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Am J Physiol Gastrointest Liver Physiol 279: G641-G651, 2000;
0193-1857/00 $5.00
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Vol. 279, Issue 3, G641-G651, September 2000

EXPEDITED ARTICLE
Inhibition of poly(ADP-ribose) polymerase attenuates inflammation in a model of chronic colitis

Humberto B Jijon1, Thomas Churchill2, David Malfair3, Andreas Wessler4, Laurence D Jewell4, Howard G Parsons1, and Karen L Madsen3

1 University of Calgary and 2 Surgical Medical Research Institute, 3 Division of Gastroenterology, and 4 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2C2, Canada

Crohn's disease is a chronic disease characterized by oxidant-induced tissue injury and increased intestinal permeability. A consequence of oxidative damage is the accumulation of DNA strand breaks and activation of poly(ADP-ribose) polymerase (PARP), which subsequently catalyzes ADP-ribosylation of target proteins. In this study, we assessed the role of PARP in the colitis seen in interleukin (IL)-10 gene-deficient mice. IL-10 gene-deficient mice demonstrated significant alterations in colonic cellular energy status in conjunction with increased permeability, proinflammatory cytokine release, and nitrosative stress. After 14 days of treatment with the PARP inhibitor 3-aminobenzamide, IL-10 gene-deficient mice demonstrated normalized colonic permeability; reduced tumor necrosis factor-alpha and interferon-gamma secretion, inducible nitric oxide synthase expression, and nitrotyrosine levels; and significantly attenuated inflammation. Time course studies demonstrated that 3-aminobenzamide rapidly altered cellular metabolic activity and decreased cellular lactate levels. This was associated with normalization of colonic permeability and followed by a downregulation of proinflammatory cytokine release. Our data demonstrate that inhibition of PARP activity results in a marked improvement of colonic inflammatory disease and a normalization of cellular metabolic function and intestinal permeability.

interleukin-10; 3-aminobenzamide; inflammatory bowel disease; intestinal permeability


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