurs in parallel with inflammation in asthmatic subjects. Despite advancements in the recognition of key cellular and molecular mechanisms involved in remodeling, there remains a paucity of information about which treatments or interactions are most likely to regulate these processes. Furthermore, it is unclear as to when is the best time to initiate treatments to modify remodeling, which components to target, and how best to monitor interventions on remodeling. Indeed, inhaled corticosteroids, which are generally considered to have limited influence on remodeling, have been shown to be beneficial in studies in which the dose and duration of treatment were increased and prolonged, respectively. Moreover, several studies have identified the need to identify novel asthma indices and phenotypes that correlate with remodeling and, as a consequence, might specifically respond to new therapies, such as anti-IgE, anti–IL-5, and anti–TNF-α mAbs. Our review will evaluate the development of remodeling in asthmatic subjects and the effects of treatment on these processes. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: September 2011. Credit may be obtained for these courses until August 31, 2013.Copyright Statement: Copyright © 2011-2013. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Sheharyar R. Durrani, MD, Ravi K. Viswanathan, MD, and William W. Busse, MDActivity Objectives1.To list biomarkers of airway remodeling.2.To describe interactions between these biomarkers relevant to the understanding of airway remodeling.3.To discuss the outcome of therapeutic interventions in the airway remodeling process.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: W. W. Busse is on the advisory board for Centocor and Merck; is a consultant for AstraZeneca, Boehringer Ingelheim, Novartis, TEVA, GlaxoSmithKline, Amgen, Pfizer, MedImmune, and Genentech; and has received research support from Novartis, AstraZeneca, GlaxoSmithKline, MedImmune, Ception, the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases, and NIH/National Heart, Lung, and Blood Institute. The rest of the authors have declared that they have no conflict of interest.Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: September 2011. Credit may be obtained for these courses until August 31, 2013. Copyright Statement: Copyright © 2011-2013. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Sheharyar R. Durrani, MD, Ravi K. Viswanathan, MD, and William W. Busse, MD Activity Objectives1.To list biomarkers of airway remodeling.2.To describe interactions between these biomarkers relevant to the understanding of airway remodeling.3.To discuss the outcome of therapeutic interventions in the airway remodeling process. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: W. W. Busse is on the advisory board for Centocor and Merck; is a consultant for AstraZeneca, Boehringer Ingelheim, Novartis, TEVA, GlaxoSmithKline, Amgen, Pfizer, MedImmune, and Genentech; and has received research support from Novartis, AstraZeneca, GlaxoSmithKline, MedImmune, Ception, the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases, and NIH/National Heart, Lung, and Blood Institute. The rest of the authors have declared that they have no conflict of interest. Airway remodeling in asthmatic subjects represents a complex multicellular process that leads to structural changes involving the composition, content, and organization of many of the cellular and molecular constituents of the bronchial wall.1Mauad T. Bel E.H. Sterk P.J. Asthma therapy and airway remodeling.J Allergy Clin Immunol. 2007; 120: 997-1011Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar These structural changes, which have been proposed to result in lower lung function, include epithelial injury, subepithelial fibrosis, airway smooth muscle (ASM) hyperplasia, goblet cell hypertrophy and hyperplasia, and angiogenesis (Fig 1), although their specific expression in individual patients is variable in terms of onset and severity. Although there is focus on "remodeling" as a factor in the accelerated and progressive loss in lung function, it is important to point out that physiologic abnormalities in asthmatic subjects (eg, air trapping) might be another significant factor in the decreased levels of lung function seen in asthmatic subjects.2Gelb A.F. Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma.Am J Respir Crit Care Med. 2000; 162: 1778-1782Crossref PubMed Scopus (113) Google Scholar Despite these significant and important contributions, the scope of the following review will be limited to the histopathologic abnormalities associated with airway remodeling in asthmatic subjects. Airway remodeling has been considered to result in an accelerated and progressive loss of lung function in some asthmatic subjects. However, it should be emphasized that remodeling in asthmatic subjects refers to a series of histopathologic changes and not necessarily to any clinically measurable outcome. Therefore although there is an enormous body of literature associating remodeling with loss of lung function, there remains no definitive proof of this causation. Nonetheless, available evidence would suggest causation, as discussed broadly in this review, and the issue of this relationship remains significant enough to warrant ongoing research to understand airway remodeling and pathophysiologic mechanisms to promote the development of therapies to attenuate remodeling. Given this background, it is our premise that remodeling, whether structural or physiological in origin, is a component of asthma in some patients and is of interest and importance to the basic mechanisms of both the disease and the therapy used to either prevent or attenuate it. Historically, remodeling was attributed to the consequences of longstanding and persistent inflammation, as well as a subsequent dysfunctional injury and repair mechanism.3Davies D.E. Wicks J. Powell R.M. Puddicombe S.M. Holgate S.T. Airway remodeling in asthma: new insights.J Allergy Clin Immunol. 2003; 111: 215-226Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar Because chronic inflammation is considered a driving force behind airway injury and repair, it has been proposed that asthma treatments, which might specifically and effectively target airway inflammation, would also affect the remodeling process, particularly if prescribed in sufficiently high doses and for a sufficient duration.4Hoshino M. Impact of inhaled corticosteroids and leukotriene receptor antagonists on airway remodeling.Clin Rev Allergy Immunol. 2004; 27: 59-64Crossref PubMed Google Scholar Additionally, it has been believed that the use of anti-inflammatory medications early in the expression of asthma would attenuate inflammation and, consequently, prevent remodeling and the resultant accelerated decrease in lung function. Finally, it has been believed that effective use of anti-inflammatory medications might reverse existing airway remodeling and thus improve lung function.4Hoshino M. Impact of inhaled corticosteroids and leukotriene receptor antagonists on airway remodeling.Clin Rev Allergy Immunol. 2004; 27: 59-64Crossref PubMed Google Scholar An apparent lack of effectiveness of traditional therapies to attenuate inflammation (eg, inhaled corticosteroids [ICSs]), especially in those with severe asthma and children with the finding of early changes in airway histopathology, have questioned the concept that "persistent inflammation leads to remodeling."5Jenkins H.A. Cool C. Szefler S.J. Covar R. Brugman S. Gelfand E.W. et al.Histopathology of severe childhood asthma: a case series.Chest. 2003; 124: 32-41Crossref PubMed Scopus (129) Google Scholar Specifically, there is mounting histologic evidence that the presence of remodeling, such as epithelial loss, reticular basement membrane (RBM) thickening, and angiogenesis, might occur as early as 4 years of age in asthmatic subjects.6Barbato A. Turato G. Baraldo S. Bazzan E. Calabrese F. Panizzolo C. et al.Epithelial damage and angiogenesis in the airways of children with asthma.Am J Respir Crit Care Med. 2006; 174: 975-981Crossref PubMed Scopus (279) Google Scholar, 7Turato G. Barbato A. Baraldo S. Zanin M.E. Bazzan E. Lokar-Oliani K. et al.Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma.Am J Respir Crit Care Med. 2008; 178: 476-482Crossref PubMed Scopus (125) Google Scholar, 8Payne D.N. Rogers A.V. Adelroth E. Bandi V. Guntupalli K.K. Bush A. et al.Early thickening of the reticular basement membrane in children with difficult asthma.Am J Respir Crit Care Med. 2003; 167: 78-82Crossref PubMed Scopus (430) Google Scholar However, airway remodeling was not demonstrated in "asthmatic" infants at 1 year of age,9Saglani S. Malmstrom K. Pelkonen A.S. Malmberg L.P. Lindahl H. Kajosaari M. et al.Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction.Am J Respir Crit Care Med. 2005; 171: 722-727Crossref PubMed Scopus (319) Google Scholar suggesting that remodeling can occur in parallel, rather than in sequence, with inflammation and might be a component of the natural history of asthma for some patients.6Barbato A. Turato G. Baraldo S. Bazzan E. Calabrese F. Panizzolo C. et al.Epithelial damage and angiogenesis in the airways of children with asthma.Am J Respir Crit Care Med. 2006; 174: 975-981Crossref PubMed Scopus (279) Google Scholar Although the pathogenesis of airway remodeling in asthmatic subjects remains in question, the clinical consequences are better appreciated. Airway remodeling has been implicated as playing a role in persistent airway hyperresponsiveness (AHR),10McParland B.E. Macklem P.T. Pare P.D. Airway wall remodeling: friend or foe?.J Appl Physiol. 2003; 95: 426-434Crossref PubMed Scopus (177) Google Scholar excessive airflow narrowing,11Pare P.D. McParland B.E. Seow C.Y. Structural basis for exaggerated airway narrowing.Can J Physiol Pharmacol. 2007; 85: 653-658Crossref PubMed Scopus (41) Google Scholar and ultimately fixed airflow obstruction, especially in subjects with severe asthma.12Royce S.G. Tan L. Koek A.A. Tang M.L. Effect of extracellular matrix composition on airway epithelial cell and fibroblast structure: implications for airway remodeling in asthma.Ann Allergy Asthma Immunol. 2009; 102: 238-246Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The clinical consequences of persistent airflow obstruction can be dramatic and irreversible and, as such, imply a need to develop new therapeutic approaches or interventions to specifically target components of airway remodeling to either prevent or reverse these processes. Unfortunately, such a proposal is easier said than done with current treatments. First, it is unclear which components of remodeling should be targeted and at what point in the natural history of asthma such treatments should be initiated to achieve the best results. Second, it is unclear whether all components of remodeling are actually detrimental to the pathophysiology of asthma. For example, asthmatic airways might become "stiffer" because of remodeling (eg, fibrosis), and these changes might actually counteract excessive airway narrowing.1Mauad T. Bel E.H. Sterk P.J. Asthma therapy and airway remodeling.J Allergy Clin Immunol. 2007; 120: 997-1011Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar Therefore developing a treatment directed toward a specific aspect of airway remodeling, the physiologic consequence of which might ultimately have been of benefit in asthmatic subjects, might be counterproductive. As a result, it is necessary to have a more clear understanding of the clinical consequences of specific components of remodeling. There is also uncertainty as to whether certain aspects of remodeling determine asthma severity and its progression.13James A. Remodelling of airway smooth muscle in asthma: what sort do you have?.Clin Exp Allergy. 2005; 35: 703-707Crossref PubMed Scopus (19) Google Scholar Finally, there is a need to better understand which asthma indices correlate with detrimental components of airway remodeling and which aspects might best direct the treatment of remodeling to attenuate its progression to irreversible airflow obstruction. The following review summarizes current interventions in asthmatic subjects and their effects on aspects of airway remodeling. The majority of experience to date involves the effects of corticosteroids, and as such, our review will focus largely on the influence of corticosteroid treatment on remodeling. Although more limited, we will also review the experiences with other interactions, such as anti-IgE, anti–IL-5, and anti–TNF-α, on airway remodeling. Corticosteroids, either inhaled (ICSs) or systemic (oral corticosteroids), modulate acute and chronic inflammation in asthmatic subjects, particularly in those with milder disease, and have broad pharmacologic actions.14Bateman E.D. Hurd S.S. Barnes P.J. Bousquet J. Drazen J.M. FitzGerald M. et al.Global strategy for asthma management and prevention: GINA executive summary.Eur Respir J. 2008; 31: 143-178Crossref PubMed Scopus (2285) Google Scholar, 15Expert Panel Report 3 (EPR-3): guidelines for the diagnosis and management of asthma—summary report 2007.J Allergy Clin Immunol. 2007; 120: S94-S138PubMed Google Scholar Consequently, glucocorticoids are considered the therapeutic mainstay for chronic asthma and its underlying inflammation. Indeed, as a result of the "chronic inflammation leads to remodeling" paradigm, corticosteroids have long played a central role in interventional studies to assess the effect of treatment on airway remodeling in asthmatic subjects. However, the aforementioned recent childhood airway studies have cast doubt on this model. New evidence suggests remodeling might arise from asthma exacerbations and not chronic inflammation,5Jenkins H.A. Cool C. Szefler S.J. Covar R. Brugman S. Gelfand E.W. et al.Histopathology of severe childhood asthma: a case series.Chest. 2003; 124: 32-41Crossref PubMed Scopus (129) Google Scholar, 6Barbato A. Turato G. Baraldo S. Bazzan E. Calabrese F. Panizzolo C. et al.Epithelial damage and angiogenesis in the airways of children with asthma.Am J Respir Crit Care Med. 2006; 174: 975-981Crossref PubMed Scopus (279) Google Scholar, 7Turato G. Barbato A. Baraldo S. Zanin M.E. Bazzan E. Lokar-Oliani K. et al.Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma.Am J Respir Crit Care Med. 2008; 178: 476-482Crossref PubMed Scopus (125) Google Scholar, 8Payne D.N. Rogers A.V. Adelroth E. Bandi V. Guntupalli K.K. Bush A. et al.Early thickening of the reticular basement membrane in children with difficult asthma.Am J Respir Crit Care Med. 2003; 167: 78-82Crossref PubMed Scopus (430) Google Scholar and these events ultimately lead to an exaggerated decrease in lung function.16Bai T.R. Vonk J.M. Postma D.S. Boezen H.M. Severe exacerbations predict excess lung function decline in asthma.Eur Respir J. 2007; 30: 452-456Crossref PubMed Scopus (253) Google Scholar, 17O'Byrne P.M. Pedersen S. Lamm C.J. Tan W.C. Busse W.W. Severe exacerbations and decline in lung function in asthma.Am J Respir Crit Care Med. 2009; 179: 19-24Crossref PubMed Scopus (314) Google Scholar These observations imply that airway remodeling might be due to worsening of airway inflammation associated with asthma exacerbations and support the paradigm that inflammation and remodeling occur in concert.16Bai T.R. Vonk J.M. Postma D.S. Boezen H.M. Severe exacerbations predict excess lung function decline in asthma.Eur Respir J. 2007; 30: 452-456Crossref PubMed Scopus (253) Google Scholar For example, the Inhaled Steroid Treatment As Regular Treatment trial found that the decrease in lung function associated with exacerbations might be attenuated by ongoing treatment with low-dose ICSs.17O'Byrne P.M. Pedersen S. Lamm C.J. Tan W.C. Busse W.W. Severe exacerbations and decline in lung function in asthma.Am J Respir Crit Care Med. 2009; 179: 19-24Crossref PubMed Scopus (314) Google Scholar These clinical findings and those of Bai et al16Bai T.R. Vonk J.M. Postma D.S. Boezen H.M. Severe exacerbations predict excess lung function decline in asthma.Eur Respir J. 2007; 30: 452-456Crossref PubMed Scopus (253) Google Scholar indicate that corticosteroids might affect remodeling, especially if administered during critical periods of asthma development and airway injury (ie, exacerbations). Therefore to appreciate the role and contribution of remodeling to asthma and the effects of treatment on these processes, our discussion will focus on individual aspects of remodeling and the effects of medication on these airway features. Although our discussion might focus on individual components of remodeling and the effects of treatment, it is more likely that the repair process involves multiple changes at the same time, and if an intervention is beneficial, the improvement might represent a broad-based effect. Many factors contribute to remodeling. A prominent feature of remodeling is subepithelial fibrosis, which consists of subepithelial lamina reticularis thickening underneath the true basement membrane and is referred to as reticular basement membrane thickening. RBM thickening is a characteristic feature of airway remodeling (Fig 1). It is important to note that the true basement membrane (ie, basal lamina of the bronchial epithelium) is not affected in asthma; rather, when the phrase basement membrane thickening is used, it most often refers to a thickening of the RBM and involves the replacement of a typically loose network of collagen fibrils with a dense network of collagen (type I and III), laminin, tenascin, fibronectin, and proteoglycans.18Halwani R. Al-Muhsen S. Hamid Q. Airway remodeling in asthma.Curr Opin Pharmacol. 2010; 10: 236-245Crossref PubMed Scopus (113) Google Scholar, 19Roche W.R. Beasley R. Williams J.H. Holgate S.T. Subepithelial fibrosis in the bronchi of asthmatics.Lancet. 1989; 1: 520-524Abstract PubMed Scopus (961) Google Scholar RBM thickening is one of the most commonly studied components of remodeling, in part because of the relative ease of access to airway tissue with bronchoscopy, with samples retrieved predominantly from the large airways. The primary cellular and molecular mechanisms of RBM thickening/subepithelial fibrosis are thought to arise from an imbalance between synthesis and degradation of matrix components by key effector cells (eg, fibroblasts, myofibroblasts, and eosinophils).20Todorova L. Gurcan E. Westergren-Thorsson G. Miller-Larsson A. Budesonide/formoterol effects on metalloproteolytic balance in TGFbeta-activated human lung fibroblasts.Respir Med. 2009; 103: 1755-1763Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Under normal conditions, matrix metalloproteinases (MMPs), which regulate the deposition of collagen, and tissue inhibitors of metalloproteinases (TIMPs), which prevent this process, are in equilibrium. In asthmatic subjects increased levels, activity, or both of MMPs are common and can occur after allergen challenge,21Kelly E.A. Busse W.W. Jarjour N.N. Increased matrix metalloproteinase-9 in the airway after allergen challenge.Am J Respir Crit Care Med. 2000; 162: 1157-1161Crossref PubMed Scopus (170) Google Scholar during asthma exacerbations, and in subjects with severe asthma.20Todorova L. Gurcan E. Westergren-Thorsson G. Miller-Larsson A. Budesonide/formoterol effects on metalloproteolytic balance in TGFbeta-activated human lung fibroblasts.Respir Med. 2009; 103: 1755-1763Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Interestingly, increased levels of TIMPs are also found in asthmatic subjects with increased airway fibrosis, which suggests that remodeling might also be the consequence of excessive repair.20Todorova L. Gurcan E. Westergren-Thorsson G. Miller-Larsson A. Budesonide/formoterol effects on metalloproteolytic balance in TGFbeta-activated human lung fibroblasts.Respir Med. 2009; 103: 1755-1763Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar TGF-β is considered a key mediator in remodeling and is synthesized by airway cells, epithelial cells, fibroblasts, and eosinophils.22Broide D.H. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling.J Allergy Clin Immunol. 2008; 121: 560-572Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar TGF-β induces TIMP-1 to stimulate fibroblasts to produce extracellular matrix (ECM) proteins and promotes myofibroblasts to produce collagen.22Broide D.H. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling.J Allergy Clin Immunol. 2008; 121: 560-572Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar Furthermore, TGF-β expression correlates with the degree of subepithelial fibrosis and is significantly increased in subjects with severe asthma with associated eosinophilia.22Broide D.H. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling.J Allergy Clin Immunol. 2008; 121: 560-572Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 23Ohno I. Nitta Y. Yamauchi K. Hoshi H. Honma M. Woolley K. et al.Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation.Am J Respir Cell Mol Biol. 1996; 15: 404-409Crossref PubMed Scopus (239) Google Scholar RBM thickening is associated with many pathophysiologic features of asthma, can be found in subjects with all degrees of asthma severity,24Shiba K. Kasahara K. Nakajima H. Adachi M. Structural changes of the airway wall impair respiratory function, even in mild asthma.Chest. 2002; 122: 1622-1626Crossref PubMed Scopus (40) Google Scholar, 25Bourdin A. Neveu D. Vachier I. Paganin F. Godard P. Chanez P. Specificity of basement membrane thickening in severe asthma.J Allergy Clin Immunol. 2007; 119: 1367-1374Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar and correlates directly with airflow obstruction24Shiba K. Kasahara K. Nakajima H. Adachi M. Structural changes of the airway wall impair respiratory function, even in mild asthma.Chest. 2002; 122: 1622-1626Crossref PubMed Scopus (40) Google Scholar, 26Kasahara K. Shiba K. Ozawa T. Okuda K. Adachi M. Correlation between the bronchial subepithelial layer and whole airway wall thickness in patients with asthma.Thorax. 2002; 57: 242-246Crossref PubMed Scopus (181) Google Scholar and AHR.27Milanese M. Crimi E. Scordamaglia A. Riccio A. Pellegrino R. Canonica G.W. et al.On the functional consequences of bronchial basement membrane thickening.J Appl Physiol. 2001; 91: 1035-1040PubMed Google Scholar Changes in RBM, in contrast, are negatively correlated with airway distensibility.12Royce S.G. Tan L. Koek A.A. Tang M.L. Effect of extracellular matrix composition on airway epithelial cell and fibroblast structure: implications for airway remodeling in asthma.Ann Allergy Asthma Immunol. 2009; 102: 238-246Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 28Ward C. Johns D.P. Bish R. Pais M. Reid D.W. Ingram C. et al.Reduced airway distensibility, fixed airflow limitation, and airway wall remodeling in asthma.Am J Respir Crit Care Med. 2001; 164: 1718-1721Crossref PubMed Scopus (119) Google Scholar Furthermore, RBM thickening has not been demonstrated in symptomatic infants with reversible airway obstruction,9Saglani S. Malmstrom K. Pelkonen A.S. Malmberg L.P. Lindahl H. Kajosaari M. et al.Airway remodeling and inflammation in symptomatic infants with reversible airflow obstruction.Am J Respir Crit Care Med. 2005; 171: 722-727Crossref PubMed Scopus (319) Google Scholar whereas it is found in older children with more severe asthma.8Payne D.N. Rogers A.V. Adelroth E. Bandi V. Guntupalli K.K. Bush A. et al.Early thickening of the reticular basement membrane in children with difficult asthma.Am J Respir Crit Care Med. 2003; 167: 78-82Crossref PubMed Scopus (430) Google Scholar These findings suggest that RBM thickening occurs once the asthma process is started. The resulting subepithelial fibrosis increases airway narrowing by reducing airway elastance and generating a greater force of contraction as the bulk of ASM increases.29Bramley A.M. Thomson R.J. Roberts C.R. Schellenberg R.R. Hypothesis: excessive bronchoconstriction in asthma is due to decreased airway elastance.Eur Respir J. 1994; 7: 337-341Crossref PubMed Scopus (106) Google Scholar The clinical implications of attenuating or preventing subepithelial fibrosis are significant, but the effects associated with corticosteroid treatment are poorly understood and, at times, conflicting (Table I).30Sont J.K. Willems L.N. Bel E.H.