Protective effects of gastrin-releasing peptide receptor antagonist RC-3095 in an animal model of hepatic ischemia/reperfusion injury
- PMID: 30656798
- DOI: 10.1111/hepr.13315
Protective effects of gastrin-releasing peptide receptor antagonist RC-3095 in an animal model of hepatic ischemia/reperfusion injury
Abstract
Aim: We aimed to evaluate effects of RC-3095 on mice with hepatic ischemia followed by reperfusion (I/R) injury and further explore the possible underlying mechanism.
Methods: Mice were subjected to partial hepatic ischemia for 60 min followed by different durations of reperfusion. Levels of gastrin-releasing peptide (GRP) and GRP receptor (GRPR) in the blood and liver were detected by enzyme-linked immunosorbent assay (ELISA) or western blotting (WB) after 3, 6, 12, or 24 h of reperfusion. RC-3095 or normal saline (control) was given i.p. at the time of reperfusion. Expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in blood and liver samples were examined with ELISA. Neutrophil influx into the liver was assessed by flow cytometry and myeloperoxidase assay. Hematoxylin-eosin staining of the liver and terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling assay were used to determine hepatic injury and hepatocellular necrosis. Activation of nuclear factor (NF)-κB and p38/extracellular regulated protein kinase (ERK) mitogen activated protein kinase (MAPK) was investigated with WB.
Results: The expression of GRP was upregulated within 3 h after reperfusion and remained elevated for up to 24 h in the liver, whereas GRPR was also upregulated after 3 or 6 h of reperfusion, but returned to baseline levels within 24 h. RC-3095 significantly reduced the inflammatory hepatic injury, liver neutrophil accumulation, and hepatocellular apoptosis, probably by inhibiting activation of NF-κB or p38/ERK MAPK.
Conclusion: These findings supported that GRP-GRPR played an important role in hepatic I/R injury, and RC-3095 ameliorated liver damage by suppressing the inflammatory response and hepatocellular necrosis.
Keywords: RC-3095; gastrin-releasing peptide; inflammation; ischemia/reperfusion; liver injury.
© 2019 The Japan Society of Hepatology.
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