Reviews and feature articleImmunologic and inflammatory mechanisms that drive asthma progression to remodeling
Section snippets
Progression of asthma to airway remodeling: epidemiology
Asthma is a chronic inflammatory disease of the airway that affects approximately 7% of the population of the United States.1 The chronic inflammatory response in the airway in asthma is characterized by the presence of increased numbers of TH2 lymphocytes, eosinophils, and activated mast cells.2 In addition to the presence of inflammatory cells in the airway, the airways of patients with asthma exhibit varying levels of structural changes termed airway remodeling.3, 4, 5 Characteristic
Is there a link among immune cells, airway inflammation, and airway remodeling?
Although it is well recognized that airway inflammation is a prominent feature of asthma, the relationship between individual components of airway inflammation and the progression of inflammation to remodeling of the airways in asthma is not well understood. Evidence that immune mechanisms and inflammation are important in the pathogenesis of airway remodeling are derived either from studies in animal models of airway remodeling in asthma or from human studies of patients with asthma with
T cells
Although TH2 cells play an important role in the pathogenesis of allergic inflammation and asthma17 (Fig 2), the contribution of TH2 cells to the pathogenesis of airway remodeling requires further investigation. Insight into the role of T-cell subsets in allergen-induced airway remodeling has been derived from the study of transgenic mice with enhanced expression of transcription factors that direct lineage commitment of T cells to either TH1 or TH2 cells. For example, studies of airway
Selected candidate mediators of airway remodeling
Although multiple mediators are likely to participate in the pathogenesis of airway remodeling, several mediators (TGF-β, matrix metalloproteinase [MMP]–9, a disintegrin and metalloproteinase [ADAM]–33, VEGF) have been the focus of considerable investigation.
Asthma genes and airway remodeling
Although more than 100 genes have been linked to asthma,76 these studies have generally focused on identifying linkage of genes to airway responsiveness, IgE, atopy, and asthma, rather than linkage of genes to airway remodeling. The identification that a genetic polymorphism in ADAM-33 is associated with an accelerated decline in lung function over time in asthma68 suggests that there may be a subset of genes associated with airway remodeling. Further studies are needed to confirm this
Acute exacerbations of asthma and airway remodeling
Although patients with asthma exhibit a greater decline in lung function compared with controls without asthma, analysis of the rate of decline in lung function in patients with asthma as a group may obscure a greater decline in a subset of subjects with asthma. Thus, it is possible that patients with asthma who have inadequate airway repair mechanisms and/or inadequately treated episodes of inflammation may have prolonged episodes of airway inflammation that lead to significantly remodeled
Is airway remodeling reversible? Endobronchial biopsy studies
Corticosteroids are the most effective anti-inflammatory therapy in asthma. Several studies using bronchial biopsies have also demonstrated that corticosteroids reduce airway inflammation in asthma.83 Although the ability of corticosteroids to improve features of airway inflammation is well established, the ability of corticosteroids to reduce airway remodeling on the basis of airway biopsy studies is not as well established. There are airway biopsy studies that support as well as refute a role
Limitations of current approaches to quantitating airway remodeling in asthma
In general, studies of airway remodeling in asthma use either noninvasive or invasive methods to quantitate levels of airway remodeling. Each of these approaches has strengths and weaknesses that need to be taken into account when interpreting the results of such studies.
Key concepts and therapeutic implications
Airway remodeling may be a result of persistent inflammation and/or aberrant tissue repair mechanisms. Different features of airway remodeling are likely mediated by different inflammatory pathways.
Several important candidate mediators of remodeling have been identified, including TGF-β and TH2 cytokines (including IL-5 and IL-13) as well as VEGF, ADAM-33, and MMP-9.
Although decline in lung function is used as a very important surrogate for airway remodeling in asthma, longitudinal studies
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(Supported by an educational grant from Merck & Co., Inc.)
Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD
Supported by the National Institutes of Health.
Disclosure of potential conflict of interest: The author has declared that he has no conflict of interest.
Terms in boldface and italics are defined in the glossary on page 561.