fr-167653 and Pancreatitis

The p38 mitogen-activated protein kinase (MAPK) pathway is important in Th1 immunity, macrophage activation, and apoptosis. Since they may be associated with beta-cell destruction during the development of type 1 diabetes, we investigated the role of the p38 MAPK pathway in female nonobese diabetic (NOD) mice. Phosphorylated p38 MAPK was observed immunohistochemically in CD4+ cells that had infiltrated into the islets and part of beta-cells, increasing in proportion to the severity of insulitis. Continuous oral administration of 0.08% FR167653, a specific p38 MAPK pathway inhibitor, significantly reduced the ex vivo production of interferon-gamma by splenic Th1 cells without affecting interleukin-4 production by Th2 cells. FR167653 administration from 4-30 weeks of age prevented NOD mice from developing diabetes without affecting the severity of insulitis. Treatment with FR167653 after insulitis had developed (i.e. from 10-30 weeks of age) also prevented diabetes, further suggesting that treatment with the p38 MAPK pathway inhibitor keeps insulitis benign in NOD mice, partly by inhibiting Th1 immunity. These findings suggest that p38 MAPK is a key mediator that switches insulitis from benign to destructive in the development of type 1 diabetes.

Topics: Animals; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Female; Immunosuppressive Agents; Interferon-gamma; Islets of Langerhans; Male; Mice; Mice, Inbred NOD; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pancreatitis; Pyrazoles; Pyridines; Spleen; Th1 Cells

This study was designed to evaluate the possible role of cytokines (IL-1 and TNF-alpha) in the pathogenesis of acute pancreatitis in the early stage of the disease and to evaluate the protective effect of the cytokine suppressive agent, FR167653, against pancreatic injuries. Acute pancreatitis was induced in rats by closed duodenal loop. However, the free passage for the gastrointestinal contents was maintained by inserting the tube into the duodenum. In this model, the survival rate was significantly decreased as compared with the control sham-operated rats at 48 h after induction of pancreatitis. Marked hyperamylasemia and a significant increase in pancreatic water and trypsin contents were observed at 24 h after induction of pancreatitis. Pancreatic subcellular redistribution of lysosomal enzyme cathepsin B from the lysosomal fraction to the zymogen fraction was also observed. However, treatment with FR167653 at a dose of 1.5 mg/kg (four times, every 6 h after induction of pancreatitis) significantly prevented all these pancreatic injuries, improving the survival rate. These results indicate that cytokines such as IL-1 and TNF-alpha may be involved in the pathogenesis of acute pancreatitis in the early stage of the disease, and that a cytokine-suppressive agent might be of therapeutic value for the treatment of acute pancreatitis.

Topics: Acute Disease; Animals; Cathepsin B; Duodenum; Interleukin-1; Lysosomes; Male; Pancreatitis; Pyrazoles; Pyridines; Rats; Rats, Wistar; Survival Rate; Time Factors; Tumor Necrosis Factor-alpha