Asthma and COPD are characterized by an over-excited sensory nervous system leading to excessive reflex bronchospasm and secretions, along with persistent unproductive coughing and dyspnea that can be unmatched to lung function. These hallmark symptoms can be evoked by stimulation of nociceptors. Nociceptors are the predominate type of nerve that innervates the airways. They comprise mainly vagal afferent C-fibers and A-fibers. We have characterized three non-redundant subtypes of vagal nociceptors in the respiratory tract (a unique A? cough receptor and two distinct types of C-fibers). Our long-range goal is to determine the ion channels and mechanisms that underlie the excitability of these nociceptor subtypes, as well as the reflex consequences of nociceptor subtype activation. The present proposal focuses on voltage-gated sodium channels (NaVs). NaVs are critically involved in action potential generation, conduction, and in setting the threshold for nerve activation. There are 9 NaVs termed NaV1-NaV9. This proposal builds on our seminal observations that the three nociceptor subtypes in the airways express almost exclusively NaV 1.7, NaV 1.8, and NaV 1.9. These channels are not present in skeletal or cardiac muscle and are very modestly expressed in the central nervous system. This renders them ideal targets for drugs aimed at normalizing dysregulated nociception. Over the past decade, these channels have been recognized in pain nerves, leading to the rapid pharmaceutical development of selective NaV 1.7, 1.8, and 1.9 blockers. Some of these are presently in clinical trials for inflammatory and neuropathic pain. There is a dearth of knowledge about the function of these pivotal ion channels in airway nociceptors. To the extent that they have been studied in the somatosensory system, our knowledge is based largely on studies at the cell bodies in the dorsal root ganglia, as well as from behavioral studies on pain sensation. This proposal is based on our ability to study the excitability of each nociceptor subtype at the level of the nerve endings in the tissue (Aim 1) and at the level of respiratory defensive reflex consequences of their activation (Aim 2). These properties will be investigated in control animals and in animals in which we employ innovative methods to selectively eliminate, via genetic silencing or pharmacologically, NaV 1.7, 1.8, and 1.9 expression and/or function. We will do this in both mice and guinea pigs at baseline states as well as during states of hyperexcitabilty caused by inflammatory mediators (Aim 1), or in hyperreflexic states caused by respiratory virus infections (Aim 2). This work will advance our basic understanding of how the excitability of visceral nociceptor terminals are regulated in health and disease. In addition, the will provide a rational framework with which to base future clinical studies with NaV selective blockers (already in man) aimed at reducing the exacerbations and suffering of those with asthma, COPD, and chronic cough.

Public Health Relevance

Inappropriate activation of vagal sensory nerves in the airways can lead to symptoms of airway diseases including severe reflex bronchospasm, excessive secretions, nonproductive coughing, and sensations of breathlessness. The long-range goal of this proposal is to develop a better understanding of the mechanisms that regulate the activity of vagal sensory nerves innervating the bronchopulmonary tree.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Noel, Patricia
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kocmalova, Michaela; Kollarik, Marian; Canning, Brendan J et al. (2017) Control of Neurotransmission by NaV1.7 in Human, Guinea Pig, and Mouse Airway Parasympathetic Nerves. J Pharmacol Exp Ther 361:172-180
Mazzone, Stuart B; Undem, Bradley J (2016) Vagal Afferent Innervation of the Airways in Health and Disease. Physiol Rev 96:975-1024
Hewitt, Matthew M; Adams Jr, Gregory; Mazzone, Stuart B et al. (2016) Pharmacology of Bradykinin-Evoked Coughing in Guinea Pigs. J Pharmacol Exp Ther 357:620-8
West, Peter W; Canning, Brendan J; Merlo-Pich, Emilio et al. (2015) Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies. Am J Respir Crit Care Med 192:30-9