Surgeons In the News

Blockade of RAGE Promotes Regeneration in the Massively Injured Liver

Jean C. Emond, MD

Ann Marie Schmidt, MD

The Division of Abdominal Organ Transplantation and the Division of Surgical Science at NewYork-Presbyterian Hospital/Columbia University Medical Center (NewYork-Presbyterian/Columbia) are collaborating on research studies that explore the limits of liver regeneration. By better understanding regeneration, physician-researchers hope to learn how to overcome its natural limits and thereby potentially expand the role of transplantation.

Lead investigators Jean C. Emond, MD, Clinical Vice Chair, Transplantation, and Ann Marie Schmidt, MD, Chief, Division of Surgical Science, are focusing their efforts on the blockade of RAGE (Receptor for Advanced Glycation End products), a cell surface receptor molecule, as a novel strategy to promote regeneration in the massively injured liver. Their initial findings were published in the February 7, 2005 issue of The Journal of Experimental Medicine.

The liver has a remarkable ability to regenerate itself when injured. A multi-functional organ, the liver fights infections and stops bleeding. It removes drugs and other poisons from the bloodstream and it stores energy for when we need it. The liver manufactures proteins, and it also makes bile acids and fats that are needed for digestion and for the transport of nutrients. "Unlike many human bodily organs, if the liver is injured, it has the dramatic potential to repair itself. However, if a disproportionate amount of the liver is surgically removed, the liver can fail to regenerate, threatening the survival of the organ," says Dr. Emond.

"In past research experiments using a mouse model, investigators traditionally resected 70% of the liver. When they resected 70%, they essentially found that certain pathways would turn on that would regenerate the remaining liver in the vast majority of the animals," explains Dr. Schmidt. "However, in our recent studies we discovered if you took out more, such as 85% of the liver, the results were drastically different. With an 85% resection, we saw a highly significant increase in the death of the animals—an extreme difference from the virtually complete survival rate for the 70% resection."

The Columbia researchers determined that the RAGE receptor was one of the important factors leading to the failure of regeneration after a massive resection. When they blocked that receptor, the liver would regenerate and the animals would survive—even after an 85% resection.

"We tried to figure out which RAGE expressing cells were pivotal for the regeneration process. The answer signified a fascinating discovery in our research. It appears that the dendritic cells in the liver are expressing the receptor. This is where the RAGE receptor is upregulated in the injury—in these very dendritic cells," says Dr. Schmidt. "These findings strongly suggest that RAGE-expressing dendritic cells in the liver are key culprits in the mechanisms leading to failure of regeneration after massive injury."

Dr. Emond adds, "Our newfound understanding of the role of RAGE and, in particular, the role of RAGE in dendritic cells, has vast clinical implications. It suggests RAGE blockade in humans may provide new therapies for what were once devastating liver diseases."