PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion.
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-alpha (TNF-alpha). 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-alpha 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
Salvatore
S
Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, Messina, Italy. salvator@unime.it
Di Paola
Rosanna
R
Mazzon
Emanuela
E
Cortes
Ulrich
U
Genovese
Tiziana
T
Muià
Carmelo
C
Li
Weixing
W
Xu
Weizheng
W
Li
Jia-He
JH
Zhang
Jie
J
Wang
Zhao-Qi
ZQ
D000818:Animals; D001158:Arteries; D002445:Celiac Artery; D003250:Constriction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D007082:Ileum / Q000098:blood supply / Q000737:chemistry / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007422:Intestines / Q000098:blood supply* / Q000737:chemistry / Q000473:pathology; D008297:Male; D017538:Mesenteric Artery, Superior; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D012769:Shock; D013152:Splanchnic Circulation; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D004791:Enzyme Inhibitors; D005449:Fluorenes; C502402:N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase