Mitomycin C-induced colitis in rats: a new animal model of acute colonic inflammation implicating reactive oxygen species.
The mechanism of the tissue damage induced by colonic inflammation in ulcerative colitis is not established. We therefore developed and characterized a simple new rat model of acute colonic inflammation induced by a single systemic injection of mitomycin C. After an intraperitoneal injection of mitomycin-C, colon histologic examination revealed transient (3 to 14 days) diffuse, colonic inflammation and injury that, like human ulcerative colitis, was limited to the mucosal layer. The rest of the gastrointestinal tract was spared. Gut permeability, as measured by urinary excretion of orally administered lactulose and mannitol, was unchanged 3 days after injection, when inflammation was already present; permeability was increased at 7 days, when inflammation was maximal. Mitomycin C did not produce inflammation in experimentally bypassed segments of small bowel despite the presence of colonic-type bacteria, suggesting that lack of intraluminal bacteria was not responsible for the absence of inflammation in the small intestine. Chemiluminescence, a means of estimating levels of reactive oxygen species, was greater in the intact, inflamed colon of mitomycin C-treated rats than in bypassed segments. Moreover, inflamed mucosal scrapings produced more in vitro luminol-enhanced chemiluminescence. Furthermore, the reactive oxygen species scavengers allopurinol, catalase, and WR-2721 decreased inflammation severity. We therefore conclude: (1) the mitomycin C-treated rat is a novel, easy to prepare animal model of acute inflammation of colonic mucosa, with morphologic similarities to the acute phase of ulcerative colitis in human beings; (2) increased gut permeability in mitomycin C-treated rats is the result, not the cause, of the inflammation; and (3) reactive oxygen species play an important role in colonic inflammation and tissue injury in this model, and possibly in human ulcerative colitis.
Keshavarzian
A
A
Department of Medicine, Loyola University Medical Center, Maywood, IL 60153.
Doria
M I
MI
Sedghi
S
S
Kanofsky
J R
JR
Hecht
D
D
Holmes
E W
EW
Ibrahim
C
C
List
T
T
Urban
G
G
Gaginella
T
T
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000382:microbiology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016166:Free Radical Scavengers; D007413:Intestinal Mucosa / Q000503:physiopathology; D007700:Kinetics; D008163:Luminescent Measurements; D008165:Luminol / Q000494:pharmacology; D008297:Male; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D016685:Mitomycin; D008165:Luminol