Asthma, accompanied by lung inflammation, bronchoconstriction, and airway hyper-responsiveness, is a significant public health burden.  Currently, asthma treatments such as anticholinergics target the hypersensitive nerves connecting the brain to parasympathetic neurons in the smooth muscle of the airway.  Therefore, insights into the neural mechanisms underlying the pathogenesis of asthma are highly desirable.  Now, a study from researchers at Johns Hopkins identifies skin itch receptors in the airways that appear to contribute to bronchoconstriction and airway hypersensitivity, known as hallmarks of asthma. The team states the biochemical receptor, known as a G protein-coupled receptor, was discovered on nerve cells in the lower respiratory tracts of lab mice.  The study is published in the journal Nature Neuroscience.

Earlier studies from the group involved patients who reported itchiness in their lungs just prior to full-blown asthma symptoms such as wheezing, inspiring the researchers to study the sensation in the airway under asthmatic conditions. Though the team had been studying the G protein-coupled receptor on the skin for many years, they had not yet looked for it in other parts of the body.  The current study uses fluorescent antibodies designed specifically to light up the receptor in mice, to identify G protein-coupled receptors on vagus nerves, known to serve as a main biochemical connection between airway cells and the brain.

The current study explores the effects of the receptor on the airway using a protein called BAM8-22, an itch activator specifically targeting the G protein-coupled receptor. Results show mice breathed more rapidly and with more effort after exposure to the receptor activator than mice who weren’t exposed who also have G protein-coupled receptors, indicating the receptors are activated before an asthma-like attack.  To investigate what role vagus neurons have in this system the team repeated the experiments, while also irritating the airway smooth muscles using acetylcholine, a neurotransmitter responsible for activating muscles throughout the nervous system. Data findings show stimulation of the G protein-coupled receptors increases airway constriction more than activating the airway smooth muscles alone.

The group then infected specially bred mice carrying G protein-coupled receptors and those without the receptor with an influenza virus, known to trigger asthma attacks in humans. Results show when the researchers administered acetylcholine to the mice through the nebulizer, they observed mice with the G protein-coupled receptors reacted more vigorously than those with only smooth muscle reactions.  The lab states these receptor mice also exhibited increased airway restriction compared to their counterparts without the receptor.

The team surmises data shows G protein-coupled receptors are expressed in a subset of vagal sensory neurons innervating the airway and mediating bronchoconstriction and airway hyper-responsiveness.  For the future, the researchers state their experiments suggest that the receptors’ activation directly aggravates airway constriction and may be a promising new target for the development of drug therapies.

Source: Johns Hopkins

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