Chymase as a Novel Therapeutic Target in Acute Pancreatitis.

Toru Kuramoto,Kohei Taniguchi,Koji Komeda,Denan Jin,Kazuhisa Uchiyama,Shinji Takai,Fumitoshi Hirokawa

doi:10.3390/ijms222212313

Abstract

Acute pancreatitis is still a life-threatening disease without an evidenced therapeutic agent. In this study, the effect of chymase in acute pancreatitis and the possible effect of a chymase inhibitor in acute pancreatitis were investigated. Hamsters were subcutaneously administered 3.0 g/kg of L-arginine to induce acute pancreatitis. Biological markers were measured 1, 2, and 8 h after L-arginine administration. To investigate the effect of a chymase inhibitor, a placebo (saline) or a chymase inhibitor TY-51469 (30 mg/kg) was given 1 h after L-arginine administration. The survival rates were evaluated for 24 h after L-arginine administration. Significant increases in serum lipase levels and pancreatic neutrophil numbers were observed at 1 and 2 h after L-arginine administration, respectively. Significant increases in pancreatic neutrophil numbers were observed in the placebo-treated group, but they were significantly reduced in the TY-51469-treated group. A significant increase in the pancreatic tumor necrosis factor-α mRNA level was observed in the placebo-treated group, but it disappeared in the TY-51469-treated group. Chymase activity significantly increased in the placebo-treated group, but it was significantly reduced by treatment with TY-51469. The survival rate significantly improved in the TY-51469-treated group. A chymase inhibitor may become a novel therapeutic agent for acute pancreatitis.

Highlights

Acute pancreatitis is a systemic inflammatory disease triggered by autolysis due to the activation of pancreatic enzymes
Japanese guideline for treating acute pancreatitis mentioned a trypsin-like protease inhibitor, gabexate mesylate, as a possible therapeutic agent, but no significant reduction in mortality was reported in a meta-analysis of clinical studies [2]
In a rat taurodeoxycholate-induced acute pancreatitis model, activated mast cells and increased mRNA levels of tumor necrosis factor (TNF)-α were observed in the pancreas, but they were prevented by pretreatment with a mast cell stabilizer, cromolyn [5]

Summary

Introduction

Acute pancreatitis is a systemic inflammatory disease triggered by autolysis due to the activation of pancreatic enzymes. Treatment with a mast cell stabilizer, ketotifen, before an injection of cerulein, significantly reduced neutrophil infiltration into the pancreas before an injection of cerulein, significantly reduced neutrophil infiltration into the pancreas in the model, along with a significant attenuation of the mast cell number [6]. These results indicate the significance of mast cells in initiating acute pancreatitis. Mast cells include several inflammatory mediators, such as histamine, serotonin, cyto of 11 kines, and serine proteases It remains unclear which factor might play an important role in the initiation of acute pancreatitis

Methods

Results

Discussion

Conclusion