The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma

Abstract

While asthma is an inflammatory disorder of the airways involving mediator release from mast cells and eosinophils and orchestrated by T cells, inflammation alone is insufficient to explain the chronic nature of the disease and its progression. Evidence is presented that the epithelium is fundamentally disordered in chronic asthma manifest by increased fragility, and an altered phenotype to one that secretes mucus, mediators, cytokines, chemokines and growth factors. Epithelial injury is mediated by exogenous factors such as air pollutants, viruses and allergens as well as by endogenous factors including the release of proteolytic enzymes from mast cells (tryptase, chymase) and eosinophils (MMP-9). Following injury, the normal epithelium should respond with increased proliferation driven by ligands acting on epidermal growth factor (EGF) receptors or through transactivation of the receptor. The epithelial response to these stimuli in asthma appears to be impaired despite upregulation of CD44 capable of enhancing presentation of EGF ligands to epidermal growth factor receptors (EGFR). Because the epithelium is 'held' in this repair phenotype, it becomes a continuous source of proinflammatory products as well as growth factors that drive airway wall remodelling.