Nitro-oleic acid protects against endotoxin-induced endotoxemia and multiorgan injury in mice

Abstract

Nitroalkene derivatives of nitro-oleic acid (OA-NO2) are endogenous lipid products with potent anti-inflammatory properties in vitro. The present study was undertaken to evaluate the in vivo anti-inflammatory effect of OA-NO2in mice given LPS. Two days before LPS administration, C57BL/6J mice were chronically infused with vehicle (LPS vehicle) or OA-NO2(LPS OA-NO2) at 200 μg·kg−1·day−1via osmotic minipumps; LPS was administered via a single intraperitoneal (ip) injection (10 mg/kg in saline). A third group received an ip injection of saline without LPS or OA-NO2and served as controls. At 18 h of LPS administration, LPS vehicle mice displayed multiorgan dysfunction as evidenced by elevated plasma urea and creatinine (kidney), aspartate aminotransferase (AST) and alanine aminotransferase (ALT; liver), and lactate dehydrogenase (LDH) and reduced ejection fraction (heart). In contrast, the severity of multiorgan dysfunction was less in LPS OA-NO2animals. The levels of circulating TNF-α and renal TNF-α mRNA expression, together with renal mRNA expression of monocyte chemoattractant protein-1, ICAM-1, and VCAM-1, and with renal mRNA and protein expression of inducible nitric oxide synthase and cyclooxygenase 2, and renal cGMP and PGE2contents, were greater in LPS vehicle vs. control mice, but were attenuated in LPS OA-NO2animals. Similar patterns of changes in the expression of inflammatory mediators were observed in the liver. Together, pretreatment with OA-NO2ameliorated the inflammatory response and multiorgan injury in endotoxin-induced endotoxemia in mice.