Associate editor: P.S. FosterAirway remodelling in asthma: Current understanding and implications for future therapies
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.
Section snippets
Consequences of airway remodelling
Reduced forced expiratory volume in 1 sec (FEV1) and increased AHR are used routinely in the clinical diagnosis of asthma. FEV1 is the most frequently used test for assessment of pulmonary function in asthma. A deep breath is taken to maximally fill the lungs and expired as forcefully as possible into a spirometer. FEV1 is reduced with bronchoconstriction. Airway responsiveness is assessed by measuring changes in FEV1 following exposure to increasing doses of bronchoconstrictor (such as
Repeated episodes of allergic inflammation
Allergic inflammation in asthma is thought to be an important primary cause of airway remodelling and may contribute to all aspects of the remodelling process. Repeated cycles of acute allergic inflammation not only contribute to AHR and reduced lung function by inducing mucosal oedema and inflammatory cell migration to the lumen, but also stimulate irreversible components of long-term airway structural change.
A characteristic feature of allergic inflammation is the predominance of Th2
Fibrosis
Fibrosis in the airway wall is a central feature of airway remodelling in asthma. This fibrosis is prominent in the lamina reticularis below the true BM (Roche et al., 1989) and may also occur in the deeper submucosa, around smooth muscle and arterioles (Wilson & Li, 1997). The development of fibrosis in the lamina reticularis is specific to asthma and does not occur in other airway disease (Roche et al., 1989). The ECM proteins deposited in the lamina reticularis include collagen types I and
Glucocorticoids
Glucocorticoids are effective for the treatment of allergic inflammation in asthma and also result in reduced AHR which is thought to be due to reduced inflammation (Djukanovic et al., 1992). However, long term treatment of asthmatics with inhaled corticosteroids (ICS) does not completely eliminate AHR or resolve airway obstruction (van Essen-Zandvliet et al., 1994). This suggests that the corticosteroid agents may have a limited impact on the progression of airway remodelling changes.
However,
Genetic susceptibility to airway remodelling
It is well known that asthma, like other allergic diseases, has an inherited component.
Only a handful of asthma susceptibility genes have so far been identified but it is probable that many of these will affect airway remodelling. One example is an orphan G-coupled protein receptor called GPRA which is differentially-expressed in epithelial cells and smooth muscle cells in asthmatics and in mice with OVA-induced AAD, compared to controls (Laitinen et al., 2004). The best known asthma gene is a
Conclusion
Asthma is a common disease that frequently has its onset in childhood and may persist lifelong. Airway remodelling is a characteristic feature of asthma that has deleterious consequences on lung function, causing AHR and fixed airway obstruction. The mechanisms regulating airway remodelling remain poorly understood. While airway inflammation is known to play a role in the progression of remodelling changes, other factors are also likely to be important in the regulation of this process. A
Acknowledgment
The authors wish to acknowledge Tiffany Bamford for providing the stained sections in Fig. 1.
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