title: Inhibition of poly(ADP-ribose) polymerase attenuates the severity of acute pancreatitis and associated lung injury.
abstract: The severity of acute pancreatitis results from the transmigration and activation of leukocytes within the pancreas and the local synthesis and release of proinflammatory-soluble mediators that transform a local injury into a systemic inflammatory response. Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear DNA-binding protein that has been shown to play a relevant role in cell necrosis and organ failure in various diseases associated with inflammation. Therefore, we set out to investigate whether the genetic deletion of PARP-1 or PARP-2 (a new member of the PARP family) genes, or pharmacological inhibition of PARP activity might affect the development and severity of acute pancreatitis and pancreatitis-associated lung injury. Secretagogue-induced acute pancreatitis was achieved by 12 hourly intraperitoneal injections of cerulein in mice deficient in PARP-1 or PARP-2 genes, and wild-type (WT) littermate mice untreated or treated with PARP activity inhibitors. The severity of pancreatitis was assessed by measurements of serum amylase, lipase, interleukin-1beta and IL-6, pancreatic water content, histologic grading and pancreas myeloperoxidase (MPO) activity. Lung injury was evaluated by quantifying MPO activity and morphological changes. We found that the severity of acute pancreatitis and pancreatitis-associated lung injury was significantly attenuated in mice lacking PARP-1, but not PARP-2, compared with WT mice. Interestingly, administration of PARP inhibitors, 3-aminobenzamide or PJ34 (N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethyacetamide HCl), in WT mice markedly decreased acute pancreatitis severity and pulmonary-associated injury in a larger extension than genetic deletion of PARP-1. Our results support the potential therapeutic application of PARP inhibitors in the development and severity of acute pancreatitis and associated lung injury.
authors.affiliation: Department of Surgery, School of Medicine, University of Murcia, Murcia, Spain.
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mota
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Bueno
authors.forename: Luis
authors.initials: L
authors.lastname: Saenz
authors.forename: David
authors.initials: D
authors.lastname: Hernández-Espinosa
authors.forename: Jaime
authors.initials: J
authors.lastname: Jimeno
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Tornel
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martínez-Torrano
authors.forename: Pablo
authors.initials: P
authors.lastname: Ramírez
authors.forename: Pascual
authors.initials: P
authors.lastname: Parrilla
authors.forename: José
authors.initials: J
authors.lastname: Yélamos
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002108:Ceruletide; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008049:Lipase / Q000097:blood; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D009195:Peroxidase / Q000032:analysis; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D007375:Interleukin-1; D015850:Interleukin-6; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D002108:Ceruletide; C025160:3-aminobenzamide; D009195:Peroxidase; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse; D008049:Lipase; D000681:Amylases