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

Humberto B Jijon, Thomas Churchill, David Malfair, Andreas Wessler, Laurence D Jewell, Howard G Parsons, Karen L Madsen
2000 American Journal of Physiology - Gastrointestinal and Liver Physiology  
Inhibition of poly(ADPribose) polymerase attenuates inflammation in a model of chronic colitis. Am J Physiol Gastrointest Liver Physiol 279: G641-G651, 2000.-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
more » ... ed 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-␣ and interferon-␥ 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
doi:10.1152/ajpgi.2000.279.3.g641 pmid:10960365 fatcat:wv4uz2wbf5dgrjnd2ilaqhxrhm