The aim of this study was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) and NO onthe modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. A severe model of mesentericischemia and reperfusion was produced by subjecting mice to 45 min occlusion followed by reperfusion of thesuperior mesenteric artery and celiac trunk. In this experimental protocol, wild-type mice treated with GW274150 (5 mg/kgi.p.), a novel, potent, and selective inhibitor of iNOS activity, and mice lacking of the gene for iNOS (iNOS ‘knock-out’,iNOS-KO) exhibited no difference in the rate of mortality in comparison with wild-type control mice. In a second study,using a less severe model of mesenteric injury obtained by occlusion of the superior mesenteric artery only for 45 min, weevaluated the survival rate. Under these conditions, wild-type mice treated with GW274150 and iNOS-KO mice showeda significant difference in the rate of mortality in comparison with wild-type. Therefore, wild-type mice treated withGW274150 and iNOS-KO mice when compared with wild-type littermates showed a significant reduction of the mesentericinjury, upregulation of P-selectin and intercellular adhesion molecule-1, and neutrophil infiltration, as well as a significantinhibition of the degree of oxidative and nitrosative damage, indicated by malondialdehyde levels, formation of nitrotyrosineand poly(ADP-ribose)polymerase (PARP), respectively. Plasma levels of the proinflammatory cytokines tumournecrosis factor-, interleukin (IL) 6, and IL-1 were also significantly reduced in iNOS-KO mice in comparison with controlwild-type mice. Wild-type mice treated with GW274150 and iNOS-KO mice were also found to have reduced activation ofthe transcriptional factor nuclear factor-B in the ileum. These results suggest that the induction of iNOS and NOproduction are essential for the upregulation of the inflammatory response in splanchnic ischemia/reperfusion and participatein end organ damage under these conditions.
Role of induced nitric oxide in the initiation of the inflammatory response after postischemic injury
Dugo L;
2002-01-01
Abstract
The aim of this study was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) and NO onthe modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. A severe model of mesentericischemia and reperfusion was produced by subjecting mice to 45 min occlusion followed by reperfusion of thesuperior mesenteric artery and celiac trunk. In this experimental protocol, wild-type mice treated with GW274150 (5 mg/kgi.p.), a novel, potent, and selective inhibitor of iNOS activity, and mice lacking of the gene for iNOS (iNOS ‘knock-out’,iNOS-KO) exhibited no difference in the rate of mortality in comparison with wild-type control mice. In a second study,using a less severe model of mesenteric injury obtained by occlusion of the superior mesenteric artery only for 45 min, weevaluated the survival rate. Under these conditions, wild-type mice treated with GW274150 and iNOS-KO mice showeda significant difference in the rate of mortality in comparison with wild-type. Therefore, wild-type mice treated withGW274150 and iNOS-KO mice when compared with wild-type littermates showed a significant reduction of the mesentericinjury, upregulation of P-selectin and intercellular adhesion molecule-1, and neutrophil infiltration, as well as a significantinhibition of the degree of oxidative and nitrosative damage, indicated by malondialdehyde levels, formation of nitrotyrosineand poly(ADP-ribose)polymerase (PARP), respectively. Plasma levels of the proinflammatory cytokines tumournecrosis factor-, interleukin (IL) 6, and IL-1 were also significantly reduced in iNOS-KO mice in comparison with controlwild-type mice. Wild-type mice treated with GW274150 and iNOS-KO mice were also found to have reduced activation ofthe transcriptional factor nuclear factor-B in the ileum. These results suggest that the induction of iNOS and NOproduction are essential for the upregulation of the inflammatory response in splanchnic ischemia/reperfusion and participatein end organ damage under these conditions.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
