title: The detrimental effect of nitric oxide on tissue is associated with inflammatory events in the vascular endothelium and neutrophils in mice with dextran sodium sulfate-induced colitis.
abstract: Nitric oxide (NO) is thought to be a key molecule in the progression of ulcerative colitis and experimental colitis induced by dextran sodium sulfate (DSS). However, the detrimental effect of DSS-induced NO production on the colonic mucosa is incompletely understood. Increases in the expression of adhesion molecules in the vascular endothelium and activated neutrophils (thereby releasing injurious molecules such as reactive oxygen species) are reportedly associated with the pathogenesis of DSS-induced colitis. We investigated if the detrimental effect of NO production on the colonic mucosa was attributable to the activation of neutrophil infiltration by NO in mice with DSS-induced colitis. NO(2)(-)/NO(3)(-) content in the middle and distal colon was increased on days 5 and 7, but alterations in the proximal colon were not observed. Myeloperoxidase (MPO) activity and expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) were significantly increased in the entire colon, whereas TNF-α levels were significantly increased only in the middle and distal colon on day 7. The pathology of colitis and increases in colonic MPO activity, P-selectin, ICAM-1, and TNF-α levels were suppressed by the inducible NO synthase (iNOS)-specific inhibitor aminoguanidine and NO scavenger c-PTIO, whereas all but TNF-α levels were increased by the non-specific NOS inhibitor L-NAME. These findings suggest that iNOS-derived NO increases TNF-α levels in the middle and distal colon and increased TNF-α levels induce expression of P-selectin and ICAM-1, thereby promoting the infiltration of activated neutrophils, which leads to damage to colonic tissue.
authors.affiliation: Department of Bio-functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Yasukawa
authors.forename: Hiroto
authors.initials: H
authors.lastname: Tokuda
authors.forename: Xin
authors.initials: X
authors.lastname: Tun
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000633:toxicity*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D009569:Nitric Oxide / Q000633:toxicity*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester