A study reported in the October issue of Gastroenterology (Volume 177, pages 1-12) shows that tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory protein, plays an important role in the development of early liver damage associated with alcohol consumption. Researchers from the University of North Carolina at Chapel Hill (UNC-CH) found that wild-type mice fed alcohol continuously over four weeks exhibited liver pathology almost seven times as severe as that in genetically selected mice without the TNF-alpha receptor (TNF-R1).

"This major increase in our understanding of the mechanisms of liver injury brings us one step closer to therapies for alcoholic liver disease," said Enoch Gordis, M.D., Director, National Institute on Alcohol Abuse and Alcoholism (NIAAA), a component of the National Institutes of Health.

The placebo-controlled study offers the first solid proof that TNF-alpha mediates the development of early liver injury associated with long-term alcohol consumption. The exact role of TNF-alpha in liver disease pathogenesis is not clear, although this cytokine earlier was associated with high mortality from alcoholic hepatitis and TNF-alpha antibodies have been known to exert a protective effect on liver cells against alcohol attack.

Supported by a grant from the NIAAA, the researchers combined gene knockout technology and the enteral feeding techniques originally developed by Tsukamoto and French to allow continuous tube infusion of a high-fat diet with alcohol into mice without severely limiting their mobility. The research team assessed liver enzyme levels, degree of steatosis (fatty liver), inflammation, and necrosis as liver damage indicators.

"The use of animals lacking TNF-alpha receptors provides a direct way to test the hypothesis that this cytokine is important in the initiation and progression of alcohol-induced liver injury," said senior study author Ronald Thurman, Ph.D., professor of pharmacology and nutrition at the UNC-CH School of Medicine.

According to Dr. Thurman, phagocytes, or Kupffer cells, produce TNF-alpha in the liver. These cells engulf foreign bodies, including endotoxin-producing bacteria that enter the liver from the gastrointestinal tract. Increased gut permeability from alcohol consumption can increase endotoxin levels, triggering the release of potent inflammatory molecules including TNF-alpha. This discharge could lead to hepatocellular damage.

Alcoholic liver disease is more common in men than women, but overweight women are the most sensitive population. "These new findings should help us to develop drug therapies for conditions that affect 11 million people in the United States alone," Dr. Thurman says. "The next step will be to try out our knockout technology for cirrhosis. We would use the same model, just go longer with it."

To contact Dr. Thurman, telephone 919/966-4745 or e-mail thurman@med.unc.edu. To schedule an interview with Dr. Gordis or other NIAAA staff, telephone NIAAA Press at 301/443-3860. For additional alcohol research information, visit http://www.niaa.nih.gov/.