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.