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.