title: Hindlimb ischemia/reperfusion-induced remote injury to the small intestine: role of inducible nitric-oxide synthase-derived nitric oxide.
abstract: Systemic inflammatory response syndrome, as a consequence of ischemia/reperfusion (I/R), negatively influences the function of the affected organs. The objective of this study was to assess the role of nitric oxide (NO) in remote intestinal inflammatory response elicited by hindlimb I/R. To this end, C57BL/6 (wild type; WT) and inducible nitric-oxide synthase (iNOS)-deficient mice were subjected to bilateral hindlimb ischemia (1 h) followed by 6 h of reperfusion. Some WT mice were injected with iNOS inhibitor N-[3-(aminomethyl)benzyl] acetamidine (1400W) (5 mg/kg s.c.) immediately before reperfusion, and proinflammatory response was assessed 6 h later. Hindlimb I/R resulted in dysfunction of the small intestine as assessed by the increase in permeability [blood-to-lumen clearance of Texas Red-dextran (molecular mass 3 kDa)] and an increase in the luminal levels of tumor necrosis factor (TNF)-alpha protein and nitrate/nitrite (NO(2)(-)/NO(3)(-)). The above-mentioned changes were accompanied by up-regulation of the proinflammatory phenotype in the mucosa of small intestine with respect to 1) an increase in TNF-alpha and iNOS protein expression, 2) leukocyte accumulation, 3) formation of edema, 4) an increase in leukocyte rolling/adhesion in the submucosal microvasculature, and 5) activation of transcription factor nuclear factor-kappaB and up-regulation of adhesion molecule expression. Interestingly, the most profound changes with respect to intestinal dysfunction were found in jejunum and ileum, whereas duodenum was affected the least. Interfering with iNOS activity (1400W and iNOS-deficient mice) significantly attenuated hindlimb I/R-induced inflammatory response and dysfunction of the small intestine with respect to the above-mentioned markers of inflammation. The obtained results indicate that hindlimb I/R induces remote inflammatory response in the small intestine through an iNOS-derived NO-dependent mechanism.
authors.affiliation: The Centre for Critical Illness Research, Lawson Health Research Institute, London, ON N6A 4G5, Canada.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katada
authors.forename: Aurelia
authors.initials: A
authors.lastname: Bihari
authors.forename: Amit
authors.initials: A
authors.lastname: Badhwar
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yoshida
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Richard F
authors.initials: RF
authors.lastname: Potter
authors.forename: Gediminas
authors.initials: G
authors.lastname: Cepinskas
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D019040:E-Selectin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D006614:Hindlimb / Q000473:pathology*; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007962:Leukocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000578:Amidines; D001596:Benzylamines; D019040:E-Selectin; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D016328:NF-kappa B; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse