ILLUSTRATION: ARTVILLE

In the parasympathetic neuromuscular synapse, the neuron releases acetylcholine (ACh) into the synaptic junction, where stimulatory muscarinic receptors on smooth muscle cells transduce the chemical signal into a contraction response. Simultaneously, ACh feeds back to presynaptic inhibitory receptors on the axon terminus called M2 muscarinic receptors (M2Rs), limiting further ACh release.

Viral infection causes M2R dysfunction, interrupting the negative feedback loop and leading to increased release of ACh. For the vagus nerve, which innervates the trachea, lungs, and heart, M2R dysfunction translates into increased bronchoconstriction and bradycardia (a heart rate that is too slow). Moreover, exacerbations of asthma have been correlated with infection by RNA viruses, particularly rhinoviruses. Interferons, often produced in response to viral double-stranded RNA (dsRNA), can reduce M2R gene transcription in cultured neurons and may provide the missing link between viral infection and bronchoconstriction.

On the basis of these findings, Bill Bowerfind and researchers at Johns Hopkins University (Baltimore) proposed that dsRNA, a replicative intermediate produced by some viruses, potentiates airway hyperreactivity by causing dysfunction of M2R (J. Appl. Physiol., in press).

To test their hypothesis, these scientists gave intraperitoneal injections of synthetic dsRNA to guinea pigs. They found that the treatment increased bronchoconstriction and bradycardia upon electrical stimulation of the vagus nerve. To demonstrate that muscarinic receptors did, in fact, mediate these effects, they treated the animals with pilocarpine, a muscarinic agonist, and found that animals receiving dsRNA were insensitive to the treatment while those that had not received dsRNA showed drug-dependent bronchoconstriction. Furthermore, several other control studies were carried out to home in on the process, all indicating a dsRNA-triggered interferon response that leads to M2R dysfunction.

However, much work remains to elucidate the mechanism of M2R regulation. According to Bowerfind, these results provide “evidence for a common pathway” of noninflammatory asthma responses and point toward a medication which “either turns on M2R expression or affects interferon release” as an effective treatment for asthma exacerbations.