Oxidative and nitrosative stress in acute pancreatitis. Modulation by pentoxifylline and oxypurinol

• Published in: Biochemical pharmacology Vol. 83; no. 1; pp. 122 - 130
• Main Authors: Escobar, Javier, Pereda, Javier, Arduini, Alessandro, Sandoval, Juan, Moreno, Mari Luz, Pérez, Salvador, Sabater, Luis, Aparisi, Luis, Cassinello, Norberto, Hidalgo, Juan, Joosten, Leo A.B., Vento, Máximo, López-Rodas, Gerardo, Sastre, Juan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 2012; Elsevier
• Subjects: acinar cells; Acute pancreatitis; Animals; anti-inflammatory agents; Biological and medical sciences; Cell Line, Tumor; Drug Therapy, Combination; Gastroenterology. Liver. Pancreas. Abdomen; Glutathione; inflammation; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; mechanism of action; Medical sciences; MEK1/2; Mice; mortality; Nitro Compounds - metabolism; Nitrosation - drug effects; Nitrosation - physiology; Other diseases. Semiology; oxidation; oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Oxypurinol; Oxypurinol - administration & dosage; pancreas; pancreatitis; Pancreatitis, Acute Necrotizing - drug therapy; Pancreatitis, Acute Necrotizing - metabolism; Pentoxifylline; Pentoxifylline - administration & dosage; Pharmacology. Drug treatments; Rats; Rats, Wistar; reactive oxygen species; receptors; TNF-α; xanthine; Pentoxifylline; Acute pancreatitis; Oxypurinol; TNF-α; MEK1/2; Glutathione; Oxidative stress; Hypouricemic agent; Vasodilator agent; Enzyme; Transferases; Acute; Cytokine; Pancreatitis; Enzyme inhibitor; Mitogen-activated protein kinase; Modulation; Digestive diseases; Xanthine oxidase; Xanthine derivatives; Oxidoreductases; Oxipurinol; Tumor necrosis factor α; Pancreatic disease
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.09.028

Co-treatment with oxypurinol (O) and pentoxifylline (P) prevents oxidative and nitrosative stress in pancreas in acute pancreatitis (AP). The effect of oxypurinol may be ascribed to inhibition of MEK1/2 activity.
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.