The bronchoconstriction of asthma squeezes airway epithelial cells. This mechanical perturbation triggers a cascade of cellular signaling events that had previously been attributed largely to immune based inflammatory mechanisms. Over the past several years we have shown that mechanical stress-induced signaling events modify the phenotype of the epithelial cells themselves and activate fibroblasts in co-culture in a manner reminiscent of that observed in human asthma. In fact, this pattern of multicellular activation recapitulates in vitro, without activation of any immune inflammatory mechanism, the pro-fibrotic and mucus secretory micro-environment present in the asthmatic airway. Microarray analysis of the genes expressed in mechanically stressed airway epithelial cells has suggested that the downstream effects of mechanical stress on epithelial and mesenchymal cells are specific and targeted. We have demonstrated that mechanical perturbation of the airway epithelium can modify the phenotype of epithelial cells in culture leading to the microenvironmental availability of epidermal growth factor ligands and members of the urokinase plasminogen activator family. In the proposed work we will define the mechanisms that link the availability of these factors with the phenotypic changes that occur in co-cultured fibroblasts when these cells are placed in proximity to airway epithelial cells undergoing a single episode of mechanical stress. We will also define the mechanisms that link repeated episodes of mechanical stress on airway epithelial cells with the changes in secretory phenotype that occur as a result of this stress. Our work comprises a systematic investigation of the role played by these critical candidate pathways in the native context of the multicellular epithelial-mesenchymal structure of the airway wall. The data we propose to gather will elucidate the molecular mechanisms that link the various biochemical effector systems that are activated by compressive stress. This work will provide the evidence needed to validate the paradigm shift from regarding airway remodeling events as arising predominantly from an immunological mechanism to one which shows that bronchoconstriction alone can leave a specific remodeling signature on the airway. Lay Summary: When airways narrow during an asthma attack the cells lining these airways are compressed. Our data show that this compression activates these cells in a way similar to that observed in human asthma. In this research we will investigate the links between compression of cells and the changes in their activation state. This understanding could lead to new strategies for treating asthma.
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