May 17, 2002

Gene vital in ending radiation lung scars

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Olivier Boutaud, Ph.D., displays a model of acetaminophen. (photo by Dana Johnson)

Gene vital in ending radiation lung scars

Eliminating a gene that regulates inflammation can significantly reduce long-term scarring caused by radiation therapy to the chest, Vanderbilt-Ingram Cancer Center investigators report.

The findings, published in the May 15 issue of the Journal of the National Cancer Institute, suggest that someday patients could avoid lifelong complications of radiation therapy using drugs to block the action of this gene. Such drugs are being developed.

“Many of these patients go home on oxygen or at least unable to golf or garden or do whatever they did before,” said Dr. Dennis E. Hallahan, professor and chairman of Radiation Oncology and professor of Biomedical Engineering. “If we can eliminate or reduce the side effects and complications of treatment, we make cancer therapy better and improve patients’ quality of life.”

Radiation therapy delivered to the chest is often a component of treatment for patients with breast, lung, esophageal and other cancers. Virtually all these patients develop some level of lung inflammation, known as pneumonitis, which typically gets better in a matter of weeks, Hallahan said. “The radiation causes injury to the lungs and the inflammatory cells of the immune system respond as they would to a wound,” he said.

However, some patients also go on to develop pulmonary fibrosis, a scarring of the lung tissue that can cause breathing problems and interfere with exercise and other physical activities.

Hallahan and his colleagues had previously demonstrated that pneumonitis could be prevented in animals by using a drug to block the action of a gene that regulates this inflammatory response. In the current study, the investigators confirmed those findings in “gene knock-out mice” engineered to lack the gene, known as intracellular adhesion molecule (ICAM1).”If you eliminate ICAM1, you eliminate the inflammatory response,” Hallahan said.

So the next question to be addressed was whether the initial inflammation was the cause of the subsequent fibrosis and whether preventing the inflammation would in turn prevent the scarring. “In the mice that did not have ICAM1, we saw an improvement in pulmonary function tests and a significant reduction in fibrosis,” Hallahan said.

Hallahan noted that most of the wildtype mice, with two functional copies of ICAM1, developed respiratory problems compared to a small percentage of the ICAM1-deficient mice. “From this we concluded that inflammation does in fact contribute to fibrosis,” he said. “However, there are other processes that also contribute because some lung scarring still occurs. That’s another area we need to examine, to identify other mechanisms contributing to fibrosis.”

This study may have implications for other areas of the body where radiation therapy also may induce inflammation and scarring, such as the colon or the skin.

In an accompanying editorial, Lisa Kachnic of Boston Medical Center and Simon Powell of Massachusetts General Hospital note that during the past decade, combinations of chemotherapy and radiation have improved survival of lung cancer patients previously treated with radiation therapy alone. Because these combined or sequential therapies can increase the risk of short-term or long-term respiratory problems, blocking ICAM1 activity may be more important for these patients, they suggest.

They also suggest that this research be followed up by additional experiments with knockout mice to identify other mechanisms involved in the development of pulmonary fibrosis in these patients.

Hallahan’s co-authors in the study, supported by the National Cancer Institute, were Dr. Ling Geng, research assistant professor of Radiation Oncology; and Yu Shyr, Ph.D., associate professor of Preventive Medicine.