Effect of Simultaneous Inhibition of TNF-alpha Production and Xanthine Oxidase in Experimental Acute Pancreatitis: the Role of Mitogen Activated Protein Kinases

Overview

Journal Ann Surg

Specialty General Surgery

Date 2004 Jun 24

PMID 15213626

Citations 37

Authors

Javier Pereda

Luis Sabater

Norberto Cassinello

Luis Gomez-Cambronero

Daniel Closa

Emma Folch-Puy

Luis Aparisi

Julio Calvete

Miguel Cerda

Salvador Lledo

Jose Vina

Juan Sastre

Affiliations

Soon will be listed here.

Abstract

Objective: To assess the effects of inhibiting both tumor necrosis factor (TNF)-alpha production and xanthine oxidase activity on the inflammatory response, mitogen-activated protein kinase (MAPK) activation and mortality in necrotizing acute pancreatitis in rats.

Summary Background Data: Pancreatic injury triggers 2 major pathways involved in the systemic effects of severe acute pancreatitis: pro-inflammatory cytokines and oxidative stress.

Methods: Pancreatitis was induced by intraductal infusion of 3.5% sodium taurocholate. We examined whether treatment with oxypurinol, a specific inhibitor of xanthine oxidase, and/or pentoxifylline, an inhibitor of TNF-alpha production, affects pancreatic damage, ascites, lung inflammation, and MAPK phosphorylation.

Results: Oxypurinol prevented p38 phosphorylation in the pancreas and partially avoided the rise in lung myeloperoxidase activity. Pentoxifylline prevented erk 1/2 and JNK phosphorylation in the pancreas, and it partially reduced ascites and the rise in lung myeloperoxidase activity. Combined treatment with oxypurinol and pentoxifylline almost completely abolished ascites, MAPK phosphorylation in the pancreas, and the increase in lung myeloperoxidase activity. Histology revealed a reduction in pancreatic and lung damage. These changes were associated with a significant improvement of survival.

Conclusions: : Simultaneous inhibition of TNF-alpha production and xanthine oxidase activity greatly reduced local and systemic inflammatory response in acute pancreatitis and decreased mortality rate. These effects were associated with blockade of the 3 major MAPKs.

Citing Articles

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