April 17, 1998

Investigator tracks clues to inflammatory bowel disease

Investigator tracks clues to inflammatory bowel disease

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Dr. Brent Pol is studying how inflammatory bowel disease progresses. (Photo by Donna Jones Bailey).

Research at Vanderbilt Children's Hospital into inflammatory bowel disease is building the basic science foundation for future advances in treatment of this potentially debilitating condition.

Dr. D. Brent Polk, associate professor of Pediatrics, and his colleagues are studying two different factors involved in the development and progression of inflammatory bowel disease.

In one line of research, Polk is studying how epidermal growth factor (EGF) promotes the closure of ulcers in the intestinal lining. In the other, he is investigating how the pro-inflammatory agent tumor necrosis factor alpha (TNF-alpha) prevents healing.

"The internal lining of the intestine is made up of a single layer of cells," Polk said.

"Once you lose part of those cells, other cells have to migrate to cover that wound or ulceration. Otherwise, the cells below are exposed to bacteria and other environmental antigens in the gastrointestinal tract, which causes an inflammatory reaction. In inflammatory bowel disease, that reaction becomes an exaggerated response that the immune system can't seem to shut off.

"It's too much of a good thing."

The term chronic inflammatory bowel disease refers primarily to two illnesses: ulcerative colitis and Crohn's disease.

Ulcerative colitis typically involves only the colon, and in the most severe cases can result in removal of the colon, Polk said. Crohn's disease is trickier because it can occur at any point along the gastrointestinal tract and because it tends to recur after surgery.

Both diseases typically begin after the age of 10 and continue to worsen over time, he said. Rarely, children present as early as 2 years of age.

"It's relatively common," Polk said. "At Vanderbilt Children's Hospital, we follow about 200 children with inflammatory bowel disease, and most of the children we see are in the 10-21 age range.

"There are also other chronic inflammatory bowel diseases, which we don't fully understand, that seem to be present at birth and which probably represent some disregulation of the immune system."

Three components appear to be required to begin the vicious cycle of inflammatory bowel disease, Polk said. These are a source of ulceration, a chronic stimulation of inflammation, and a disturbance of the immune system so that the response is exaggerated and continuous.

Polk's research is aimed at the basic biochemical mechanisms that carry out this cycle, with the goal of identifying potential targets for treatment.

Last year, for example, he and his colleagues were the first to describe the presence of TNF-alpha receptors in the cells that line the intestine. They also reported in the journal Gastroenterology that cell proliferation prompted by growth factors continues when there are low doses of TNF-alpha present. However, at the high levels of TNF-alpha which are present in inflammatory bowel disease, cell proliferation shuts down.

In May, the group will report at the national meeting of the American Gastroenterological Association that a drug called 5-ASA, which has long been used to treat ulcerative colitis and Crohn's disease, prevents TNF-alpha's activation of a protein called nuclear factor kappa B (NF-kappa B). NF-kappa B is a transcription factor that, when activated, moves from the cytoplasm of the cell into the nucleus to stimulate the production of pro-inflammatory agents called cytokines.

"The importance is that if we can figure out at which point the drug is causing the blockage of NF-kappa B activation, we may be able to describe the mechanism and more specific drugs can be designed," Polk said. "One of the drawbacks of 5-ASA is that it has to be used in high concentrations to be effective, and about 15 percent of patients cannot tolerate it because of side effects."

Polk's work is also aimed at better understanding how EGF promotes the migration of cells to close a wound in the intestinal lining.

"If we can figure out precisely where TNF-alpha is causing its effects, and where EGF is causing its effects, we hope that medication can be designed that not only prevents the negative effects of TNF-alpha but promotes the beneficial effects of the EGF receptor."

Polk's EGF research is funded by the National Institutes of Health, while his work with TNF-alpha is funded by the Crohn's and Colitis Foundation of America. Polk's is the first grant awarded to a Vanderbilt researcher by the foundation, and one of only two in the country awarded to a researcher based in a department of Pediatrics.