Molecular Hydrogen Attenuates hypoxia/reoxygenation Injury of Intrahepatic Cholangiocytes by Activating Nrf2 Expression

Toxicol Lett. 2015 Nov 4;238(3):11-9. doi: 10.1016/j.toxlet.2015.08.010. Epub 2015 Aug 11.


Hypoxia/reoxygenation (H/R) injury of cholangiocytes causes serious biliary complications during hepatobiliary surgeries. Molecular hydrogen (H2) has been shown to be effective in protecting various cells and organs against oxidative stress injury. Human liver cholangiocytes were used to determine the potential protective effects of hydrogen against cholangiocyte H/R injury and explore the underlying mechanisms. We found that H2 ameliorated H/R-induced cholangiocytes apoptosis. Our study revealed that H2 activated NF-E2-related factor 2 (Nrf2) and downstream cytoprotective protein expression. However, the protective function of H2 was abolished when Nrf2 was silenced. Apoptosis in cholangiocytes isolated from a rat model of liver ischemia/reperfusion injury indicated that H2 significantly attenuates ischemia/reperfusion cholangiocyte injury in vivo. In conclusion, our study shows that H2 protects intrahepatic cholangiocytes from hypoxia/reoxygenation-induced apoptosis in vitro or in vivo, and this phenomenon may depend on activating Nrf2 expression.

Keywords: Hypoxia/reoxygenation; Intrahepatic cholangiocytes; Ischemia/reperfusion; Molecular hydrogen; NF-E2-related factor 2; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bile Ducts, Intrahepatic / blood supply
  • Bile Ducts, Intrahepatic / pathology*
  • Gene Silencing
  • Hydrogen / pharmacology
  • Hydrogen / therapeutic use*
  • Liver Diseases / drug therapy*
  • Liver Diseases / etiology
  • Liver Diseases / metabolism
  • Male
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / prevention & control*
  • Signal Transduction


  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • Hydrogen