The concept of a circulating population of neutrophils which responds abnormally to in vitro tests of activation is well established experimentally and in certain clinical conditions. The goal of this proposal is to determine the pathophysiologic significance of alterations in the functional responses of circulating neutrophils. The applicant would determine the ability of activated neutrophils to produce endothelial injury in order to test the hypothesis that when compared to the injuries produced by activation of a normal circulating population of neutrophils, in vivo activation of down regulated circulating neutrophils would produce less severe microvascular injury, while in vivo activation of primed circulating neutrophils would produce a more severe injury. Since neutrophils function as a vital link in defense against bacterial infection, the applicant would test the ability of circulating neutrophils to clear bacteria injected intravascularly and to migrate to a site of infection produced by intratracheal administration of bacteria. The applicant hypothesizes that down regulated neutrophils would be insufficiently armed to effectively kill bacteria. Therefore, clearance of injected bacteria would be delayed with resultant microvascular injury associated with septicemia and evidence of infection in other organs (liver, spleen and kidney). Down regulated neutrophils would accumulate in the alveolar airspaces in response to bacterial seeding and would form phagosomes, but killing would be impaired. In contrast, the applicant hypothesizes that primed neutrophils would be more efficient as phagocytes against an intravascular or intra-alveolar load of bacteria. Finally, the applicant would address potential mechanisms of neutrophil down regulation and priming. In both instances, the applicant suggests that the effects are mediated through second messengers in which synthesis is initiated by the primary stimulus (complement anaphylatoxins or endotoxin). The applicant hypothesizes that down regulation results from release of an anti-inflammatory cytokine(s) while endotoxin-induced priming is the result of released tumor necrosis factor and/or interleukin 1. Intravascular macrophages, which are prevalent in the pulmonary circulation of sheep, and lymphocytes are likely sources of released cytokines.
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