Breathe easy. Drugs targeting the neurons leading to the lungs and airways could ease asthma symptoms or prevent attacks.

David Marchal/Science Source

Breathe easy. Drugs targeting the neurons leading to the lungs and airways could ease asthma symptoms or prevent attacks.

Nervous system may hold key to treating asthma attacks

The wheezing, coughing, and gasping for breath that come with a sudden asthma attack aren’t just the fault of an overactive immune system. A particularly sensitive bundle of neurons stretching from the brain to the lungs might be to blame as well, researchers have found. Drugs that alter these neurons could provide a new way to treat some types of asthma.

“This is an exciting confirmation of an idea that’s been around for decades,” says Allison Fryer, a pulmonary pharmacology researcher at Oregon Health & Science University in Portland, who was not involved in the new study.

An asthma attack can be brought on by a variety of triggers, including exercise, cold temperatures, pollen, and dust. During an attack, a person’s airways become inflamed, mucus clogs their lungs, and the muscles surrounding their airways tighten. Asthma is often considered a disease of the immune system because immune cells go into overdrive when they sense a trigger and cause inflammation. But a bundle of nerves that snakes through the neck and chest, the vagus nerve, has long been suspected to play a role; the cells it contains, after all, control the airway muscles. Studying which cell types and molecular pathways within the thick nerve bundle are involved, though, has been tough—the vagus contains a multitude of different cells that are physically intertwined.

Working together at the Howard Hughes Medical Institute’s Janelia Farm Research Campus in Ashburn, Virginia, neurobiologists Dimitri Tränkner, now at the University of Utah in Salt Lake City, and Charles Zuker of Columbia University turned to genetics to work out the players. They selectively shut off different sets of the neurons in mice based on which genes each neuron expressed, rather than their physical location. Then, through a series of injections, they gave the animals an egg white allergy that causes asthmalike symptoms.

After exposure to egg white protein, most mice suffered an immune reaction and a narrowing of their airways. But in rodents in which the researchers had genetically inactivated nerve cells expressing a receptor called transient receptor potential vanilloid 1 (TRPV1), egg white proteins failed to make the airways constrict, even when the immune system ramped up. And when the researchers next boosted the activity of the TRPV1-containing cells, symptoms of an asthma attack worsened in mice already prone to the attacks, they report online today in the Proceedings of the National Academy of Sciences.

“These cells really tie everything together,” Tränkner says. The last piece of the puzzle, though, came when the group showed that the TRPV1-expressing nerve cells could be activated by a substance that’s known to be released by immune cells in the lungs of asthmatics, a molecule called sphingosine-1-phosphate. The observation suggests communication between the immune system and the neurons.

“If it were as simple as some people having different TRPV1 cells, researchers likely would have already found genetic mutations that cause asthma,” Tränkner says. “Our guess is that instead, the immune system can permanently change these neurons during some initial immune response.” As an allergy develops, he says, not only does the immune system become primed for an asthma attack, but immune molecules also likely interact with the neurons, altering their behavior and the receptors they express, and making them more likely to cause airway constriction.

“The technological approach used in this paper is really unprecedented in the field,” says neuroscientist Sven-Eric Jordt of Duke University School of Medicine in Durham, North Carolina. But more studies will be needed, he says, to show whether the same pathways are important in human asthma. The mouse egg white allergy isn’t a perfect model of the human disease, because mice don’t actually develop asthma, but instead show airway symptoms of an allergy.

If the findings hold true, Fryer says, they could lead to new classes of asthma drugs that not only treat symptoms, but also reverse the hypersensitivity that leads to attacks. Such drugs could target either the TRPV1 protein or the sphingosine-1-phosphate receptor, and they might work in patients who don’t respond to existing treatments, she says. “People have actually proposed both of those as drug targets before, but this really reinforces the rationale behind that idea.”

Posted in Biology, Brain & Behavior, Health