LEUKOTRIENES AND PULMONARY ANTIBACTERIAL DEFENSE

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DESCRIPTION (Adapted from applicant's abstract and specific aims): Leukotrienes (LTs) are potent mediators implicated in the pathogenesis of inflammatory lung diseases, and new pharmacologic agents that inhibit LT synthesis or actions will soon be available for the treatment of asthma. It is generally assumed that inflammatory cascades have evolved for the purpose of host defense against microbial invasion, yet little is known about the possible importance of endogenous LTs in mediating the host response to infection. This applicator hypothesize that 1) endogenous LTs play an integral role in the host response to pulmonary infection, and 2) exogenous LTs exert pharmacologic actions which augment this response. These hypotheses will be tested by a series of in vivo and in vitro experiments designed to address the following Specific Aims. Aim 1 will ascertain the roles of specific endogenous 5-LO products in the host response to K. pneumonia, using pharmacologic agents which inhibit LT synthesis or actions. Aim 2 will determine the kinetics, profile, and cellular sources of LTs produced in the murine lung during the course of Klebsiella pneumonia. Aim 3 will determine the molecular mechanisms by which specific 5-LO products augment phagocytosis and killing of K. pneumonia in AMs and PMNs. Aim 4 will test the potential of intrapulmonary LT administration to augment the host response to Klebsiella challenge.