Reduction in the development of cerulein-induced acute pancreatitis by treatment with M40401, a new selective superoxide dismutase mimetic.

Abstract

Oxidative stress plays an important role in the early stage of acute pancreatitis, as well as in the associated multiple organ injury. This study tests the hypothesis that M40401, a new superoxide dismutase mimetic, attenuates experimental acute pancreatitis. Intraperitoneal injection of cerulein in mice resulted in a severe, acute pancreatitis that was characterized by edema, neutrophil infiltration, tissue hemorrhage, and cell necrosis, as well as increases in the serum levels of amylase and/or lipase. The infiltration of the pancreatic tissue of these animals with neutrophils (measured as an increase in myeloperoxidase activity) was associated with expression of intercellular adhesion molecule-1, as well as signs of enhanced lipid peroxidation (e.g., increased tissue levels of malondialdehyde). Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for nitrotyrosine and poly (ADP-ribose) polymerase in the pancreas of cerulein-treated mice. In contrast, the degree of pancreatic inflammation and tissue injury (histological score), the expression of intercellular adhesion molecule-1, the staining for nitrotyrosine and poly (ADP-ribose) polymerase, and lipid peroxidation were markedly reduced in pancreatic tissue sections obtained from cerulein-treated mice administered with M40401. These results confirm our hypothesis that superoxide anions play an important role in cerulein-mediated acute pancreatitis and support the possible clinical use of low-molecular-weight synthetic superoxide dismutase mimetics in those conditions that are associated with overproduction of superoxide.