MECHANICAL STRESS AS STIMULUS FOR AIRWAY WALL REMODELING

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In patients with asthma, the airway wall is a dynamic structure that is in a continuous state of remodeling. One aspect of this remodeling is the deposition of collagen in the subepithelial connective tissue, which gives rise to the appearance of a thickened basement membrane. It is currently thought that mediators, cytokines, and growth factors derived from inflammatory cells recruited to the airway wall are responsible for airway wall remodeling. Our premise is that mechanical stimulation of the airway epithelium, as occurs during airway constriction, is a sufficient source for the molecular signals that result in airway wall remodeling. Our proposal is based on our recent demonstration that mechanical stress on airway epithelial cells can create an inflammatory microenvironment conducive to airway wall remodeling. These novel observations lead us to tender the following hypothesis: Airway epithelial cells subjected to mechanical stresses are a source of cytokines, growth factors, and mediators that can initiate the molecular events which are at the core of the airway remodeling response. To test this hypothesis, we propose three specific aims, each of which will test a specific subhypothesis. Specific Aim 1 will test the subhypothesis that human airway epithelial cells are capable of transducing mechanical signals that reflect the phenotype (i.e. secretory versus non-secretory) of the cell under study. Specific Aim 2 will test the subhypothesis that mechanotransduction results from specific intracellular force transmission pathways; these pathways will be activated by deforming human airway epithelial cells in culture using magnetic field manipulation of ligand coated ferromagnetic beads bound to the cytoskeleton. Specific Aim 3 will test the subhypothesis that epithelial mechanotransduction can lead directly to airway remodeling through effects on airway fibroblasts. Data from these experiments will allow us to determine the extent to which mechanical perturbations of airway epithelial cells can create a microenvironment that encourages airway wall remodeling. These experiments may result in a paradigm shift in our understanding of the events leading to chronic remodeling of the airway wall. The hypothesis proposed here turns traditional thinking on its head by suggesting that airway narrowing per se may be an important causal link in the chain leading to airway remodeling.