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-NO2 in 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 microg x kg(-1) x day(-1) via 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-NO2 and 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-NO2 animals. The levels of circulating TNF-alpha and renal TNF-alpha 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 PGE2 contents, were greater in LPS vehicle vs. control mice, but were attenuated in LPS OA-NO2 animals. Similar patterns of changes in the expression of inflammatory mediators were observed in the liver. Together, pretreatment with OA-NO2 ameliorated the inflammatory response and multiorgan injury in endotoxin-induced endotoxemia in mice.

Nitro-oleic acid protects against adriamycin-induced nephropathy in mice

“…In support of this finding is the observation that in cultured RAW264.7 cells, a murine macrophage cell line, OA-NO 2 attenuates the endotoxin-elicited inflammatory response via diverse mechanisms involving activation of mitogen-activated protein kinase phosphatase 1 (13) and nitroalkylation of NF-B p65 (9,11). Moreover, our previous study demonstrated anti-inflammatory and renoprotective actions of OA-NO 2 in endotoxin-induced endotoxemia in mice (30).…”

Nitro-Oleic Acid Attenuates OGD/R-Triggered Apoptosis in Renal Tubular Cells via Inhibition of Bax Mitochondrial Translocation in a PPAR-γ-Dependent Manner

“…Nitrated unsaturated fatty acids are a novel series of NO●-derived anti-inflammatory and anti-oxidative lipid signaling molecules and have potent therapeutic benefits in acute tubular injury of different etiologies [24,33,34], while recent experimental evidence points to their therapeutic potential in directly promoting cell survival in cardiac ischemic infarction [23,35,36]. How OA-NO 2 modulates pro-survival signaling against renal ischemia-reperfusion injury is not yet fully understood.…”

Characterization and quantification of endogenous fatty acid nitroalkene metabolites in human urine

“…Critical pro-infl ammatory enzymatic activities are also inhibited by fatty acid nitroalkenes, including xanthine oxidoreductase and cyclooxygenase-2 ( 52,53 ). These actions result in antiinfl ammatory responses in diverse animal models of disease including limiting restenosis after vessel injury ( 54 ), attenuation of weight gain and loss of insulin sensitivity in murine models of metabolic syndrome ( 6, 55 ), inhibition of sepsis-induced renal failure ( 56 ), prevention of ischemia-reperfusion injury ( 31,32,57 ), reduction of plaque formation in a murine ApoE Ϫ / Ϫ atherosclerosis model, and the reduction of chemically-induced infl ammatory bowel disease ( 47 ). Notably, all of these clinically-relevant responses are induced by steady state plasma concentrations of nitro-fatty acids ranging from 10 to 25 nM, well within the range of NO 2 -CLA concentrations measured in human urine (9.2 ± 4.3 nM).…”