Rationale and Objectives: Alcoholic liver disease (ALD) develops in approximately 20% of all alcoholics and alcohol abuse is the leading cause of fibrosis and cirrhosis in the United States. In 2005, liver cirrhosis was the 12th leading cause of death in the United States. Alcohol abuse is one of the major causes in the development of liver disease. Long periods of alcohol abuse, likely working in combination with family history and/or environmental factors, such as viral infections, increases the risk for fibrosis and cirrhosis. Currently, there are no effective treatments for liver cirrhosis, and patients need to undergo liver transplants if the liver disease is too severe. However, there is a growing appreciation that fibrosis, the earlier stage of liver disease, is reversible. This suggests that medical treatments aimed at slowing and/or reversing fibrosis will likely slow the progression of the disease.

The development of fibrosis and cirrhosis is a complex process involving all the cell types within the liver. The progression can take years; patients first develop fatty liver, followed by inflammation in the liver, and then fibrosis, which is characterized by a hardening of the liver because of increased deposits of extracellular matrix proteins. Interestingly, many of the processes contributing to hepatic fibrosis are typical of tissue responses to injury, such as wound healing in the skin and soft tissues. Liver fibrosis can be considered as excessive "scar" formation after an injury. Continued alcohol abuse may disorder the highly regulated "wound healing response," resulting in continued liver damage, inflammation, and fibrosis.

In order to investigate the mechanisms for ALD, we have developed a mouse model of accelerated fibrosis that combines alcohol exposure at a low concentration (11% of total calories, equivalent to 2 to 4 drinks per day) with exposure to the commonly used hepatotoxin carbon tetrachloride (CCl4). Exposure to alcohol for as little as 4 to 14 days acclerates fibrosis. Alcohol increased the amount of "scar" formation in the liver. During the metabolism of alcohol in the liver, there is an increased production of a small, regulatory molecule called adenosine. Adenosine has been shown to be involved in wound healing responses. Therefore, we propose that increased adenosine in the liver during alcohol consumption increases the amount of scar that accumulates in the liver. By making use of specific drugs that block the effects of adenosine, we may be able to prevent this excess scar formation.

Impact: Since there is currently no treatment for ALD, our work is important because it will test a potentially useful therapy for ALD. The current studies will only be carried out in animal models. But upon completion of the proposed preclinical studies, we will have a more complete understanding of the molecular mechanisms for ALD and gain insight into the potential efficacy for drugs that block the effect of adenosine in the treatment of hepatic fibrosis resulting from chronic alcohol abuse.