Nitric oxide supplementation ameliorates dextran sulfate sodium-induced colitis in mice.
Nitric oxide (NO) synthesis is up-regulated in inflammatory bowel disease. However, its role in the pathophysiology of this condition is controversial. The aims of this study were to assess whether nitric oxide administration ameliorates experimental colitis and to determine the possible mechanisms underlying its effects on intestinal inflammation. For this purpose, the NO donor diethylamine NONOate (DETA/NO; 0.01, 0.1, 1, 5, or 10 mg/kg/day), or the DETA moiety, was administered daily to mice with dextran sulfate sodium-induced colitis. Daily body weight and colonic pathologic alterations at Day 10 were determined. Leukocyte endothelial cell interactions in colonic venules were assessed with intravital microscopy, and expression of endothelial cell adhesion molecules was determined using radiolabeled antibodies. IL-12 and IFN-gamma production were measured in intestinal tissue. Colitis induced a significant loss of body weight, reduction of colon length, and increase in colon weight and myeloperoxidase activity. Administration of 1 mg/kg/day DETA/NO significantly attenuated these pathologic changes. The marked increase in leukocyte rolling and adhesion in colonic venules of colitic mice were significantly reduced by administration of 1 mg/kg/day DETA/NO. Development of colitis was associated with a marked increase in endothelial expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and P-selectin. Supplementation with NO significantly attenuated the up-regulation of endothelial intercellular adhesion molecule-1 and P-selectin, but not vascular cell adhesion molecule-1, in colonic tissue. NO abrogated the increase in IL-12 and IFN-gamma mRNA expression in the colon of colitic mice. The DETA moiety alone did not have any effect on any of the parameters studied. In conclusion, exogenous NO supplementation significantly ameliorates dextran sulfate sodium-induced colitis. This effect is related to a reduction in leukocyte recruitment and proinflammatory cytokine production.
Salas
Azucena
A
Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Gironella
Meritxell
M
Salas
Antonio
A
Soriano
Antonio
A
Sans
Miquel
M
Iovanna
Juan
J
Piqué
Josep M
JM
Panés
Julián
J
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D006834:Hydrazines / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use*; D009589:Nitrogen Oxides; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014699:Venules / Q000187:drug effects / Q000502:physiology
D015815:Cell Adhesion Molecules; D006834:Hydrazines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D016264:Dextran Sulfate; D009195:Peroxidase