"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-a
mediates the development of early liver injury associated
with long-term alcohol consumption. The exact role of TNF-a
in liver disease pathogenesis is not clear, although this cytokine
earlier was associated with high mortality from alcoholic hepatitis and TNF-a
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-a
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-a
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-a.
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 firstname.lastname@example.org. To schedule an interview with Dr. Gordis or other
NIAAA staff, telephone NIAAA Press at 301/443-3860. For additional alcohol research information, visit www.niaaa.nih.gov.