Discovery could lead to new asthma treatments

An unexpected discovery of taste receptors in lungs may provide asthma sufferers with more effective ways to restore free breathing during an attack, researchers at the University of Maryland School of Medicine say.

Experiments with mice and human tissues revealed that the receptors, identical to those found on the tongue, respond to bitter substances by signaling constricted muscles in the lungs to relax — reopening tight airways in seconds.

The findings, reported Sunday in the online journal Nature Medicine, could lead to development of the first new class of asthma inhalers in 50 years, said Dr. Stephen B. Liggett, lead author of the study.

A professor of medicine and physiology at the university, Liggett is also director of its Cardiopulmonary Genomics Program. He's been doing research for 30 years, and said he's never found anything this unexpected with as much potential for helping patients.

"I want this to go all the way from basic discovery to patients," he said.

Dr. Norman H. Edelman, a pulmonologist and chief medical officer at the American Lung Association, said the discovery is not a cure. It does not address the lung inflammation asthmatics suffer, or the underlying cause of the disease. But it does offer "a totally new way of opening the airways, and that's exciting."

"It's been a long time since we've discovered an essentially new approach to the treatment of asthma," he said. "This could be a very important finding, and it's a lot of people who would be affected."

For an asthmatic enduring an attack, the simple act of drawing a breath can become a prolonged struggle that Liggett compares to "breathing through a straw." Involuntary muscles in the lungs tighten, constricting the tubes, called "bronchioles," that carry oxygen to the bloodstream.

"It's a frightening experience, as you can see in the eyes of the patient when they really can't grab a breath," said Liggett, himself an asthma patient. In the most severe attacks, patients can become exhausted by the effort, and begin to lose oxygenation. If airways can't be reopened, the patient can die.

At present, the long- and short-acting inhalers relied on by the 23 million asthmatics in the U.S. — 7 million of them children — belong to the same family, called "beta agonists." They all work the same way, by acting on a specific receptor in the lung muscles called the "beta 2 adrenergic receptor."

"I know there's a need for additional therapeutic options," Liggett said. "I take five different classes of medicines for my asthma and I remain only in partial control. … I can tell you there are large portions of the population that can benefit from more effective therapy."

Mike Tringale, spokesman for the Asthma and Allergy Foundation of America, said that while today's asthma control medications are old, "the asthma community is using them, they're living more active lives and death rates are going down. So we know they must be working for the vast majority of them."

Still, he added, "asthma management is pretty much stalled. … There's a lot of room for improvement."

And that's why Liggett's team — which eventually included researchers from the Johns Hopkins Bloomberg School of Public Health — began looking for new receptors in the lungs that might provide better avenues for dilating constricted airways.

They searched by grinding up lung muscle tissue, extracting its RNA molecules, then looking for the genetic signatures of all the muscle's chemical receptors. In the data, they quickly spotted the beta 2 receptors they already knew triggered lung constriction. And among the others they noted one oddity: a bitter taste receptor known from the tongue.

It's not a taste "bud," exactly. Taste buds are clusters of receptors on the tongue that have links to the brain. The "taste" receptors on the lung muscles, while structurally identical, communicate only with the muscle cells.

They didn't seem to be what Liggett's team was looking for. Scientists presume that the tongue's receptors for bitter tastes evolved to alert our ancestors to harmful plant toxins. "Chew on a plant toxin and it would be bitter, and you would spit it out," he said.

"We figured this was another avoidance mechanism," Liggett said. Perhaps it caused constriction in the lungs to protect from inhaling noxious substances.

"There were probably about 10 classes of receptors that we thought were sort of interesting, and this one was at the bottom of the list," Liggett said. "So the data was sitting in the laboratory for probably a year before we began to act on it."

Finally, a postdoctoral fellow on the team, Elizabeth McIlmoyle, suggested trying to stimulate the bitter taste receptor with saccharin. Although it's a sweetener, it has a bitter aftertaste.

The saccharin triggered a large release of calcium in the cells. But that's a chemical response long recognized as a signal for muscles to tighten. The team still thought they were looking at a receptor that initiated lung constriction.

But when they tried bitter aerosols on actual constricted airways in mice, or on sections of human airways freshly removed from cancer patients, they were surprised to discover the lung muscles actually did the opposite. They relaxed, a lot.

In seconds, the airways expanded to 90 percent of their original volume — three times more than they did with the beta 2 agonist inhalant.

Edelman, at the lung association, said the discovery "points out the critical role of serendipity in science. Who would have thought that lungs have bitter taste receptors that work this way? These people deserve kudos for their work."

What's still unclear is why mice and humans — and perhaps many other species — would have evolved receptors in their lungs that open airways in response to bitter inhaled substances.

Liggett and his team speculate in the paper that it may have arisen as a mechanism for surviving bouts of pneumonia or bronchitis.

"The bacteria that cause pneumonia secrete a substance which activates these receptors," he said. The secretion is bitter, and would help to keep the airways open, allowing the person to cough up bacteria-laden fluids in the lungs, hastening recovery.

Years of research, development and clinical trials with living human subjects lie ahead, Liggett said. At least there's no shortage of compounds to try.

"We have 10,000 bitter [substances] known to exist, and probably many, many others in plants that we don't know about," he said. "The best medicine may turn out to be a synthetic analog of one of these … plant toxins that could be modified to be more palatable, or more potent."

Once the best formulation is found, Liggett said, "It could clearly become one of the primary treatments for asthma. And it certainly could be an add-on therapy for those who are not doing well with traditional treatments."

"It should be effective for all the different triggers for asthma," he said, including allergens, air pollution and viral infections. Other diseases, such as emphysema and chronic obstructive pulmonary disease, may be less responsive where patients' lungs are more damaged.

But the need for better bronchodilators is growing and immediate.

"In the Baltimore area there's an epidemic of asthma, and we are seeing links between obesity and asthma, both at the genetic level and in our clinics," Liggett said. "So being able to get a full breath, and to actively participate in exercise is, I think, critical to improving overall health care."

frank.roylance@baltsun.com

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