Role of induced nitric oxide in the initiation of the inflammatory response after postischemic injury

Salvatore Cuzzocrea, Prabal K. Chatterjee, Emanuela Mazzon, Laura Dugo, Angela De Sarro, Fons A J Van De Loo, Achille P. Caputi, Christoph Thiemermann

Research output: Contribution to journalArticlepeer-review

Abstract

The aim of this study was to investigate the role of inducible nitric oxide (NO) synthase (iNOS) and NO on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. A severe model of mesenteric ischemia and reperfusion was produced by subjecting mice to 45 min occlusion followed by reperfusion of the superior mesenteric artery and celiac trunk. In this experimental protocol, wild-type mice treated with GW274150 (5 mg/kg i.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, we evaluated the survival rate. Under these conditions, wild-type mice treated with GW274150 and iNOS-KO mice showed a significant difference in the rate of mortality in comparison with wild-type. Therefore, wild-type mice treated with GW274150 and iNOS-KO mice when compared with wild-type littermates showed a significant reduction of the mesenteric injury, upregulation of P-selectin and intercellular adhesion molecule-1, and neutrophil infiltration, as well as a significant inhibition of the degree of oxidative and nitrosative damage, indicated by malondialdehyde levels, formation of nitrotyrosine and poly(ADP-ribose)polymerase (PARP), respectively. Plasma levels of the proinflammatory cytokines tumour necrosis factor-a, interleukin (IL) 6, and IL-1β were also significantly reduced in iNOS-KO mice in comparison with control wild-type mice. Wild-type mice treated with GW274150 and iNOS-KO mice were also found to have reduced activation of the transcriptional factor nuclear factor-κB in the ileum. These results suggest that the induction of iNOS and NO production are essential for the upregulation of the inflammatory response in splanchnic ischemia/reperfusion and participate in end organ damage under these conditions.

Original languageEnglish
Pages (from-to)169-176
Number of pages8
JournalShock
Volume18
Issue number2
Publication statusPublished - Aug 2002

Keywords

  • Adhesion molecules
  • Free radicals
  • ICAM-1
  • Inos
  • Lipid peroxidation
  • P-selectin
  • Peroxynitrite

ASJC Scopus subject areas

  • Physiology
  • Critical Care and Intensive Care Medicine

Fingerprint Dive into the research topics of 'Role of induced nitric oxide in the initiation of the inflammatory response after postischemic injury'. Together they form a unique fingerprint.

Cite this