Growth Factor Supresses Intestinal Lesions
SAN FRANCISCO--Individuals with inflammatory bowel disease "have forgotten what it's like to feel well," Marshall Z. Schwartz, MD, FACS, said. Patients with the disease, which includes chronic ulceratic cholitis and Crohn's disease, have bouts of crampy abdominal pain, fre-quent diarrhea, and mucus and blood in their stools. These patients often experience weight loss and have little or no appetite. Because of the inflammatory nature of the disease, the patients also have joint problems, such as arthritis, and skin rashes. "If you've had occasion to know some-one with either of these disease processes, you know that they are coping with multiple physical and emotional problems," according to Dr. Schwartz, vice-chair and professor of surgery and pediatrics at Thomas Jefferson University, Philadelphia, PA and the Alfred I. Dupont Hospital for Children, Wilmington, DE.
Patients with inflammatory bowel disease gain some temporary relief from symptoms by taking anti-inflammatory drugs, including steroids; however, these medications do not attack the underlying inflammatory condition, which is the result of the body's immune system attacking normal cells in the intestine, skin, and joints. Nor do these drugs prevent progression of disease. Consequently, in some individuals with ulcerative colitis, the colon can become so diseased that it has to be removed surgically. Surgical procedures also may be needed for patients with Crohn's disease when obstruction of the bowel or abnormal connections between loops of intestine (fistulae) develop. Furthermore, most patients with long-term inflammatory bowel disease are at increased risk for colon cancer.
The first experimental studies of hepatocyte growth factor have suppressed inflammatory bowel disease to the point where most of the visible lesions in the bowel were eliminated. Even more definitive proof of the effect of the growth factor was the more than 50 percent reduction in the number of lesions seen microscopically. "I do not think there is any single medication that has had this kind of dramatic response," Dr. Schwartz said. Findings from the study were reported at the 1999 Clinical Congress of the American College of Surgeons.
Hepatocyte growth factor, which is produced in liver cells, as well as other cells including the small intestine, reduced gross lesions in the small and large intestine of animals by 90 percent, and it decreased the number of histologic lesions by 53 percent. The growth factor was studied in an animal model that mimics human inflammatory bowel disease.
The reduction in the number of sites or the percentage of involvement of the small or large intestine in these animals does not necessarily mean that the growth factor has eradicated inflammatory bowel disease. "The disease could develop at other sites, or it could recur after treatment when the growth factor is stopped," Dr. Schwartz said. In addition, it is unclear at
this point whether hepatocyte growth factor would have a similar effect on intestinal lesions in humans. Nevertheless, Dr. Schwartz believes the growth factor "represents the future, at least in part, for the treatment of inflammatory bowel disease."
Dr. Schwartz has been involved in the study of growth factors for nearly 20 years. "My interest was specific to the intestinal tract and how growth factors may be used to improve intes-tinal function," he explained. As an offshoot of this research, Dr. Schwartz began focusing on the potential benefit of growth factors on inflammatory processes in the bowel, an area that
has not been investigated before, until very recently.
The study that is being presented at the Clinical Congress describes "a novel use of growth factors," Dr. Schwartz said, "because the effect of these substances is to improve the function of cells or to cause more cells to grow. In this model of inflammatory bowel disease, the growth factor appears to exert a therapeutic benefit on the inflammatory process by perhaps providing some protective effect against the body's immunological assault on the intestine," he added.
The DNA of the animals used in the study was genetically manipulated to cause gastro-intestinal and dermatologic manifestations similar to those occurring in human inflammatory bowel disease. The animals that were treated with hepatocyte growth factor not only had fewer intestinal lesions than untreated control animals, they also exhibited less expression of a pair of inflammatory mediators--tissue necrosis factor alpha and interferon gamma. "A reduction in the expression of these substances is a corroboration of a significant decline in inflammation, and it may indicate how the growth factor works--by blocking the secretion of these mediators in intestinal cells," Dr. Schwartz said.
More sophisticated studies in animals are needed to further measure the response exerted by hepatocyte growth factor and to determine the growth factor's mechanism of action. It will probably be several years, therefore, before the substance may be used in humans. That is why Dr. Schwartz believes "it is premature to say that hepatocyte growth factor eliminates inflamma-tory bowel disease. The nature of inflammatory bowel disease is that it is cyclical. People go into remission, then they get what is referred to as flares, where they have an acute recurrence with increased pain, cramping, and diarrhea. But if you can suppress the disease to the point where there is minimal evidence of histologic lesions, you will improve the quality of life for these individuals dramatically."
In addition to Dr. Schwartz, Karim Alavi, MD; Rajeev Prasad, MD; Juan P. Palazzo, MD; Frederick Meier, MD; and Roy Proujansky, MD, participated in the study.
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