Role of cell and debris removal in fibrosis

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(Applicant's Abstract) Tissue damage and inflammation have long been associated with fibrotic changes during wound healing and in pulmonary fibrosis. Resolution of inflammatory lesions involves removal of apoptopic inflammatory cells by uptake into macrophages and surrounding tissue cells, such as epithelial cells and fibroblasts. We suggest that the engulfment of apoptotic cells is driven by a variety of adhesion ligands acting in conjunction with a critical receptor for phosphatidylserine (the PS receptor or PSR) that actually mediates the signaling for phagocytosis. Ingestion via this receptor also initiates the production of active TGF. This mediator then has important effects in limiting further generation of inflammatory mediators, as well as the potential to initiate fibroblast to myofibroblast phenotypic conversion and the process of fibrosis. It is further suggested that cell debris and membrane fragments are removed by similar mechanisms with similar consequences. To explore these suggestions, the PSR will be examined 1) for its potential ability to initiate myofibroblast conversion via a reciprocal feedback induction of TGF; 2) for its upregulation in cells adjacent to an area of damage with resultant ingestion of the damaged cells and fragments as well as local generation of TGF; and 3) for its potential role in mediating resolution of inflammation and progression to fibrosis. Because of the ability of PSR ligation to initiate TGF synthesis and secretion from a variety of cell types in vitro and in vivo, this proposal will also examine the mechanisms of this induction by determining the points in TGF synthesis, secretion and activation that are affected and to begin to examine the signaling pathways involved. Experiments will be performed in epithelial cells, fibroblasts and macrophages since each of these express the PSR, ingest apoptotic cells and respond by induction of TGF, although with different consequences. The in vivo studies will be carried out in murine models of inflammation and fibrosis and will make use of a number of valuable knockout strains. The overall objective is to examine in detail one potentially important mechanism for inducing the generation of myofibroblasts in the lung.