.) The central premise of this application is that uPA is an important element in both the maturation of lung macrophages and in the regulation of connective tissue metabolism within the lung. The hypothesis is advanced that uPA has at least two distinct functions in this regard: an autocrine role (independent of proteolytic activity) in differentiation of macrophage progenitors and a catalytic role in connective tissue metabolism mediated by more mature cells. Both functions operate in part via interaction of uPA with uPA receptors and are dependent not only on uPA synthesis but also on concomitant expression of cell surface receptors and specific uPA inhibitors (Type 1 and 2). Studies are planned with human monocytic cell lines, and blood monocytes, to define the effect of uPA binding by its receptor on the subsequent expression of regulatory and functional gene products of macrophages. The hypothesis that uPA secretion and receptor binding is a necessary prelude to further differentiation mediated by colony stimulating factors and other cytokines will be explored. The capability of cytokines and extracellular matrix proteins to regulate alveolar macrophage uPA receptor expression and, concurrently, uPA and PA inhibitor mRNA levels in vitro will also be considered. The physiological regulation of PAI-1 expression by macrophages will be defined in vitro. These studies will be complemented by direct determinations during disease (Adult Respiratory Distress Syndrome [ARDS], sarcoidosis, IPF) of uPA and Type 1 and Type 2 inhibitor mRNA by in situ hybridizations of lavaged macrophages and biopsied lung tissues.
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