Carbon monoxide liberated from CO-releasing molecule (CORM-2) attenuates ischemia/reperfusion (I/R)-induced inflammation in the small intestine.
CORM-released CO has been shown to be beneficial in resolution of acute inflammation. The acute phase of intestinal ischemia-reperfusion (I/R) injury is characterized by oxidative stress-related inflammation and leukocyte recruitment. In this study, we assessed the effects and potential mechanisms of CORM-2-released CO in modulation of inflammatory response in the small intestine following I/R-challenge. To this end mice (C57Bl/6) small intestine were challenged with ischemia by occluding superior mesenteric artery (SMA) for 45 min. CORM-2 (8 mg/kg; i.v.) was administered immediately before SMA occlusion. Sham operated mice were injected with vehicle (0.25% DMSO). Inflammatory response in the small intestine (jejunum) was assessed 4 h following reperfusion by measuring tissue levels of TNF-alpha protein (ELISA), adhesion molecules E-selectin and ICAM-1 (Western blot), NF-kappaB activation (EMSA), along with PMN tissue accumulation (MPO assay) and leukocyte rolling/adhesion in the microcirculation of jejunum (intravital microscopy). The obtained results indicate that tissue levels of TNF-alpha, E-selectin and ICAM-1 protein expression, activation of NF-kappaB, and subsequent accumulation of PMN were elevated in I/R-challenged jejunum. The above changes were significantly attenuated in CORM-2-treated mice. Taken together these findings indicate that CORM-2-released CO confers anti-inflammatory effects by interfering with NF-kappaB activation and subsequent up-regulation of vascular pro-adhesive phenotype in I/R-challenged small intestine.
Katada
Kazuhiro
K
Centre for Critical Illness Research, Lawson Health Research Institute, 800 Commissioners Rd., London, ON, N6A4G5, Canada.
Bihari
Aurelia
A
Mizuguchi
Shinjiro
S
Yoshida
Norimasa
N
Yoshikawa
Toshikazu
T
Fraser
Douglas D
DD
Potter
Richard F
RF
Cepinskas
Gediminas
G
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D002245:Carbon Dioxide / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005765:Gastrointestinal Agents / Q000378:metabolism / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007583:Jejunum / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D036904:Leukocyte Rolling / Q000187:drug effects; D008297:Male; D008641:Mesenteric Vascular Occlusion / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D019040:E-Selectin; D005765:Gastrointestinal Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; D018799:Intercellular Adhesion Molecule-1; D002245:Carbon Dioxide