U. carbon monoxide study may lead to better treatments

Scientists at the University's Medical Center have uncovered the biochemical mechanism that links long-term carbon monoxide exposure to cell damage and death, potentially leading to improved treatment. Carbon monoxide poisoning is the leading cause of poison-related deaths in the United States, resulting in thousands of fatalities each year. "You can be more directed with your development [of treatment] now that you have this mechanism," said Emergency Medicine Professor Stephen Thom, the senior author of an article on the research appearing in the September issue of Chemical Research in Toxicology. In the past, carbon monoxide was thought to damage the body by masquerading as oxygen and binding to hemoglobin within the bloodstream, depriving the body of oxygen and leading to death by asphyxiation. The new findings suggest that the causes of cell damage are actually more subtle and complex. Carbon monoxide, according to the research, binds to the same proteins which remove nitric oxide, a molecule important in cell communication within the arteries. A nitric oxide build up within an arterial cell can trigger reactions leading to the breakdown of DNA, the destruction of the cell's membrane and, eventually, cell death. "There appeared to be a wide array of biochemical insults," Thom explained. "It doesn't take a rocket scientist to say that's what's going on." Thom and the report's co-author, Biochemistry Professor Harry Ischiropoulos, used two different techniques to discover how the nitric oxide triggers the harmful reactions. First, the researchers established that carbon monoxide damages blood vessels in laboratory rats. Next, the two began studying the effect of carbon monoxide doses on the individual cells that make up the inside of a blood vessel. "We have a fairly clear picture of what carbon monoxide will do in these smaller concentrations," Thom said. "In a 24-hour span, most of the cells [in culture] will be dead after carbon monoxide exposure," he said. Thom stressed that cells in a petri dish and those same cells in a living animal react significantly different to carbon monoxide. "Clearly, man would've killed himself off at the dawn of the Industrial Revolution if the damage done [to the animal] matched the level of damage to cells in culture," he said. Carbon monoxide damages the blood vessels by killing or weakening cells, creating a thin layer of plaque within the arteries which can lead to arteriosclerosis, or hardening of the arteries. But for such damage to occur, Thom notes that carbon monoxide exposure must occur "on a repetitive basis, several hours a day, for a lifetime." Toll collectors, auto mechanics and smokers are among those at a higher risk for developing vascular disease. Thom said the findings may improve the effectiveness of future treatments by identifying a previously unknown way carbon monoxide can cause cell damage. New research foci could include searching for a drug to prevent nitric oxide build-up in cells and, more practically, minimizing regular low-level exposure to carbon monoxide. Ischiropoulos noted that the research may have already changed the Surgeon General's warning that appears on cigarette cartons. The labels now read, "Cigarette Smoke Contains Carbon Monoxide."