April 1998

Media Contacts: Sarah Goodwin, 404/727-3366 - sgoodwi@emory.edu
Kathi Ovnic, 404/727-9371 - covnic@emory.edu

An Emory University pathologist has found a potential way to manipulate natural on-off switches in the body that may eventually allow physicians to regulate and treat two chronic inflammatory diseases of the intestine - Crohn's disease and ulcerative colitis. Ulcerative colitis causes ulceration and inflammation of the inner lining of the colon and rectum, while Crohn's disease is an inflammation that extends into the deeper layers of the intestinal wall.

James Madara, M.D., W. Timmie professor of pathology and laboratory medicine at Emory University School of Medicine, has developed a laboratory model that demonstrates the molecular interactions between white blood cells and intestinal epithelial cells - the cells lining the intestinal wall. Intestinal inflammation occurs when a type of white blood cell called polymorphonuclear leukocytes (PMN) migrates into and across the intestinal epithelial cell barrier.

The inflammation in Crohn's disease and ulcerative colitis can cause abdominal pain, diarrhea, fever, weight loss and anemia and sometimes leads to more serious complications including intestinal blockage; ulcerations or fistulas affecting surrounding organs; and systemic complications. Most treatments that commonly target intestinal inflammatory diseases, including steroids, aspirin and other anti-inflammatory drugs, often cause unpleasant side effects.

Dr. Madara and other scientists recently have discovered that epithelial cells, in addition to serving as an intestinal barrier, play an active role in intestinal inflammation. When epithelial cells recognize pathogens, such as Yersinia enterocolitica, inside the intestine, they release substances that "invite" PMN to migrate across the intestinal epithelial barrier. As PMN cross the barrier, however, the barrier breaks down, allowing other pathogens to enter.

The epithelial cells then initiate a signalling pathway that allows unique proteins to bind to target endothelial cell receptors, alerting other intestinal cells to secrete fluids and electrolytes, which cause diarrhea.

A new understanding of the specific proteins and targets that allow the epithelial cells to recruit the PMN to migrate and knowledge about how the epithelial cells respond once inflammation is present has allowed Dr. Madara, in collaboration with Dr. Charles Serhan of Harvard University, to develop compounds that could interfere with these reactions. He is testing the new compounds in mice, where he expects to be able to regulate epithelial cell-PMN reactions and control inflammation. The research is funded by the National Institutes of Health.


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