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Am J Physiol Gastrointest Liver Physiol 274: G802-G808, 1998;
0193-1857/98 $5.00
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Vol. 274, Issue 5, G802-G808, May 1998

Reduction of acute and reactivated colitis in rats by an inhibitor of neutrophil activation

John L. Wallace1, Webb McKnight1, Samuel Asfaha1, and David Y. Liu2

1 Intestinal Disease Research Unit, University of Calgary, Calgary, Alberta, Canada T2N 4N1; and 2 Scios Inc., Sunnyvale, California 94086

Neutrophils have been implicated as major contributors to tissue injury in inflammatory bowel disease. In this study, we have assessed the effects of an inhibitor of neutrophil activation and adherence, NPC-18915 (4-{2-[2-(2-benzofuranyl)phenyl]-(E)-ethenyl}benzoic acid sodium salt), in models of both acute and reactivated colitis. Acute colitis was induced by intracolonic administration of a hapten. In other rats, colitis was reactivated 6 wk after a bout of acute colitis by subcutaneous administration of the hapten. NPC-18915 given during the first 4 days after induction of acute colitis significantly reduced tissue injury and the incidence of diarrhea and adhesions. When treatment of NPC-18915 was initiated after colitis was firmly established (48 h posthapten), it did not produce a significant effect. NPC-18915 was effective at significantly reducing colonic injury and granulocyte infiltration in the reactivated colitis model, and a similar effect could be observed in rats treated with antineutrophil serum. These results demonstrate that an inhibitor of neutrophil activation is effective in both acute and reactivated colitis, although in the former case, effectiveness is only seen when the drug is given before full establishment of colitis. These results also suggest that neutrophils are a critical effector cell of hapten-induced colitis in the rat, particularly in the case of reactivated colitis.

inflammation; L-selectin; adherence


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