Surgical Innovations

Sidelining Disease by Moderating Inflammation

Columbia researchers work to understand a fundamental cause of inflammation—and how to turn its associated disease process around.

Chronic inflammation is a major causative factor in a wide range of diseases, including atherosclerosis (hardening of the arteries), vascular complications of diabetes, macular degeneration, Alzheimer's disease, and autoimmune diseases such as multiple sclerosis and type 1 diabetes. Even the development of tumors is facilitated by chronic inflammation.

During inflammation, a complex series of events occurs in the body's cells. If one could look into the cells, one would see that certain components become highly activated when the process of inflammation is underway.

One such component, RAGE (receptor for advanced glycation end-products), has been the subject of long and thorough study because of its important contributions to many of the inflammatory conditions considered above. Since 1990, Ann Marie Schmidt, MD, Director, Division of Surgical Science, has made significant strides in identifying the molecule's functions in the body.

"RAGE does not appear to be critically involved in acute inflammation, such as that required to combat common bacterial infections or to heal skin wounds," says Dr. Schmidt. "Rather, RAGE is pivotal in the chronic inflammation that underpins autoimmune diseases, diabetic tissues, Alzheimer's, and other long-term conditions." Diabetes and atherosclerosis are prototypic examples of what happens when RAGE activity is increased. RAGE activity in such inflamed tissues contributes to fundamental mechanisms that lead to tissue damage.

Dr. Schmidt is currently overseeing multiple studies to investigate what happens when RAGE is antagonized (blocked) or genetically eliminated, the latter in mouse models. Her laboratory has determined that in subjects with ischemic heart disease (blocked coronary arteries), stroke, deep vein thromboses (DVTs), or hypoxia, blocking RAGE strikingly reduces the activation of a factor called early growth response-1, or EGR-1. In subjects with atherosclerosis or vascular disease, blocking RAGE dramatically inhibits the activation of another factor called NF-κB. The reduced activity of these factors acts like a switch that shuts down the inflammatory process, which dramatically reduces or eliminates those cardiovascular diseases and their consequences.

Grants from the National Institutes of Health, the National Heart Lung and Blood Institute, and the Juvenile Diabetes Research Foundation are now advancing these discoveries closer towards clinical use. In studies led by the pharmaceutical groups testing RAGE antagonists in humans, one multi-center study is testing the safety and effectiveness of blocking RAGE in people with Alzheimer's disease. Normal volunteers and patients with Alzheimer's are receiving a therapy that tricks the RAGE receptor into inactivity. "The long-term goal is to preserve or improve cognitive function in those with the disease, "Dr. Schmidt explains. "If proven safe and effective, a RAGE-based therapy would have enormous potential to help millions of people with Alzheimer's disease." In another trial, the researchers are studying the impact of RAGE inhibition on the progression of diabetes-associated kidney disease. The goal in these early studies is to determine if blocking RAGE stops or reverses the abnormal leakage of proteins into the urine that typifies diabetic complications in the kidney.

While mediating the RAGE molecule has the potential to open new treatment avenues for many complex diseases, Dr. Schmidt cautions that it is still necessary to clarify how much RAGE can be blocked without causing detrimental effects. "Much research remains to be done before RAGE-based approaches will be translated into new therapies," she says. But Dr. Schmidt is extremely optimistic about its future, and believes "this work holds tremendous promise for alleviating major causes of human disease."