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PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion

Salvatore Cuzzocrea¹, Rosanna Di Paola, Emanuela Mazzon, Ulrich Cortes^*, Tiziana Genovese, Carmelo Muià, Weixing Li, Weizheng Xu, Jia-He Li, Jie Zhang and Zhao-Qi Wang^*

Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, Messina, Italy;
^* International Agency for Research on Cancer, Lyon, France;
Guilford Pharmaceuticals Inc., Baltimore, Maryland, USA; and
Lilium Pharmaceuticals, Cockeysville, Maryland, USA

¹Correspondence: Institute of Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario, Via C. Valeria-Gazzi, 98100 Messina, Italy. E-mail: salvator{at}unime.it

Poly (ADP-ribosyl)ation, an early post-translational modification in response to DNA damage, is catalyzed by poly (ADP-ribose) polymerase (PARP-1) and catabolized by poly(ADP-ribose) glycohydrolase (PARG). The aim of this study was to investigate the role of PARG on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. SAO shock in rats and wild-type (WT) mice was associated with a significant neutrophil infiltration in the ileum and production of tumor necrosis factor- (TNF-). Reperfused ileum tissue sections from SAO-shocked WT mice and rats showed positive staining for P-selectin and ICAM-1 localized mainly in the vascular endothelial cells. Genetic disruption of the PARG gene in mice or pharmacological inhibition of PARG by PARG inhibitors significantly improved the histological status of the reperfused tissues associated with reduced expression of P-selectin and ICAM-1, neutrophil infiltration into the reperfused intestine, and TNF- production. These results suggest that PARG activity modulates the inflammatory response in ischemia/reperfusion and participates in end (target) organ damage under these conditions.—Cuzzocrea, S., Di Paola, R., Mazzon, E., Cortes, U., Genovese, T., Muià, C., Li, W., Xu, W., Li, J.-H., Zhang, J., Wang, Z.-Q. PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion.

Key Words: SAO shock • ischemia and reperfusion • PARG inhibitor • neutrophil infiltration • organ injury

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				E. Esposito, E. Mazzon, C. Muia, R. Meli, E. Sessa, and S. Cuzzocrea Splanchnic ischemia and reperfusion injury is reduced by genetic or pharmacological inhibition of TNF-{alpha} J. Leukoc. Biol., April 1, 2007; 81(4): 1032 - 1043. [Abstract] [Full Text] [PDF]

				S. Cuzzocrea, T. Genovese, E. Mazzon, C. Crisafulli, W. Min, R. Di Paola, C. Muia, J.-H. Li, E. Esposito, P. Bramanti, et al. Poly(ADP-Ribose) Glycohydrolase Activity Mediates Post-Traumatic Inflammatory Reaction after Experimental Spinal Cord Trauma J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 127 - 138. [Abstract] [Full Text] [PDF]