Therapeutic role found for carbon monoxide

Gas is shown to reverse symptoms of pulmonary hypertension

BOSTON In a medical case of Jekyll and Hyde, carbon monoxide the highly toxic gas emitted from auto exhausts and faulty heating systems has proven effective in treating the symptoms of pulmonary arterial hypertension (PAH), an extremely debilitating condition that typically leads to right heart failure and eventual death.

The new findings, made in an animal study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and the University of Pittsburgh, are described in the September 2006 issue of The Journal of Experimental Medicine (JEM).

The paradoxical theory that carbon monoxide (CO), the colorless, odorless gas often dubbed "the silent killer," could be used to prevent the onset of certain inflammatory conditions was first proposed in 1998. Since then, numerous studies have shown that when administered at low, non-toxic concentrations prior to such procedures as organ transplant surgery or balloon angioplasty, CO provides potent protective effects against organ rejection or blockage of the carotid arteries.

But, with these latest findings, explains senior author Leo Otterbein, PhD, it now appears that carbon monoxide can also be used to treat and reverse existing disease.

"Our results offer the exciting possibility that in extremely low concentrations and for brief intermittent exposures of one hour per day, CO gas might be effectively used as a therapy to treat PAH in a clinical setting," says Otterbein, an investigator in the Transplantation Center at BIDMC and Associate Professor of Surgery at Harvard Medical School.

Pulmonary arteries the blood vessels that carry blood from the heart's right ventricle to the small arteries in the lungs -- are made up primarily of endothelial cells and smooth muscle cells. PAH develops when, for unknown reasons, the smooth muscle cells rapidly and uncontrollably proliferate, leading to "remodeling," in which blood vessel walls thicken and gradual stenosis of the arteries occurs. Ultimately, the vessels thicken to the point that blood can no longer be effectively pumped through them, resulting in serious cardiopulmonary complications and in many cases, heart attack. There is no cure for the disease.

Based on CO's successful track record in helping to prevent vascular disease, Otterbein and first author Brian Zuckerbraun, MD, of the University of Pittsburgh, hypothesized that the gas might prove beneficial in treating pulmonary arterial hypertension.

To test this hypothesis, the scientists first exposed a PAH mouse model to a short, daily regimen of CO (in a modest concentration, equivalent to what a cigarette smoker might inhale) of one hour per day. As predicted, their results showed that the gas did indeed reverse PAH in the animals, resulting in the restoration of both normal pressures and heart weights (indicative of reversal of imminent heart failure).

The scientists next identified how this was happening.

"We determined that CO was exerting these effects by both arresting growth of the vessels' smooth muscle cells and inducing apoptosis, or cell death," he adds. Consequently, as the smooth muscle cells died, both the pulmonary blood vessels and right heart were restored to their normal size, what Otterbein describes as a case of "retro-remodeling."

"However, what we found most intriguing was that CO did not induce the death of all of the smooth muscle cells in the blood vessels, but rather selected out for destruction only the population that was problematic," he adds.

It was in the final arm of their study that the authors discovered how CO was able to selectively target the troublesome smooth muscle cells: It was relying on a second gas, nitric oxide (NO), for assistance.

"When we first started these experiments, we had the cells separated into two separate culture dishes endothelial cells in one, smooth muscle cells in the other," explains Otterbein. But, he adds, when they exposed these cultures to carbon monoxide, nothing happened. The cells behaved normally.

"We eventually asked ourselves, 'What if we're not seeing results in these two separate dishes because in the body, the two aren't separated. What if these two cell types somehow act in concert and need to communicate with one another as they otherwise would in vivo in order for CO to exert its beneficial effects?'"

To address this question, coauthor Beek Yoke Chin, PhD, developed a simulated blood vessel by growing the cells on a semi-permeable membrane, which enabled the two cell types to "communicate" with one another through pores. And that, says Otterbein, was when the scientists observed that in this "co-culture" setting, CO was able to induce death of the smooth muscle cells without adversely affecting the viability of the endothelial cells.

"We discovered that endothelial cells must be present and be able to generate NO via nitric oxide synthase [NOS3] -- in order for CO to induce the death of the smooth muscle cells and reverse the symptoms of PAH," explains Otterbein. To further test the role of the nitric oxide, the co-culture was treated with a select inhibitor of NOS3. Under these conditions, he adds, CO was unable to induce death to the same degree as in control-treated co-cultures.

"We concluded that the physical interaction between the two cell types plus the ability to generate NO was crucial for the positive CO effects," he says, adding that studies are now underway to determine the mechanism by which CO exposure leads to the increase in NO generation.

"Our hope is that CO will find a place in the clinic as a therapeutic option for the treatment of disease," concludes Otterbein. "CO has been around since before life began on earth and, in fact, it is thought to have contributed to the origin of life. Perhaps this was a sign of its necessary role in biology."

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In addition to Otterbein, Zuckerbraun and Chin, study coauthors include BIDMC researchers Barbara Wegiel, PhD, and Eva Czsimadia; University of Pittsburgh researchers Timothy Billiar, MD, Jayashree Rao, Shin Kanno, MD, and Emeka Ifedigbo; and Larissa Shimoda, PhD, of Johns Hopkins University School of Medicine in Baltimore.

This study was supported, in part, by grants from the National Institutes of Health and the American Heart Association.

Leo Otterbein is a paid consultant of Linde Gas Therapeutics.

Beth Israel Deaconess Medical Center is a patient care, research and teaching affiliate of Harvard Medical School and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is a clinical partner of the Joslin Diabetes Center and a research partner of the Dana-Farber/Harvard Cancer Center. BIMDC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.


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