Breaking the allergic asthma cycle…by targeting nerve endings

asthma therapeuticsExisting asthma medications work by suppressing inflammatory signaling by immune cells or by dilating constricted airways. Over time, though, these drugs’ benefits can wane. New research supports a surprising new tactic for controlling asthma: targeting sensory nerve endings in the lungs with a selective drug.

Our lungs are known to contain specialized sensory neurons known as nociceptors that connect to the brainstem. Best known for causing the perception of pain, nocieptors also trigger the cough reflex in the lungs when they detect potential harms like dust particles, chemical irritants or allergens. Nociceptor nerve endings are known to be more plentiful and more readily activated in people with asthma. Now it’s also clear that they help drive allergic inflammation.

A neuro-immune connection

In a report yesterday in Neuron, researchers led by Clifford Woolf, MD, PhD, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, and Bruce Levy, MD, chief of the Pulmonary and Critical Care Medicine Division at Brigham and Women’s Hospital, make the case for a vicious neuro-immune cycle in asthma—with nociceptors (labeled 3 below) at its center.

“There was prior evidence that neurons and the immune system talk to each other,” says Sébastien Talbot, PhD, of the Woolf lab, first author on the paper. “We wanted to see if such interplay also occurs in asthma.”

It does, the study found. The researchers induced asthma in mice by exposing them to dust mites or another allergen, ovalbumin, and made the following observations:

  • When stimulated, nociceptors release chemicals known as neuropeptides that cause immune cells to infiltrate the lungs and become more active.
  • The immune cells produce IL-5, an inflammatory molecule that in turn activates the nociceptors to produce another neuropeptide, vasoactive intestinal peptide (VIP).
  • VIP that further stimulates the inflammatory response, creating a neuro-immune feedback loop that inflames the lungs and escalates asthma symptoms.

The researchers then gave the asthmatic mice a drug called QX-314, administered via nebulizer. QX-314 selectively silences nociceptors activated by inflammation, an approach developed by the Woolf lab with Bruce Bean, PhD, a professor of neurobiology at Harvard Medical School, while doing research on pain-specific anesthetics. Given to the mice, QX-314 reduced airway inflammation and bronchial twitchiness.

Chemically related to the local anesthetic lidocaine, QX-314 cannot normally get into nerve cells, but it can enter nociceptors via ion channels that are specific to nociceptors and are activated by inflammation, Bean explains. “This limits the action of QX-314 to just the neurons activated by inflammation,” he says.

“An attractive aspect of targeting nociceptors is that this approach would be most effective when inflammation is already present and should accelerate its resolution,” adds Woolf.

Unlike lidocaine, which works nonspecifically on all neurons, QX-314 is expected to have fewer side effects. It also stays inside cells for prolonged periods without getting into the bloodstream, which the researchers believe will increase its duration of action in the lung.

With the help of the Harvard and Boston Children’s technology development offices, the Woolf and Bean labs are working on new, more potent versions of QX-314 that would enhance both its safety and its beneficial properties, with the aim of testing them clinically.

“Current asthma treatments can help to control symptoms and dampen airway inflammation; however, therapies are not available to promote the resolution of asthma,” Levy. “A treatment to interrupt the vicious cycle of neuro-immune signaling holds promise as a disease-modifying therapy and is mechanistically distinct from any of the currently available asthma therapies.”