Posted May 28, 2014
Laura Nagy, Ph.D., Cleveland Clinic Foundation
Alcohol abuse is one of the major causes of liver fibrosis, the excessive accumulation of scar tissue that results from repeated cell damage and inflammation. Chronic alcohol consumption, along with additional genetic and/or environmental factors, increases susceptibility to liver fibrosis; however, the mechanism by which chronic alcohol consumption leads to the development or exacerbation of liver fibrosis is not well understood. Previous studies have shown that ethanol consumption results in an accumulation of adenosine in the liver and that adenosine 2A receptor (A2AR) activation enhances the activity of hepatic stellate cells (HSCs), which are a source of excess extracellular matrix proteins in fibrotic liver.
Dr. Laura Nagy received a Fiscal Year 2009 Peer Reviewed Medical Research Program Investigator-Initiated Research Award to explore the role of adenosine and A2AR in alcohol-related liver fibrosis. Using a mouse model, Dr. Nagy has demonstrated that following moderate ethanol consumption, HSC activation is enhanced in response to experimentally induced liver damage and that this activation can be attenuated by administration of an A2AR antagonist. These data suggest that one mechanism by which moderate ethanol consumption exacerbates fibrosis is mediated by A2ARs. Further, the accumulation of extracellular matrix proteins in response to liver damage was decreased in mice that were treated with the A2AR antagonist, suggesting that fibrosis may be reversed in response to treatment.
Dr. Nagy also demonstrated that loss of hypoxia inducible factor 1α (HIF1α) in mice slowed the normally rapid progression of fibrosis following chronic ethanol consumption. She confirmed that HIF1α in hepatocytes is critical both for the increased activation of HSCs and collagen deposition, as well as the recruitment of highly inflammatory macrophages to the liver. These novel findings point to an important interaction among alcohol, hypoxia, and recruitment of macrophages in the exacerbation of fibrosis as a result of alcohol consumption.
Dr. Nagy's team is continuing to dissect out the mechanisms by which alcohol increases adenosine. They have found that alcohol results in hypoxia within the liver, which in turn increases adenosine. Dr. Nagy's results indicate that adenosine receptor antagonists, which are already approved for clinical investigation in other diseases, offer great potential to be used as a therapy for treatment of alcoholic liver disease.
Publication:
Chiang D, Roychowdbury S, Bush K, et al. 2013. Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis. PLoS One 8(7):e69114.
Links:
Public and Technical Abstracts: Acceleration of Hepatic Fibrosis by Alcohol: Role of Adenosine