Review and feature article
Airway remodeling contributes to the progressive loss of lung function in asthma: An overview

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Airway inflammation, airflow obstruction, and bronchial hyperresponsiveness are characteristic phenotypic features of asthma. Clinically, airflow obstruction in asthma often is not fully reversible, and many asthmatic subjects experience an accelerated and progressive loss of lung function over time. Histopathologic studies of the asthmatic airway have demonstrated stereotypic changes that might explain the loss of lung function that many patients with asthma experience. The notion of airway remodeling in asthma postulates that the alteration of the structure and function of key airway constituents, including airway smooth muscle, epithelium, blood vessels, and mucus glands, might explain, at least in part, the progressive loss of lung function that is observed clinically. Inflammation driven by CD4+ lymphocytes and mediated by effector cells, particularly the eosinophil, appears to modulate the function of mesenchymal cells, including fibroblasts and myofibroblasts, changing the composition of the airway wall matrix. Changes in the airway epithelium might alter the function of the underlying smooth muscle and the composition of the matrix and could drive inflammation. Alterations in the structure and function of airway smooth muscle change the mechanical properties of the airway wall and might also affect the function of other airway constituents. A variety of experimental models have identified candidate mechanisms and mediators for these observed changes, which are thus potential therapeutic targets. However, clinical studies to date have been disappointing, and it remains to be seen whether targeted therapies will prevent the progressive loss of lung function seen in asthma.

Section snippets

Models of airway remodeling

A number of models have been used to characterize airway remodeling in asthma. Examination of lung tissues available at autopsy have shown that profound changes in airway morphology and structure have occurred in those that have died from asthma when compared with decedents with asthma dying from other causes and those without asthma.1 In vivo, characterization of airway biopsy specimens from living subjects with asthma have been compared with those from control subjects. Many studies

ASM remodeling

Airflow obstruction and AHR are a result of the contraction of ASM and hence indicate alterations in smooth muscle function. Several studies of patients dying from severe asthma have reported an increase in the apparent muscle mass within the airway wall in subjects with severe asthma when compared with control subjects.1, 10, 11 In histologic studies an increase in mass is assumed when there is an increase in the cross-sectional area occupied by ASM. Subjects with fatal asthma have been

Changes in inflammatory cells in airway remodeling

Despite the fact that airway inflammation has been known to be a prominent feature of asthma for decades, it still is not known whether inflammation drives the remodeling response in the airway wall or whether an intrinsic abnormality of airway structure or function drives inflammation. It has been widely assumed that allergic inflammation is the initiating event. A partial list of various asthma inflammatory mediators is presented in Table II.18, 29, 37, 38, 39, 40, 41, 42, 43, 44 There is no

Epithelial cell remodeling

Asthmatic airway biopsies, autopsy studies, and animal models all show that the epithelium is remodeled in asthma. Epithelial cells are found in increased amounts in asthmatic sputum, and epithelial detachment from the basement membrane is frequently observed in the various models of asthma. Moreover, there are a higher proportion of goblet cells in the asthmatic epithelium in vivo, and subepithelial mucus glands are enlarged.69

The epithelium forms the outer cellular barrier and serves

Asthmatic subepithelium and epithelial damage and repair

Underlying the bronchial epithelial cell layer is the lamina reticularis, also known as the reticular basement membrane (RBM; reviewed by Jeffery7). Several studies have reported that this layer is thickened, and this is a characteristic feature of airway remodeling in asthma. For example, Payne et al75 compared the thickness of the RBM in children with asthma who required moderately high doses of inhaled steroids with that in healthy children and adults with asthma. Interestingly, the

Conclusions

The clinical findings of asthma were initially identified many years ago and include reversible airflow obstruction, AHR, and mucus hypersecretion. Subsequently, histopathologic studies of airways from both animals and human subjects provided a structural basis for these clinical observations and led to the development of the concept of airways remodeling. Longitudinal studies of patients with asthma suggest that a progressive loss of lung function occurs in at least some asthmatic subjects.

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    Series editor: Harold S. Nelson, MD

    Supported in part by grants HL067663 and HL074225 to SPP.

    Disclosure of potential conflict of interest: R. Pascual—none disclosed. S. Peters—As a member of the Wake Forest University Clinical Trials Group, Dr Peters has been involved in clinical trials supported by Abaris, AstraZeneca, Altana, Boehringer Ingelheim, Centocor, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Wyeth. He has also performed consulting duties under the auspices of the National Institutes of Health, Adelphi, American Thoracic Society, AstraZeneca Pharmaceuticals, Discovery, Genentech, Novartis, Omnicare, RAND Corporation, Respiratory Medicine, Respiratory Research, and SanofiAventis. He has also participated in physician education programs (including speakers' bureaus) sponsored by the American College of Chest Physicians; American Lung Association; American Academy of Allergy, Asthma and Immunology; AstraZeneca; Merck; Genentech; Novartis; and the Respiratory and Allergic Disease (RAD) Foundation.

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