Airway remodelling in asthma: Current understanding and implications for future therapies

Abstract

Airway remodelling refers to the structural changes that occur in the airway wall in asthma. These include epithelial hyperplasia and metaplasia, subepithelial fibrosis, muscle cell hyperplasia and angiogenesis. These structural changes result in thickening of the airway wall, airway hyperresponsiveness (AHR), and a progressive irreversible loss of lung function. The precise sequence of events that take place during the remodelling process and the mechanisms regulating these changes remain poorly understood. It is thought that airway remodelling is initiated and promoted by repeated episodes of allergic inflammation that damage the surface epithelium of the airway. However, other mechanisms are also likely to contribute to this process. Moreover, the interrelationship between airway remodelling, inflammation and AHR has not been clearly defined. Currently, there are no effective treatments that halt or reverse the changes of airway remodelling and its effects on lung function. Glucocorticoids have been unable to eliminate the progression of remodelling changes and there is limited evidence of a beneficial effect from other available therapies. The search for novel therapies that can directly target individual components of the remodelling process should be made a priority. In this review, we describe the current understanding of the airway remodelling process and the mechanisms regulating its development. The impact of currently available asthma therapies on airway remodelling is also discussed.

Introduction

The term remodelling refers to structural changes that occur in organs and tissues following disease pathogenesis. Airway remodelling pertains specifically to the changes that occur in and around the trachea, bronchi and bronchioles. Airway remodelling is a central feature of asthma, linking inflammation with airway hyperresponsiveness (AHR). The structural changes observed in asthma involve all components of the airway wall including the epithelial, submucosal, and smooth muscle layers as well as vascular structures. The consequences of airway remodelling are increased AHR, fixed airflow obstruction, and irreversible loss of lung function. The mechanisms regulating airway remodelling changes and the order in which these changes develop remain poorly understood. Although structural changes in the airway are strongly correlated with inflammation, aspects of airway remodelling may occur independently of airway inflammation and may precede the presentation of symptomatic asthma. In this review, we discuss each of the structural changes observed in asthma and the mechanisms by which these changes may be regulated. Understanding the molecular events leading to structural changes may facilitate the development of novel therapeutic approaches to directly target airway remodelling and hence prevent or reverse deterioration in lung function.

The major components of airway remodelling are (1) surface epithelial metaplasia with increased epithelial thickness, goblet cell hyperplasia and increased mucus secretion, (2) fibrosis with deposition of abnormal extracellular matrix (ECM) components in the basement membrane (BM) layer beneath the epithelium and in the deeper submucosa (Belleguic et al., 2002), (3) increased thickness of smooth muscle due to muscle cell and myofibroblast hyperplasia and (4) angiogenesis. The airway epithelial cells, fibroblasts and smooth muscle cells undergo significant phenotypic differentiation during the remodelling process. Epithelial cells differentiate into mucus producing goblet cells, fibroblasts acquire a contractile and collagen-synthesising phenotype known as the myofibroblast and smooth muscle cells are thought to decrease expression of contractile proteins possibly as a prelude to acquiring proliferative capacity, although this remains controversial. As a result of these remodelling changes, there is thickening of the airway wall, which makes the airways stiffer and less distensible, as well as narrowing of the airway lumen.

There is little information on the specific sequence of events during the remodelling process. The current understanding of airway remodelling changes is predominantly based upon findings from cross-sectional studies and there is a paucity of asthmatic biopsy material available over the course of the disease. Furthermore, the histopathological analysis of bronchial biopsy samples provides a relatively superficial evaluation of changes within the airway, and more detailed examination of remodelling changes is only possible with post-mortem analysis of lung tissue in fatal asthma.

Studies of human asthma have shown that elements of remodelling, including epithelial metaplasia and subepithelial fibrosis, can occur early. Remodelling changes have been documented in patients with mild intermittent asthma (Beasley et al., 1989, Jeffery et al., 1989, Roche et al., 1989), in young children with asthma (Cutz et al., 1978), and in occupational asthma shortly after diagnosis when exposure to the sensitising agent has been relatively brief (Saetta et al., 1992). Unexpectedly, there is BM thickening in infants and children, rhinitis patients and those with atopy prior to the development of symptomatic asthma (Djukanovic et al., 1992, Chakir et al., 1996, Warner et al., 2000, Pohunek et al., 2005). Likewise, significant epithelial and subepithelial remodelling can be documented early in disease even at the time of diagnosis (Djukanovic et al., 1992, Chetta et al., 1997). It is therefore likely that many asthmatics develop changes of remodelling and progressive bronchodilator-resistant airway obstruction from a very early stage in their disease. Consistent with this, it has been demonstrated that although ‘irreversible’ airway obstruction correlates strongly with the duration and severity of asthma, the highest rate of loss of airway function (Orsida et al., 1999) occurs early after diagnosis (Ulrik & Lange, 1994, Kelly et al., 1988).

Established animal models of allergic airways disease (AAD) may assist with understanding the sequence of airway remodelling changes. The most cited of these are murine ovalbumin (OVA) sensitization models in which the challenge period can be varied to simulate acute or chronic asthma (Foster et al., 1996, Bani et al., 1997, Keramidaris et al., 2001, Kumar & Foster, 2001, Leigh et al., 2002, McMillan & Lloyd, 2004). Although these and other models vary from human asthma (Pabst, 2002, Kannan & Deshpande, 2003, Epstein, 2004) they can provide some evidence for early and late events in the airway remodelling process. For example, goblet cell hyperplasia is observed after only a few days of OVA challenge and persists for weeks (Wills-Karp et al., 1998). Similarly, in a comparison of OVA models of AAD, we found that epithelial thickening and goblet cell hyperplasia were early changes that occurred after only 4 days of challenge and persisted following longer term exposure to OVA (unpublished observation). In contrast, we and others have found that subepithelial collagen deposition developed progressively and was most pronounced after long term exposure to OVA (unpublished observation; Foster et al., 2000). Greater understanding of the precise sequence of events in the progression of airway remodelling will provide insight into the regulation these processes.