Airway remodelling in asthma: models and supermodels?

Abstract

Although currently anti-inflammatory treatments are effective for most of the 5 million patients treated in the UK they do not completely control symptoms, and a minority of asthmatics continue to experience severe debilitating disease [1]. Of note, although inhaled corticosteroids reduce the Th2type eosinophilic airway inflammation and airway hyperresponsiveness (AHR) that characterize asthma, they do not restore either variable to normal [2]. For this reason attention has been focused on structural changes in the asthmatic airway termed airway remodelling. These changes include epithelial damage and goblet cell hyperplasia [3], increased airway smooth muscle [4] and recruitment and activation of myofibroblasts [5]. Increased deposition of collagens and other extracellular matrix proteins such as tenascin and fibronectin occurs both in the reticular basement membrane (RBM) [6] and throughout the bronchial mucosa and this structural remodelling is accompanied by new blood vessel formation [7]. The clinical consequences of airway remodelling in asthma remain uncertain but contributions to AHR and fixed airflow obstruction have been suggested. Mathematical modelling predicts that airways with increased smooth muscle narrow to a much greater extent than airways with less smooth muscle volume for a given degree of circumferential smooth muscle shortening [8]. Asthmatic subjects show accelerated decline in lung function over time compared with non-asthmatic subjects, and this loss of lung function is more marked in asthmatic smokers [9, 10]. Although duration and severity of asthma are the most important risk factors for development of fixed obstruction the highest rate of loss of lung function is seen during the early course of the illness. Interestingly, remodelling changes are seen early in childhood and may even pre-date the onset of symptoms [11]. The impact of current anti-inflammatory treatment on remodelling is controversial. Although partial reversal of remodelling has been reported with inhaled corticosteroid treatment, responses are seen after prolonged therapy [12] and are not confirmed in all studies. The initial rapid improvement in AHR in asthma with inhaled corticosteroid treatment may be explained by reduction in airway inflammation [13], but additional improvements over many months may reflect changes in remodelling. Important questions about airway remodelling in asthma remain unanswered (see Fig. 1). These include: