LEUKOTRIENE-DEFICIENT MICE MANIFEST ENHANCED LETHALITY FROM KLEBSIELLA-PNEUMONIA IN ASSOCIATION WITH DECREASED ALVEOLAR MACROPHAGE PHAGOCYTIC AND BACTERICIDAL ACTIVITIES

Leukotrienes (LTs) are potent mediators of inflammation derived from t he 5-lipoxygenase pathway of arachidonic acid metabolism, Although the y are known to enhance leukocyte recruitment and function, their role in antimicrobial host defense has not been established, To determine t he role of endogenous LTs in the host response to pulmonary infection, wild-type mice and mice rendered LT-deficient by targeted disruption of the 5-lipoxygenase gene (knockout mice) were studied following intr atracheal challenge with Klebsiella pneumoniae. Wild-type mice demonst rated a marked increase in lung LT levels and neutrophil numbers follo wing bacterial challenge. As compared with wildtype animals, knockout animals manifested a greater degree of lethality as well as bacteremia following challenge, Interestingly, they displayed no defect in neutr ophil recruitment to the lung. However, alveolar macrophages from knoc kout animals exhibited impairments in bacterial phagocytosis and killi ng, and these defects were overcome by in vitro addition of exogenous LTB(4). We conclude that endogenous LTs play a critical role in the de fense against bacterial pneumonia in this murine model.