Inhibition of the dephosphorylation of eukaryotic initiation factor 2α ameliorates murine experimental pancreatitis.

Abstract

BACKGROUND:

Endoplasmic reticulum (ER) stress in the pancreas is closely associated with the development of acute pancreatitis. However, the role of the protein kinase RNA-like ER kinase (PERK) in this disease is not fully understood. We investigated whether an inhibitor of the dephosphorylation of eukaryotic initiation factor 2α, salubrinal, could improve murine experimental pancreatitis through the amelioration of ER stress.

METHODS:

Acute pancreatitis was induced by the intraperitoneal administration of cerulein (50 μg/kg) six times at 1-h intervals followed by lipopolysaccharide (10 mg/kg). Salubrinal was administered intraperitoneally immediately after lipopolysaccharide injection and 3 h later. Mice were sacrificed 24 h after the first injection of cerulein, and serum amylase and proinflammatory cytokines were measured. The severity of pancreatitis was evaluated histologically using a scoring system. The expression levels of ER stress-related proteins were evaluated by Western blotting.

RESULTS:

The administration of salubrinal significantly attenuated the increase in serum amylase levels and improved histologically assessed pancreatitis. The serum levels of proinflammatory cytokines were significantly suppressed in salubrinal-treated mice, as was the expression of glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, and cleaved caspase-3.

CONCLUSIONS:

The amelioration of ER stress through augmentation of the PERK-signaling pathway may be a therapeutic target for the treatment of acute pancreatitis.

• Authors: Kazunori Aoi, Akiyoshi Nishio, Takashi Okazaki, Masahiro Takeo, Masataka Masuda, Toshiro Fukui, Kazushige Uchida, Kazuichi Okazaki
• Journal: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] (Pancreatology) Vol. 19 Issue 4 Pg. 548-556 (Jun 2019) ISSN: 1424-3911 [Electronic] Switzerland
• PMID: 31040063 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Chemical References

• Cinnamates
• Cytokines
• Eukaryotic Initiation Factor-2
• Lipopolysaccharides
• salubrinal
• Ceruletide
• Amylases
• Thiourea

Topics

• Acute Disease
• Amylases (blood)
• Animals
• Apoptosis (drug effects)
• Ceruletide
• Cinnamates (therapeutic use)
• Cytokines (blood)
• Endoplasmic Reticulum Stress (drug effects)
• Eukaryotic Initiation Factor-2 (drug effects, metabolism)
• Injections, Intraperitoneal
• Lipopolysaccharides
• Male
• Mice
• Mice, Inbred C57BL
• Pancreatitis (chemically induced, drug therapy)
• Phosphorylation (drug effects)
• Thiourea (analogs & derivatives, therapeutic use)