Helium preconditioning protects mouse liver against ischemia and reperfusion injury through the PI3K/Akt pathway.

Abstract

BACKGROUND & AIMS:

Hepatic ischemia and reperfusion (I/R) injury is a major complication of liver transplantation, hepatic resection and trauma. Helium preconditioning (HPC) exerts protection against ischemic stress. We investigated potential beneficial effects of HPC on I/R-induced liver injury and investigated mechanisms underlying HPC-induced protection.

METHODS:

We employed a model of segmental warm hepatic I/R on BALB/c mice. Serum ALT was measured and livers were analysed by histology, RT-PCR and western blot. HPC was induced by inhalation of a 70% helium/30% oxygen mixture for three 5-min periods, interspersed with three 5-min washout periods by room air. We tested which component of HPC (the helium/air mixture inhalation, the air room gap, or the interaction between these two factors) is protective.

RESULTS:

We found that HPC caused a significant increase in Akt phosphorylation in hepatocytes. The HPC-induced Akt phosphorylation resulted in decreased hepatocellular injury and improved survival rate of the treated animals. PI3K inhibitors abolished HPC induced effects. HPC-induced Akt phosphorylation affected expression of its downstream molecules. The effects of HPC on the PI3K/Akt pathway were attenuated by adenosine A2A receptor blockade, but could be re-established by PTEN inhibition. We demonstrated that the interaction of helium/air breathing and air gaps is responsible for the observed effects of HPC.

CONCLUSIONS:

HPC may be a promising strategy leading to a decrease in I/R induced liver injury in clinical settings. Additionally, the PI3K/Akt pathway plays an essential role in the protective effects of HPC in hepatic I/R injury.

• Authors: Rongjia Zhang, Ling Zhang, Anatol Manaenko, Zhouheng Ye, Wenwu Liu, Xuejun Sun
• Journal: Journal of hepatology (J Hepatol) Vol. 61 Issue 5 Pg. 1048-55 (Nov 2014) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 24972044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 European Association for the Study of the Liver. All rights reserved.

Chemical References

• Adenosine A2 Receptor Antagonists
• NF-kappa B
• Triazines
• Triazoles
• ZM 241385
• Helium
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Adenosine A2 Receptor Antagonists (pharmacology)
• Animals
• Apoptosis (drug effects)
• Disease Models, Animal
• Helium (therapeutic use)
• Ischemic Preconditioning (methods)
• Liver (drug effects, injuries, metabolism)
• Liver Transplantation (adverse effects, methods)
• Male
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• PTEN Phosphohydrolase (antagonists & inhibitors)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Reperfusion Injury (metabolism, pathology, prevention & control)
• Signal Transduction
• Transplantation Conditioning (methods)
• Triazines (pharmacology)
• Triazoles (pharmacology)
• Warm Ischemia