title: Oxidative and nitrosative stress in acute pancreatitis. Modulation by pentoxifylline and oxypurinol.
abstract: Reactive oxygen species are considered mediators of the inflammatory response and tissue damage in acute pancreatitis. We previously found that the combined treatment with oxypurinol - as inhibitor of xanthine oxidase- and pentoxifylline - as inhibitor of TNF-α production-restrained local and systemic inflammatory response and decreased mortality in experimental acute pancreatitis. Our aims were (1) to determine the time-course of glutathione depletion and oxidation in necrotizing pancreatitis in rats and its modulation by oxypurinol and pentoxifylline; (2) to determine whether TNF-α is responsible for glutathione depletion in acute pancreatitis; and (3) to elucidate the role of oxidative stress in the inflammatory cascade in pancreatic AR42J acinar cells. We report here that oxidative stress and nitrosative stress occur in pancreas and lung in acute pancreatitis and the co-treatment with oxypurinol and pentoxifylline prevents oxidative stress in both tissues. Oxypurinol was effective in preventing glutathione oxidation, whereas pentoxifylline abrogated glutathione depletion. This latter effect was independent of TNF-α since glutathione depletion occurred in mice deficient in TNF-α or its receptors after induction of pancreatitis. The beneficial effects of oxypurinol in the inflammatory response may also be ascribed to a partial inhibition of MEK1/2 activity. Pentoxifylline markedly reduced the expression of Icam1 and iNos induced by TNF-α in vitro in AR42J cells. Oxidative stress significantly contributes to the TNF-α-induced up-regulation of Icam and iNos in AR42J cells. These results provide new insights into the mechanism of action of oxypurinol and pentoxifylline as anti-inflammatory agents in acute pancreatitis.
authors: Department of Physiology, School of Pharmacy, University of Valencia, Spain. justo.escobar@uv.es
authors: Javier
authors: J
authors: Escobar
authors: Javier
authors: J
authors: Pereda
authors: Alessandro
authors: A
authors: Arduini
authors: Juan
authors: J
authors: Sandoval
authors: Mari Luz
authors: ML
authors: Moreno
authors: Salvador
authors: S
authors: Pérez
authors: Luis
authors: L
authors: Sabater
authors: Luis
authors: L
authors: Aparisi
authors: Norberto
authors: N
authors: Cassinello
authors: Juan
authors: J
authors: Hidalgo
authors: Leo A B
authors: LA
authors: Joosten
authors: Máximo
authors: M
authors: Vento
authors: Gerardo
authors: G
authors: López-Rodas
authors: Juan
authors: J
authors: Sastre
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D008297:Male; D051379:Mice; D009574:Nitro Compounds / Q000378:metabolism*; D015538:Nitrosation / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010117:Oxypurinol / Q000008:administration & dosage*; D019283:Pancreatitis, Acute Necrotizing / Q000188:drug therapy / Q000378:metabolism*; D010431:Pentoxifylline / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009574:Nitro Compounds; D010117:Oxypurinol; D010431:Pentoxifylline