Effect of simultaneous inhibition of TNF-alpha production and xanthine oxidase in experimental acute pancreatitis: the role of mitogen activated protein kinases.
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.


BACKGROUND
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.
Pereda
Javier
J
Department of Physiology, University of Valencia, Spain.
Sabater
Luis
L
Cassinello
Norberto
N
Gómez-Cambronero
Luis
L
Closa
Daniel
D
Folch-Puy
Emma
E
Aparisi
Luis
L
Calvete
Julio
J
Cerdá
Miguel
M
Lledó
Salvador
S
Viña
José
J
Sastre
Juan
J
D000818:Animals; D001201:Ascites / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress; D010117:Oxypurinol / Q000494:pharmacology; D010179:Pancreas / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010431:Pentoxifylline / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000097:blood
D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D014969:Xanthine Oxidase; D020928:Mitogen-Activated Protein Kinases; D010117:Oxypurinol; D010431:Pentoxifylline