Chest
Volume 123, Issue 3, Supplement, March 2003, Pages 417S-422S
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Airway Remodeling in Asthma

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Chronic inflammation and remodeling may follow acute inflammation or may begin insidiously as a low-grade smoldering response, especially in the case of immune reactions. The histologic hallmarks of chronic inflammation and remodeling are as follows: (1) infiltration by macrophages and lymphocytes; (2) proliferation of fibroblasts that may take the form of myofibroblasts; (3) angiogenesis; (4) increased connective tissue (fibrosis); and (5) tissue destruction. It is clear that changes in the extracellular matrix, smooth muscle, and mucous glands have the capacity to influence airway function and reactivity in asthma patients. However, it is not known how each of the many structural changes that occur in the airway wall contributes to altered airway function in asthma. In asthma, remodeling is almost always present in biopsy specimens (eg, collagen deposition on basement membrane) but is not always clinically demonstrated. Destruction and subsequent remodeling of the normal bronchial architecture are manifested by an accelerated decline in FEV1 and bronchial hyperresponsiveness. This irreversible component of airway obstruction is more prominent in patients with severe disease and even persists after aggressive anti-inflammatory treatment. Airway remodeling appears to be of great importance for understanding the long-term follow-up of asthmatic patients, but there are major gaps in our knowledge. Physiologic correlations with pathology represent a major missing link that should be filled. More long-term studies are needed to appreciate the prevention and treatment of remodeling. Future research therefore should provide better methods for limiting airway remodeling in asthma patients.

Section snippets

Demonstration of Airway Remodeling in Asthma

Various structural alterations have been described in the airways of asthmatic patients,1 all of which can contribute to an overall increase in airway wall thickness.4

Thickening of the Reticular Basement Membrane

Thickening of the reticular basement membrane (ie, the lamina reticularis) [Figs 1 and 2] is a characteristic feature of the asthmatic bronchus, occurring early on in the disease process. It appears to consist of a plexiform deposition of Ig, collagen I and III, tenascin, and fibronectin,5 but not of laminin. These proteins are likely produced by activated myofibroblasts,6 leading to a so-called subepithelial fibrosis. In some studies, the thickening could not be related to the severity,

Interstitial Matrix

The remodeling processes of the interstitial matrix are less well-documented than the thickening of the lamina reticularis. However, many features can be observed.

Blood Vessels

Airway wall remodeling in asthma patients involves a number of changes, including increased vascularity, vasodilatation, and microvascular leakage. Evidence suggests that the number and size of bronchial vessels is moderately increased in patients with asthma compared with normal controls (for a review, see Vignola et al1 and Bousquet et al3). In particular, there may be increased numbers of vessels in patients with fatal asthma,14 but the extent of neovascularization or angiogenesis is still

Smooth Muscle

Hypertrophy and hyperplasia of airway smooth muscle15 have been reported in postmortem specimens of asthmatic bronchi. In patients who died from an asthma exacerbation, the increase in smooth muscle was far greater than in those who died from another cause.15In vivo animal studies have confirmed that prolonged allergen exposure can increase smooth muscle.16

Mucous Glands

Mucous glands are distributed throughout the airways of asthma patients and, in the form of goblet cells, are even present in peripheral bronchioles where normally they are absent. The mucous glands in the segmental bronchi of asthmatic patients are considerably enlarged, and Dunnill et al17 showed that the volume of mucous glands was twice as great in asthmatic patients compared to healthy subjects. Animal models16 have indicated that goblet cell metaplasia and increased mucus production can

The Epithelium-Mesenchymal Interactions

In asthma patients, the bronchial epithelium is highly abnormal, with structural changes involving the separation of columnar cells from their basal attachments, and functional changes including increased expression and release of proinflammatory cytokines, growth factors, and mediator-generating enzymes. Beneath this damaged structure, there is an increased number of subepithelial myofibroblasts that deposit interstitial collagens, causing thickening and increased density of the subepithelial

Mast Cells and Fibroproliferative Response

In addition to epithelial cells, the activation of mesenchymal cells can be modulated by other cell types, such as mast cells.19 Recently, an increased number of tryptase-positive mast cells was found in the bundles of airway smooth muscle from subjects with asthma, suggesting that the infiltration of airway smooth muscle by mast cells is associated with the disordered airway function in asthma patients.26 One mediator that is released in high concentrations from degranulating mast cells is

Fibroblasts and Myofibroblasts

Fibroblasts and myofibroblasts can contribute to tissue remodeling by releasing ECM components such as elastin, fibronectin, and laminin.1 Increased numbers of myofibroblasts are found in the airways of asthmatic patients, and their number appears to correlate with the size of the basement reticular membrane.19 Following bronchial allergen challenge, myofibroblast numbers are increased, the cells undergo a differentiation process, and present with structural and ultrastructural features that

Smooth Muscle Cells

In patients who died from an asthma exacerbation, the increase in smooth muscle was far greater than in those who died from another cause, and in vivo animal studies have confirmed that prolonged allergen exposure can increase smooth muscle thickness.16 Cell culture studies have disclosed a wide range of soluble factors that can promote the proliferation of human airway smooth muscle cells, suggesting that, through autocrine loops, these cells can regulate their own proliferative rate. Evidence

Proteases and Protease Inhibitors

MMPs selectively degrade ECM components. MMPs also play a crucial role in the trafficking of inflammatory and structural cells. Imbalances between MMPs and their inhibitors may contribute to tissue damage and some of the remodeling features seen in asthma. MMP-9 can degrade native type IV and type V collagens, denatured collagens, entactin, proteoglycans, and elastin. An excess of tissue inhibitor of matrix metalloproteinase (TIMP)-1 over MMP-9 in stable asthma patients may interfere with cell

Conclusion

The presence of structural changes in the airways of asthmatic patients has clearly been established. It is equally clear that this remodeling process could have a profound influence on airway behavior. It also appears that airway inflammation and remodeling are interdependent processes that clearly influence the clinical long-term evolution of asthma. Thus, understanding the cellular and molecular mechanisms underlying airway remodeling is of great importance for the development of new and

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