Role of inducible nitric oxide synthase in the regulation of VCAM-1 expression in gut inflammation

The objectives of this study were to assess the role of the inducible isoform of nitric oxide synthase (iNOS) on vascular cell adhesion molecule I (VCAM-1) expression in vivo in an acute model of inflammation induced in iNOS-deficient (iNOS(-/-)) mice and compare these data to those obtained by pharmacological inhibition of iNOS in a CD4(+) T lymphocyte-dependent model of chronic colitis. VCAM-1 expression was quantified in vivo using the dual radiolabel monoclonal antibody technique. We found that intraperitoneal injection of 10 mu g/kg tumor necrosis factor-a (TNF-alpha) enhanced VCAM-1 expression by approximately twofold in the colon, cecum, and stomach but not small intestine in iNOS(-/-) mice compared with TNF-alpha-injected wild-type mice. Injection of wild-type mice with 25 mu g/kg TNF-alpha further enhanced VCAM-1 expression by approximately twofold compared with wild-type mice injected with 10 mu g/kg TNF-alpha; however, VCAM-1 expression was not further enhanced in any gastrointestinal organ system in iNOS(-/-) mice. In a second series of experiments, we found that continuous inhibition of iNOS using oral administration of N-G-iminoethyl-L-lysine did not alter the enhanced levels of VCAM-1 expression in the colon nor did it alter the severity of colonic inflammation in SCID mice reconstituted with CD4(+), CD45RB(high) T cells. We conclude that iNOS may regulate VCAM-1 expression in acute inflammation; however, this effect is modest and tissue specific and occurs only when VCAM-1 expression is submaximal, iNOS does not appear to modulate VCAM-1 expression in an immune model of chronic colitis.