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

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University of Calgary, 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.

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