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

Crohn's disease is a chronic disease characterized by oxidant-induced tissu e 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 coliti s seen in interleukin (IL)-10 gene-deficient mice. IL-10 gene-deficient mic e 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 coloni c permeability; reduced tumor necrosis factor-alpha and interferon-gamma se cretion, inducible nitric oxide synthase expression, and nitrotyrosine leve ls; and significantly attenuated inflammation. Time course studies demonstr ated that 3-aminobenzamide rapidly altered cellular metabolic activity and decreased cellular lactate levels. This was associated with normalization o f colonic permeability and followed by a downregulation of proinflammatory cytokine release. Our data demonstrate that inhibition of PARP activity res ults in a marked improvement of colonic inflammatory disease and a normaliz ation of cellular metabolic function and intestinal permeability.