Pulmonary emphysema is a progressive disabling disorder in humans characterized by destruction of the alveolar walls in enlargement of the peripheral airspaces in the lung. Protease/anti-protease imbalance significantly contributes to the pathogenesis of pulmonary emphysema. Proteolytic processing of extracellular matrix (ECM) and cell surface molecules by serine proteases and metalloproteinases (primarily of neutrophil and macrophage origin_ involves a variety of receptor- mediated intracellular significant events which regulate gene expression and affect proliferation, migration, differentiation, as well as viability of the injured cells. After injury inadequate repair of damaged lung tissue results in remodeling of airways and organ dysfunction. In preliminary studies we found that neutrophil elastase (NE) induces the down- regulation of EGF receptor (EGFR) and activation of extracellular signal regulated kinases 1 and 2 (ERK) in vitro in cultured pulmonary fibroblasts and in vivo of the injured lung. We also found that NE- initiated signaling leads to the decrease of elastin mRNA in cultured cells. We hypothesize that the NE-initiated EGFR-mediated ERK pathway can suppress elastin re-synthesis in NE-injured lung, and thus contribute to the progression of pulmonary emphysema, Our current working model predicts that NE by degrading specific ECM components releases the cell surface anchored EGFR to initiate its endocytosis and signaling towards ERK. The focus of Project 3 will be to determine the mechanism of NE-initiated EGFR-mediated ERK activation in cultured lung fibroblasts and to examine the impact of this signaling pathway on the progression of NE-induced emphysema in mice.
Three specific aims are proposed. 1. Determine the mechanism of NE-initiated EGFR down- regulation and signaling in pulmonary fibroblasts. 2. Investigate the role of EGFR signaling pathway in elastogenic, proliferative, and apoptotic responses of NE-injured pulmonary fibroblasts; 3. Examine the role of EGFR signaling in an animal model of NE-induced pulmonary emphysema.
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