Pulmonary fibrosis is a late developing result of any one or combination of deleterious influences. Although considerable data are available regarding the end stages, little is known about the early stages of fibrotic development. Fibrosis must reflect a cascade of events involving both cellular and matricial components of the septal wall. Data are being accumulated on the roles of various cell types in the alveolar septal wall which can influence the rate and direction of fibrotic development. Among the cell types which have been proposed to affect fibrotic initiation are macrophages, fibroblasts, lymphocytes, type II pneumocytes and endothelial cells. Although the end target cell for fibrosis is the fibroblast, its susceptibility to factors in an altered milieu have been suggested to affect markedly how the fibrotic process progresses. For example, macrophages have been reported to secrete both fibronectin and alveolar macrophage derived growth factor, both of which are strong chemoattractants for fibroblasts. Recently attention has been directed toward the role of fibroblasts, particularly in that different subpopulations of fibroblasts exist and may respond differently to stimuli. At least two types, the lipid-containing and the contractile fibroblasts have been observed. To derive information regarding their behavior, the subpopulations must be isolated and their function elucidated. We propose to isolate fibroblast subpopulations from normal an fibrotic mouse lungs by cell elutriation, laser flow cytometry, cell sorting and transmission and scanning electron microscopy. When isolated, the cells will be tested for interleukin-1 and gamma- interferon susceptibility, and for the potential for fibroblast types to become antigen presenting cells. Our method of fibrotic induction will be radiation, with which we have had considerable experience. In our hands, during fibrotic development, lipid- containing fibroblasts reappear, having been very prominent in the fetal/neonatal lung development. Their role in fibrotic development will be elucidated.
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