Chest
Volume 129, Issue 4, April 2006, Pages 1068-1087
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Special Feature
Structural Changes in Airway Diseases: Characteristics, Mechanisms, Consequences, and Pharmacologic Modulation

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In airway diseases such as asthma and COPD, specific structural changes may be observed, very likely secondary to an underlying inflammatory process. Although it is still controversial, airway remodeling may contribute to the development of these diseases and to their clinical expression and outcome. Airway remodeling has been described in asthma in various degrees of severity, and correlations have been found between such features as increase in subepithelial collagen or proteoglycan deposits and airway responsiveness. Although the clinical significance of airway remodeling remains a matter of debate, it has been suggested as a potential target for treatments aimed at reducing asthma severity, improving its control, and possibly preventing its development. To date, drugs used to treat airway diseases have a little influence on airway structural changes. More research should be done to identify key changes, valuable treatments, and proper interventional timing to counteract these changes. The potential of novel therapeutic agents to reverse or prevent airway remodeling is an exciting avenue and warrants further evaluation.

Section snippets

Airway Structure and Remodeling Features

From a histologic perspective, the human airway can be divided into three layers: the inner wall, the outer wall, and the smooth-muscle layers.1 The inner wall layer refers to the epithelium, the basement membrane, and the submucosa. The outer wall layer consists of loose connective tissue between the muscle layer and surrounding parenchyma. In comparison to healthy airways, all airway layers have been shown to present some alterations in airway obstructive diseases. Epithelial alterations,

Inflammation-Mediated Remodeling

Asthma is considered to be an inflammatory disease of the airways that is mostly triggered by allergen exposure in sensitized individuals, viral infections, and toxic exposures. The Th2-mediated inflammatory response, a complex interaction between a wide network of inflammatory and structural cells, is typical of asthma.86 Many asthma-related mediators and cytokines, such as TGF-β, IL-11, IL-17, and leukotriene D4 have potent remodeling properties. Th2 lymphocytes, mast cells, and eosinophils

Does Airway Remodeling Occur Before Airway Diseases Become Symptomatic?

We previously showed that subjects with allergic rhinitis without asthma or AHR display evidence of airway remodeling, although to a lesser extent than in asthma.22 Furthermore, subjects with asymptomatic AHR show focal bronchial subepithelial fibrosis on bronchial biopsies, and when respiratory symptoms develop, the subjects show evidence of an increase in subepithelial fibrosis and in the number of CD25/CD4-positive T-cells.147 These observations suggest that the structural airway changes

Protective Effects

It has also been proposed that the remodeling process might be beneficial in airway diseases. Lambert and colleagues149 suggested that airway wall thickening protects against bronchoconstriction. Peribronchiolar fibrosis correlated with milder COPD stage, suggesting that fibrosis can be protective, preventing narrowing.67 Collagen deposition in subepithelial matrix may inhibit narrowing by making the airway wall stiffer, representing an additional load on ASM.23 Hyaluronan and versican

Corticosteroids

Control of persistent asthma can be usually achieved by early treatment and maintenance therapy with ICS.168 Some evidence supports the role of ICS in preventing or reducing the decline of airway function in asthmatic patients,169170 with a greater benefit if therapy with ICS is started early after asthma diagnosis.171 However, the Childhood Asthma Management Program study172 reported no significant long-term prevention in the decline of lung function with ICS in children presenting

Nonpharmacologic Interventions

Bronchothermoplasty is an original mode of intervention that consists of applying an electric current to segmental and subsegmental bronchi, with the goal of destroying the smooth muscle and therefore reducing its capacity to contract. Although studies should determine the usefulness of this treatment, it has been shown to alter airway structure in a possibly beneficial way. In fact, Cox and colleagues249 report a persistent improvement of 2.9 doubling dose of methacholine bronchoprovocation

Remaining Questions and Future Research

Airway remodeling is a complex phenomenon that includes a variety of changes whose specific contributions to the change in airway function need further analyses. The time course and mechanisms by which such changes translate into modifications of airway responsiveness and symptomatic airway obstruction are to be evaluated more extensively in term of effects of the different treatments used for these conditions. Various methodologic aspects should, however, be taken into account when studying

Conclusions

Although this is still controversial, we have evidence that the airway remodeling process may have untoward consequences in obstructive diseases, in the clinical expression of the disease, in its development, and in the decline in pulmonary function. The common factor underlying all the structural changes in airway diseases is an injury/repair process. In asthma, the damage follows an allergenic or nonallergenic Th2 inflammation and mechanical stress. In COPD, the initial trigger is cigarette

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