INCREASED NITRIC OXIDE SYNTHESIS DURING THE DEVELOPMENT OF ENDOTOXIN TOLERANCE

摘要

The role of nitric oxide (NO) synthesis was investigated in endotoxin (LPS) tolerance induced in rats by intraperitoneal injection of a sublethal dose ofSalmonella enteritidisLPS (100 μg/kg intraperitoneally). Peritoneal macrophages were harvested 6 and 24 h after LPS injection and stimulatedin vitrowith LPS. LPS significantly stimulated arachidonic acid metabolism, as assessed by 6-keto-prostaglandin F1α(6-keto-PGF1α) levels, and NO production, as assessed by nitrite, in macrophages collected from control rats. In macrophages from tolerant rats LPS-stimulated 6-keto-PGF1αproduction was significantly reduced, while nitrite production was increased compared to control macrophages (p .001). Inin vivomortality studies, rats that were pretreated 24 h earlier with sublethal LPS were resistant to the lethal effect of a subsequent dose of LPS (15 mg/kg intravenously) in comparison to control rats (p .001).NG-Nitro-l-arginine-methyl ester, an inhibitor of NO synthase, decreased mean survival time in control rats and abrogated the resistance to the lethal effect of LPS in tolerant rats. In contrast, molsidomine, a NO donor, improved survival in control rats but did not modify the resistance to the lethal dose of LPS in tolerant rats. The results suggest that sustained NO synthesis may be a beneficial mechanism for the induction of LPS tolerance.