Alterations in the structure and function of the airway epithelium are prominent features of asthma. The airway epithelium responds dramatically to cytokines produced in response to allergens and other stimuli. The Th2 cytokine interleukin-13 (IL-13) is directly responsible for the development of mucus-producing goblet cells (mucus metaplasia) in allergic models. Direct effects of IL-13 on epithelial cells can also cause airway hyperreactivity, another characteristic feature of asthma. We identified a remarkably small set of gene expression changes that are consistently associated with mucus metaplasia and airway hyperreactivity and are independent of inflammation. Our major goals are to identify the pathways responsible for these IL-13 triggered gene expression changes and to determine how specific gene expression changes contribute to airway disease. We hypothesize that IL-13 activates metalloproteinases leading to cleavage of EGFR pro-ligands and activation of the EGFR pathway, which in turn leads to reduced FOXA2 transcription and finally increased mucin gene expression. We also hypothesize that two members of the small set of genes induced by direct effects of IL-13 on epithelial cells make novel and important contributions to airway disease. One of these genes encodes the anion exchanger SLC26A4, and we found that nasal epithelial SLC26A4 expression was much higher in subjects with asthma than in controls and that allergen-challenged SIc26a4-/- mice have less airway hyperreactivity and eosinophilic inflammation than wild type mice. The other IL-13-induced gene encodes the goblet cell-specific secreted protein anterior gradient 2 (AGR2), which is a member of a family of proteins involved in cell adhesion and migration and in differentiation of mucus producing cells.
Our specific aims are 1) to determine the role of the EGF receptor pathway in the airway epithelial cell response to IL-13, 2) to determine the role of the transcription factor FOXA2 in the airway epithelial cell response to IL-13, 3) to determine how the IL-13-inducible epithelial anion exchanger SLC26A4 contributes to allergic airway disease, and 4) to determine how the IL-13-inducible goblet cell-specific secreted protein AGR2 contributes to allergic airway disease. The proposed studies will substantially advance our understanding of how the epithelium is altered in the allergic airway and how this contributes to pathogenesis. Relevance to public health: These studies are designed to produce new insights into basic mechanisms of disease that are relevant to asthma. Asthma is a major public health problem that affects tens of millions of Americans and this work will help to identify and assess several potential new targets for asthma treatment. ? ? ?
