The lung interstitial macrophage has been relatively neglected in studies of pulmonary macrophages and remains poorly characterized. The importance of these cells is suggested by their substantial numbers, proliferative capacity and their central position within the active lesions of injured lungs. The capacity of alveolar macrophages to secrete proteolytic enzymes, inflammatory mediators, and factors that modulate fibroblasts has been well established. In contast, similar characterization of interstitial macrophages is lacking, despite the more intimate relationship of this cell to lung matrix, fibroblasts and endothelium. We have found that important antigenic distinctions between alveolar and interstitial macrophages exist and can be used to isolate viable, functionally intact populations of interstitial macrophages for further in vitro characterization. The role of these cells isolated from normal lungs will be defined by quantitating capacities relevant to normal lung defense mechanisms. The role of these cells in diseased lungs will be defined in relationships to the pathogenesis of various lung diseases, e.g., modulation of fibroblast proliferation, release of chemotactic factors, release of proteolytic enzymes. Regulation of interstitial macrophage proliferation will be studied using colony forming unit assays. Isolated interstitial macrophages will be studied in vitro to analyze differentiation to and acquisition of the alveolar macrophage phenotype. Parallel studies of both hamster and human lung tissue will be undertaken since we have found useful antigenic discriminants in both systems. By defining the structure, differentiation and function of isolated interstitial macrophages, these studies will clarify the role of these cells in normal lungs and in the pathogenesis of interstitial lung diseases. The candidate is ideally suited for this award because of his training, demonstrated research interest and commitment to an academic career as an independent investigator in pulmonary disease. The environment is an established laboratory with proven success in training individuals with interest in cellular mechanisms in respiratory biology. The full support of the sponsors and the available expertise in their affiliated departments will assure a comprehensive and productive training program, resulting in a well-rounded independent investigator in pulmonary disease.
