Mechanisms of airway epithelial damage: epithelial-mesenchymal interactions in the pathogenesis of asthma.

Abstract

The aims of this article are to understand the shortfalls in thinking of asthma purely as an atopic disorder, to gain insight into the epithelial abnormalities of asthma and how these interface with the environment, and to view asthma as a disease of airway wall restructuring that engages activation of the epithelial mesenchymal trophic unit (EMTU). Furthermore, based on these developments, possible novel therapeutic targets for chronic asthma are identified. It has long been recognised that T‐helper cell (Th) type‐2 airway inflammation underpins airway dysfunction in asthma. Atopy is also a key feature of this disease but accounts for <40% of the population attributable risk. Based on a careful pathological and functional assessment of chronic asthma, the authors propose that altered epithelial-mesenchymal communication is also fundamental to disease pathogenesis. A number of factors contribute to a thickened hyperresponsive airway that provides an ideal microenvironment for the persistence of Th2‐mediated inflammation, including a more susceptible epithelium to injury, delayed epithelial repair, an altered trajectory of epithelial repair to a mucus-secreting phenotype, generation of growth factors that drive mesenchymal cell proliferation and differentiation towards increased matrix deposition and smooth muscle, and the production of neural and vascular growth factors. Cytokines and mediators derived from infiltrating inflammatory cells interact with this EMTU to augment and prolong responses. The “remodelling” changes of asthma have been observed in childhood asthma and may, indeed, precede the development of the disease. The recent recognition that atopy per se is not a key factor in the initiation of asthma (although it is important in aggravating the disease) suggests that gene-environmental interactions involving similar processes to those occurring in branching morphogenesis are critical for the full asthma phenotype to develop. A recent National Institutes for Health Workshop and a European Respiratory Society Task Force both concluded that more work …