Jan. 20, 2003 PITTSBURGH, Jan. 19 – Exposing rats to low levels of carbon monoxide (CO) prior to aorta transplantation prevents arteriosclerosis associated with chronic organ rejection and can also suppress stenosis after balloon-angioplasty-induced carotid artery injury, according to a study published in the Feb. 1 edition of Nature Medicine. The article is published online today.
"These findings demonstrate a significant protective role for CO in vascular injury and support its use as a therapeutic agent," according to study author Leo Otterbein, Ph.D., research assistant professor, University of Pittsburgh School of Medicine, division of pulmonary and critical care medicine.
The rats that received the aorta grafts were exposed to 250 parts per million (PPM) of CO immediately following transplantation and for the subsequent 56 days of the study. Those rats in the balloon injury portion of the study were exposed to the same PPM of CO for one hour prior to injury and then returned to room air for the subsequent 2 weeks.
As controls, researchers transplanted aortic segments from ten Norway rats to Lewis rats, none of which were exposed to CO. Arteriosclerotic lesions began to appear after 20-30 days and were significant by 50-60 days. Lesions were characterized by intimal hyperplasia (vessel wall thickening), an increase in smooth muscle cells and leukocyte accumulation in the transplanted aorta. These processes are indications of arteriosclerosis and limit the success of transplants and angioplasties in humans. In the rats exposed to CO, intimal hyperplasia was significantly reduced by 61 percent.
In the second group of rats, their carotid arteries developed intimal hyperplasia 14 days after balloon injury. Intimal hyperplasia in rats exposed to CO for only one hour prior to injury, was reduced by 74 percent over control rats exposed to air.
"Currently the best available treatment of clogged arteries is through angioplasty and a stent or via bypass surgery," said Brian S. Zuckerbraun, M.D., general surgery resident at the University of Pittsburgh School of Medicine and co-author of the study. "But these have their limitations and a significant failure rate. If you could pre-treat patients with CO it might result in a better long term outcome."
"Our research suggests that the protective effect of CO relies on its ability to block leukocyte infiltration/activation as well as small muscle cell proliferation," Dr. Otterbein said. "CO may prove to be beneficial in the treatment of a broad range of vascular diseases. The fact that a one-hour pre-exposure of a rat to low levels of CO markedly diminished the intimal proliferation that usually follows balloon injury, used here as a model of angioplasty, supports the use of CO clinically."
In the study, there were no observed negative effects of the CO exposure on the animals. According to Dr. Otterbein, studies are currently underway in a pig model.
Others involved in the research project at the University of Pittsburgh include Augustine Choi, M.D., chief of pulmonary, allergy and critical care medicine; Timothy Billiar, M.D., chairman of the department of surgery; Edith Tzeng, M.D., assistant professor of surgery in the division of vascular surgery; Ruiping Song, M.D., Ph.D., post doctoral fellow; and Fang Liu, technician. This study was done in collaboration with a team of researchers at Harvard Medical School.
The study was supported by grants from the National Institutes of Health, an Atorvastin Research Award, sponsored by Pfizer, American Heart Association, and the Ethicon-Society of University Surgeons Resident Research Award.
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