Reduced oxidative and nitrosative damage in murine experimental colitis in the absence of inducible nitric oxide synthase.
BACKGROUND
Oxidative and nitrosative stress have been implicated in the pathogenesis of inflammatory bowel diseases.


OBJECTIVE
To study the role of nitric oxide (NO) derived from inducible NO synthase (iNOS) in an experimental model of murine enterocolitis.


METHODS
Trinitrobenzene sulphonic acid (TNBS) was instilled per rectum to induce a lethal colitis in iNOS deficient mice and in wild type controls. The distal colon was evaluated for histological evidence of inflammation, iNOS expression and activity, tyrosine nitration and malondialdehyde formation (as indexes of nitrosative and oxidative stress), myeloperoxidase activity (as index of neutrophil infiltration), and tissue localisation of intercellular adhesion molecule 1 (ICAM-1).


RESULTS
TNBS administration induced a high mortality and weight loss associated with a severe colonic mucosal erosion and ulceration, increased myeloperoxidase activity, increased concentrations of malondialdehyde, and an intense staining for nitrotyrosine and ICAM-1 in wild type mice. Genetic ablation of iNOS gene conferred to mice a significant resistance to TNBS induced lethality and colonic damage, and notably reduced nitrotyrosine formation and concentrations of malondialdehyde; it did not, however, affect neutrophil infiltration and intestinal ICAM-1 expression in the injured tissue.


CONCLUSIONS
Data show that activation of iNOS is required for nitrosative and oxidative damage in experimental colitis.
Children's Hospital Medical Centre, Division of Critical Care, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.
B
B
Zingarelli
C
C
Szabó
A L
AL
Salzman
D000818:Animals; D004760:Enterocolitis / Q000139:chemically induced / Q000201:enzymology*; D004789:Enzyme Activation; D005260:Female; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D014302:Trinitrobenzenesulfonic Acid
D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D008315:Malondialdehyde; D014302:Trinitrobenzenesulfonic Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse