# Cholinergic mechanisms involved in transduction of airway defensive reflexes

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $517,165

## Abstract

The symptoms of obstructive lung diseases, which include airways hyperresponsiveness, reversible airways
obstruction, chest tightness, dyspnea, mucus hypersecretion and cough, are in large part the result of an
excessive and/ or inappropriate activation of the vagal afferent nerves innervating the airways and lungs.
Understanding the mechanisms by which these sensory nerves are activated in health and disease and the
reflexes and sensations evoked as a consequence of their activation have been longstanding goals of the
research carried out in our laboratories. Visceral afferent nerves often rely on specialized chemosensory
signaling mechanisms at their nerve terminals to transduce mucosal irritation. We recently described a
chemosensory transduction pathway in the airways mucosa that relies on the transmitter acetylcholine and the
nicotinic subclass of acetylcholine receptors (nAChRs) to initiate changes in breathing pattern in response to
mucosal irritation. The involvement of nAChRs is noteworthy, as their activity is inappropriately and
excessively recruited in the airways of patients exposed to cigarette smoke or the nicotine-containing vapors of
eCigarettes. The central hypothesis of this research proposal is that nAChRs play essential roles in
transducing reflexes initiated endogenous irritants acting on subsets of vagal sensory nerves, and modulate
airway defensive reflexes both peripherally and centrally. We also hypothesize that the regulatory functions of
nAChRs are corrupted by chronic mucosal irritation associated with asthma and COPD, and by smoking.
Studies proposed herein aim to: 1) characterize the vagal afferent nerve subtypes responsible for nAChR-
dependent exacerbations of obstructive lung diseases and the nAChR subtypes involved; 2a) determine the
transduction mechanisms for nAChR-dependent coughing and other airway defensive reflexes both at the
peripheral nerve terminals and centrally at the termination sites of the neural crest C-fibers that are selectively
stimulated through nAChR activation; 2b) once the mechanisms for nAChR-dependent reflexes are established
in healthy animals, we will evaluate changes in transduction mechanisms following chronic nicotine
administration and during allergen-induced cough hypersensitivity; and 3) building upon our intriguing recent
discovery of α7 nAChR subtype dependent inhibition of evoked coughing through central sites of action, we will
determine the CNS effects of nAChR activation on airway defensive reflexes, and how these central regulatory
pathways are altered by chronic nicotine administration and during cough hypersensitivity. For all of these
studies, we will utilize techniques that are unique to our laboratories, including single cell recording and
molecular approaches, reflex physiological recordings and in vivo imaging of nAChR occupancy. We
anticipate that the results of these proposed studies will reveal the novel and essential roles of nAChRs in
transducing mucosal irrita...

## Key facts

- **NIH application ID:** 10000962
- **Project number:** 5R01HL141251-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** BRENDAN J CANNING
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $517,165
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000962

## Citation

> US National Institutes of Health, RePORTER application 10000962, Cholinergic mechanisms involved in transduction of airway defensive reflexes (5R01HL141251-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000962. Licensed CC0.

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