sq-23377 and Pneumonia

The role of a cytosolic phospholipase A(2)-alpha (cPLA(2)-alpha) in neutrophil arachidonic acid release, platelet-activating factor (PAF) biosynthesis, NADPH oxidase activation, and bacterial killing in vitro, and the innate immune response to bacterial infection in vivo was examined. cPLA(2)-alpha activity was blocked with the specific cPLA(2)-alpha inhibitor, Pyrrolidine-1 (human cells), or by cPLA(2) -alpha gene disruption (mice). cPLA(2)-alpha inhibition or gene disruption led to complete suppression of neutrophil arachidonate release and PAF biosynthesis but had no effect on neutrophil NADPH oxidase activation, FcgammaII/III or CD11b surface expression, primary or secondary granule secretion, or phagocytosis of Escherichia coli in vitro. In contrast, cPLA(2)-alpha inhibition or gene disruption diminished neutrophil-mediated E. coli killing in vitro, which was partially rescued by exogenous arachidonic acid or PAF but not leukotriene B(4). Following intratracheal inoculation with live E. coli in vivo, pulmonary PAF biosynthesis, inflammatory cell infiltration, and clearance of E. coli were attenuated in cPLA(2)-alpha(-/-) mice compared with wild type littermates. These studies identify a novel role for cPLA(2)-alpha in the regulation of neutrophil-mediated bacterial killing and the innate immune response to bacterial infection.

Topics: Animals; Arachidonic Acid; Bronchoalveolar Lavage Fluid; CD11b Antigen; Cytosol; Dose-Response Relationship, Drug; Escherichia coli; Group IV Phospholipases A2; Humans; Inflammation; Ionomycin; Leukotriene B4; Mice; Mice, Transgenic; NADPH Oxidases; Neutrophils; Oxygen; Phagocytosis; Phospholipases A; Phospholipases A2; Platelet Activating Factor; Pneumonia; Pyrrolidines; Receptors, IgG; Time Factors; Tumor Necrosis Factor-alpha