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7.12.10

When belched out of cars and factories at high levels, the noxious gasses nitric oxide, carbon monoxide and hydrogen sulfide are deadly poisons. But scientists are finding that, in miniscule doses, those same gases can serve as medicines.


"There's been an explosion of work in the last decade looking at these molecules in terms of therapeutics," says Dr. Mark Gladwin, a lung specialist and researcher at the University of Pittsburgh Medical Center.

These unwholesome components of smog, automobile emissions and industrial exhaust also happen to be essential chemicals in the body, where they exist in minute amounts. Called "gaseotransmitters," they lower blood pressure, block inflammation and regulate oxygen use.

That makes researchers optimistic that these gasses can be put to widespread medical use. Drugs that use nitric oxide are already common. Carbon monoxide is poised to help transplanted organs settle into their new homes. And hydrogen sulfide produces a Sleeping Beauty-like state of suspended animation in animals that might be useful in keeping trauma patients alive until they reach a hospital.

The difference between deadly fumes and life-saving medicine comes down to dosing, says David Lefer, a cardiovascular physiologist at the Emory University School of Medicine in Atlanta. "The levels in the body are thousands-fold lower than the industrial toxic levels."

All three gasses function as chemical messengers, similar to hormones. After they enter a cell, they seek out and turn on proteins. These proteins, in turn, activate or deactivate others, allowing a message to move from protein to protein like a line of falling dominoes. The final result is a change in the amount of energy a cell produces or the genes it activates. Gaseotransmitters also open doorways in the cell's membrane, allowing energy-carrying molecules to pass through and alter the cell's metabolism.

Nitric oxide, carbon monoxide and hydrogen sulfide share many functions. Lefer thinks nitric oxide may be the primary gaseotransmitter, with the other two serving as backup.

Nitric oxide (not to be confused with the laugh-inducing nitrous oxide at your dentist's office) is the best understood of these gases, and is already the basis for several medicines. Its main effect is to turn on chemical pathways that widen blood vessels, thus lowering blood pressure. Since 1999, doctors have used the gas to treat newborns who have high blood pressure in the lungs.

Other medicines are not made of nitric oxide but rely on it to work. Nitroglycerin, once inside the body, is metabolized into nitric oxide, which opens blood vessels and soothes angina. The most famous nitric oxide moderator is Viagra, which amplifies the effects of the body's own nitric oxide to increase blood flow and tumescence at the desired location.

Scientists are now studying possible nitric oxide therapies for sickle cell anemia, heart failure, wound healing and a host of other possibilities.

Carbon monoxide has many functions; among them, it appears to dampen inflammation. The gas binds to proteins that contain metals — such as hemoglobin — and changes their shape, leading to a cascade of changes that suppresses the body's inflammatory response.

Organ transplants are one area of great interest, since the immune system's natural instinct is to attack a new kidney, heart or liver, causing inflammation. Carbon monoxide appears to stifle that inflammation, says Leo Otterbein, a physiologist at Harvard Medical School in Boston. Researchers also are scrutinizing the gas' activity in conditions as varied as malaria, arthritis and cancer.

In a paper last month in the American Journal of Transplantation, Otterbein and colleagues reported on pigs that received kidney transplants with or without carbon monoxide treatment. Pigs that breathed plain air turned on more inflammation-related genes than animals that inhaled carbon monoxide.

Their new kidneys started working sooner too. When the scientists measured blood markers for kidney function, the gas-treated animals were back to normal within six days of their surgeries, when animals in the plain air group still had subnormal kidney function.

In an unpublished safety study, researchers recruited healthy people to inhale carbon monoxide at a dose of 3 milligrams per kilogram of body weight per hour — far below the levels found in the environment. There were no severe side effects, and a clinical trial of carbon monoxide for kidney transplant patients is now underway at several hospitals around the country, Otterbein says.

The newest gaseotransmitter is stinky hydrogen sulfide, which slows the cell's energy-producing machinery, thus lowering metabolism. With metabolism running at hibernation-like levels, an animal can survive with very little oxygen.

This suspended animation works in worms and mice, but no one has succeeded in larger animals such as pigs, Lefer says, so he's doubtful it would work in people. But he believes it is possible to slow down individual organs, and he envisions a targeted hydrogen sulfide therapy to help people recover from heart attacks.

The idea is to dial down the heart's energy needs so the organ requires less blood to survive. Lefer and colleagues found that injections of sodium sulfide — which the body converts to hydrogen sulfide — protected cardiac muscle in mice who had heart attacks. The next day, the area of damage in treated mice was only one-quarter the size found in untreated mice. And when the researchers performed echocardiograms, they found that the hearts of sulfide-treated animals functioned better, according to a 2007 report in Proceedings of the National Academy of Sciences.

"That was really able to salvage the heart cells from death and improve the pump function of the heart," Lefer says. "The animals survived."

In another experiment, published this summer in the journal Circulation, he and colleagues found that daily sodium sulfide injections improved heart function in mice with heart failure.

Given the toxicity of gaseotransmitters, scientists are taking great care as they investigate new treatments. Companies such as Ikaria Inc. in Clinton, N.J., are working on equipment that will stringently regulate a person's intake of a gaseous medicine. Other drugs will likely be available as gas-releasing pills or injections, which would be more convenient for patients.

Because the potent gases travel and act throughout the body, side effects are also a concern. However, Gladwin adds, some of those side effects might turn out to be beneficial. A case in point: Viagra was discovered as an unexpected side effect of a drug designed to treat high blood pressure.


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