New Evidence For Growth Factor Role In Crohn's Disease

August 25, 1998

A protein molecule that helps regulate body growth may play an important role in the development and progression of Crohn's disease (CD), a chronic, incurable, and frequently disabling inflammatory bowel disorder, new research shows.

Scientists led by Dr. P. Kay Lund, professor of physiology at the University of North Carolina School of Medicine have used radioactive gene probes to find significantly increased production of insulin-like growth factor (IGF-I) in inflamed and thickened intestinal tissue samples of CD patients but not in otherwise healthy bowel tissue from the same individuals. The tissue came from patients during bowel resection surgery.

"Somehow the gene for IGF-I was switched on in these cells and is not switched on in normal or non-diseased cells," Lund says. She also notes finding no evidence of increased IGF-I activity in bowel tissue from surgery patients with ulcerative colitis, the second major inflammatory bowel disorder, one that involves only the colon.

Lund says the bowel in some CD patients "tries to overgrow, something goes wrong and the structural support elements of the tissue grow excessively, and so you get a bowel that's thickened and obstructed because the wrong cells grow. This abberrant growth is termed fibrosis and is associated with deposition of lots of collagen -- a molecule associated with scarring." During this thickening, whole sections of intestinal smooth muscle cells can become encased in a dense overgrowth of fibrous collagen.

According to the UNC scientist, the new findings raise the possibility that treatment aimed at blocking IGF-I in the bowel could prevent fibrosis complications, such as intestinal stricture (narrowing) and obstruction. Such complications frequently require removal of major portions of bowel. Since CD often eventually reappears elsewhere in the bowel, surgeries for recurrent complications can result in "short bowel syndrome" -- not enough small intestine for nutrient absorption -- which leaves many patients relying for life on intravenous feeding.

In addition, Lund points out that bowel-removal surgery itself may exacerbate fibrosis. "You will often get stricture or obstruction of the bowel close to the point where you once had surgery," she says.

Dr. Ellen Zimmermann of the University of Michigan , while a post-doctoral fellow in Lund's lab in 1993, discovered that IGF-I was massively expressed in the areas of fibrosis. Lund says more recent in vitro laboratory experiments in her UNC physiology lab support the concept that IGF-I "could be a culprit in fibrosis formation, causing bowel cells to make more collagen and to grow inappropriately."

Still, as Lund points out, such findings don't tell us definitively if IGF-I acts the same way on bowel cells in vivo -- in live animals. That's why she and her colleagues are studying strains of transgenic mice -- animals genetically engineered to overproduce IGF-I in cells that are involved in the fibrosis of CD. "Then if we experimentally give them bowel inflammation, do we get this excessive fibrogenic response?" she asks.

The UNC researcher speculates that if IGF-I proves a major culprit in CD progression, inhibitors of its action such as IGF binding proteins (IGFBPs) may be used therapeutically to help prevent fibrosis and its complications.

An estimated six new Crohn's disease cases per 100,000 population occur in most developed countries, including the U.S., each year. Peak ages are in adolescence and early adulthood and after age 60. Symptoms of CD include abdominal pain, fever, diarrhea, and weight loss. Its cause is unknown. However, some researchers suggest the disease arises from an excessive immune response to bacteria in the bowel.

Drs. Lund and Zimmermann presented the human bowel tissue findings to a national conference of the American Gastroenterological Association at the end of May. An abstract of the study is available upon request.

University of North Carolina Health Care

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