A major goal of this PPG proposal is to understand the molecular basis for remodeling of lung structure during inflammation and disease. In that context, significant evidence now exists that airway epithelial cells may be specially programmed for normal immune defense (especially against respiratory viruses) and abnormally programmed in airway disease. For the present project, we have extended this line of reasoning to ask how epithelial behavior becomes abnormal. In that regard, we now find that transient paramyxoviral bronchiolitis in mice causes acute loss and then long-term hyperplasia of ciliated airway epithelial cells whenthe infection occurs in a susceptible genetic background. Similar to the pattern in airway disease, the hyperplastic epithelium in mice exhibits persistent activation of epidermal growth factor receptor (EGFR) signaling. Despite activation of growth factor signal and concomitant hyperplasia, there is no evidence of persistent proliferation of airway epithelial cells. This finding raises the unexpected possibility that prolonged cell survival is critical for remodeling and perhaps normal maintenance of epithelial structure. In support of that possibility, study of airway epithelial cells in culture indicates that ciliated cell survival depends on uninterrupted EGFR signaling. Although the precise determinants of this signal are still being defined, it appears that selective overexpression of upstream ligand (e.g., amphiregulin) and consequent activation ofdownstream kinases (especially PI3K and Akt) are critical for maintenance of function. Otherwise, the ciliated cells may proceed toward programmed cell death (via caspase-9 and caspase-3) in a manner that appears analogous to virus-inducible apoptosis. To test these proposals, we have the following specific aims--I. Using genetically homogeneous mice, define the mechanism for long-term hyperplasia of ciliated epithelial cells after damage due to viral infection and other inflammatory stimuli. These experiments concentrate on the role of the EGFR signaling pathway in long-term virus-induced ciliated cell hyperplasia and compare this response to other conditions, especially exposure to inhaled cigarette smoke. II. Using isolated airway epithelial cells, define the components of the EGFR signaling pathway that mediate ciliated epithelial cell survival. These experiments concentrate on precisely defining the intricate signaling pathways that control the balance between ciliated epithelial cell death and survival and so determine the cellular makeup of the epithelial barrier.
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