St. Louis, July 10, 2001 ó Small fatty molecules called prostaglandins promote liver regrowth after injury, according to a study by researchers at Washington University School of Medicine in St. Louis. "When we blocked prostaglandin synthesis, we found that the liverís regenerative response was significantly impaired in a mouse model system," says David A. Rudnick, M.D., Ph.D., the studyís first author and an instructor in pediatrics. "This finding brings scientists one step closer to understanding liver disease and developing potential treatments."
Prostaglandins help regulate blood pressure, muscle contraction and blood clotting, but their role in liver regeneration was not well characterized. The research is reported in the July 10 issue of Early Edition of the Proceedings of the National Academy of Sciences.
The work was performed in the laboratory of Louis J. Muglia, M.D., Ph.D., assistant professor of pediatrics, of obstetrics and gynecology and of molecular biology and pharmacology, and in collaboration with David H. Perlmutter, M.D., who is now at the University of Pittsburgh School of Medicine. Unlike most organs, the liver can grow back after infection, trauma, chemical damage or other assaults. In the mouse study, Rudnick and colleagues removed part of the liver and watched it grow back over hours and days.
Before the surgery, they treated some of the mice with drugs called COX inhibitors. These compounds, which also are used to treat inflammatory disorders such as arthritis, inhibit one or both of two enzymes that make prostaglandins: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Control mice had the surgery but did not receive the drugs.
Forty-two hours after surgery, the livers of the control mice exhibited a robust and appropriate regenerative response in the remaining tissue, while the livers of the animals treated with an inhibitor of both COX enzymes or with a COX-2 inhibitor did not. An additional experiment on genetically altered mice showed that COX-2 plays an important role in liver regeneration with or without COX-1. "These results show that prostaglandins are required for efficient liver regeneration in this model system and implicate a role for them in the regenerative response seen in liver disease," Rudnick says.
He notes that the ancient Greeks described liver regeneration. Prometheus, who stole fire from Zeus and gave it to humans, was punished by being chained to a rock. Every day, an eagle tore out his liver, which grew back completely every night. "That story has many things in common with our mouse model," Rudnick says. "The liver grows back until it is 100 percent of its former size, and then the regenerative response stops. If it is injured again, it can grow back again, and it can do this over and over."
The researchers now are determining how prostaglandins affect gene expression during liver regeneration.
Rudnick DA, Perlmutter DH, Muglia LJ. Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration. Early Edition of the Proceedings of the National Academy of Sciences, 2(28), Article # 2179, July 10, 2001.
Funding from the National Institutes of Health, American Digestive Health Foundation, American Gastroenterological Association and Burroughs Wellcome Fund supported this research.
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