Poly (ADP-Ribose) synthetase mediates intestinal mucosal barrier dysfunction after mesenteric ischemia

Recent evidence demonstrates that peroxynitrite-mediated DNA strand breaks trigger PARS activation, resulting in intracellular energetic failure and tissue dysfunction. Here we investigated the role of poly (ADP-ribose) synthetase (PARS) activation on the inflammatory and functional response of the intestine to mesenteric ischemia-reperfusion injury. Exposure of rats to 15 min of mesenteric ischemia and 10 min of reperfusion increased ileal mucosal PARS activity, neutrophil infiltration (myeloperoxidase activity), lipid peroxidation (malondialdehyde), paracellular epithelial permeability (lumen to plasma flux of a 4,000 MW dextran), and histologic injury. Inhibition of PARS by 3-aminobenzamide or nicotinamide reduced histologic injury, mucosal hyperpermeability, and neutrophil infiltration. Depletion of glutathione, an endogenous antioxidant and a scavenger of peroxynitrite, by L-buthionine-(S,R)-sulfoximine, exacerbated reperfusion-induced hyper-permeability, while nitric oxide synthase inhibition, which blocks the production of peroxynitrite, ameliorated hyperpermeability and histologic injury. In mice subjected to 15 min of ischemia and 180 min of reperfusion, targeted gene disruption of PARS ameliorated ileal mucosal lipid peroxidation and ileal mucosal and pulmonary neutrophil infiltration. Our data demonstrate the crucial role of PARS in mediating regional and remote tissue injury in the early and late phases of mesenteric reperfusion. Pharmacological inhibition of PARS may be a novel approach for the protection of tissues from reperfusion-related damage.