Modulation of superoxide anion generation by manoalide, arachidonic acid and staurosporine in liver infiltrated neutrophils in a rat model of endotoxemia.
1993
Early accumulation of polymorphonuclear leukocytes (PMN) in the liver after in vivo exposure to Escherichia coli lipopolysaccharide (LPS) and concomitant in vitro phorbol myristate acetate (PMA)-stimulated superoxide anion (O2-) generation has recently been described in a rat model of endotoxemia. The purpose of this investigation was to study the role of phospholipase A2 (PLA2), arachidonic acid (AA), its metabolites, and protein kinase C (PKC) in the mechanism of PMA-stimulated O2- generation of liver infiltrated PMN as compared to circulating blood PMN. Rat PMN were isolated after a 1.5-h infusion of saline or LPS from the blood (SAL-PMN) or the liver (LPS-PMN), respectively. The following results were observed in both SAL-PMN and LPS-PMN: 1) Inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase [eicosatetraynoic acid, WY 50,295 tromethamine and VZ 65, 4-(11-hydroxy-1,9-undecadiin)-brenzcatechin] pathways did not inhibit O2- generation; 2) the potent marine PLA2 inhibitor Manoalide inhibited O2- generation in a dose-dependent manner (IC50 = 0.5 microM); 3) exogenously added AA enhanced PMA-stimulated O2- generation in a time- and dose-dependent manner and partially reversed the effect of Manoalide in LPS-PMN; 4) staurosporine, a putative PKC inhibitor, blocked PMA-stimulated O2- generation completely in the absence of AA and 79% in the presence of AA. It was concluded that LPS-induced liver sequestration of PMN does not alter the role PLA2, AA and PKC play in PMA-stimulated O2- generation. These findings should have implications on the design of novel therapeutic approaches for the modulation of O2- release in the pathogenesis of LPS hepatotoxicity.
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