Airway irritation and cough evoked by inhaled cigarette smoke: Role of neuronal nicotinic acetylcholine receptors

doi:10.1016/j.pupt.2006.10.007

Pulmonary Pharmacology & Therapeutics

Volume 20, Issue 4, August 2007, Pages 355-364

https://doi.org/10.1016/j.pupt.2006.10.007 Get rights and content

Abstract

In a series of studies carried out in different experimental models, we investigated the type(s) of lung afferents and mechanism(s) underlying the cigarette smoke-induced airway irritation and cough. In healthy non-smokers, the intensity of airway irritation and cough evoked by cigarette smoke was markedly reduced after premedication with hexamethonium. A similar pattern of responses was also triggered by inhalation of nicotine aerosol. These studies in human subjects suggested nicotine as the primary causative agent in cigarette smoke that evokes airway irritation. Indeed, single-fiber recording experiments performed in anesthetized dogs showed that both C-fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one puff of cigarette smoke, and the intensity of this stimulatory effect was related to the nicotine content in the cigarette and abolished by hexamethonium. To further study the direct effect of nicotine on these sensory nerves, we measured the change in intracellular calcium concentration ([Ca²⁺]_i) of pulmonary sensory neurons isolated from the nodose and jugular ganglia of adult rats. Our results showed that nicotine evoked an abrupt and transient increase in [Ca²⁺]_i in ∼34% of the 522 neurons tested, and 1,1-dimethyl-4-phenylpiperazinium, a selective agonist of the neuronal nicotinic acetylcholine receptors (NnAChRs), evoked a similar pattern of response as that of nicotine in these neurons. In conclusion, results of these studies show that nicotine exerts a direct stimulatory effect on vagal pulmonary sensory neurons. This stimulatory effect of nicotine is primarily responsible for the airway irritation and cough evoked by inhaled cigarette smoke, and is mediated through an activation of the NnAChRs.

Introduction

Inhaled cigarette smoke causes airway irritation and cough, and is undoubtedly one of the most common inhaled irritants to the human respiratory tract. Furthermore, intense, prolonged or repetitive occurrences of airway irritation can lead to neurogenic inflammation and tissue damage, which may play a critical part in the chronic smoking-induced airway dysfunction. The following studies were carried out in our laboratory to answer the following questions concerning the cigarette smoke-evoked airway irritation: (1) What is the primary constituent(s) in the cigarette smoke that triggers the irritant effect of cigarette smoke? (2) What type(s) of sensory endings in the airways/lungs is (are) responsible for evoking the airway irritation? (3) What are the mechanisms underlying the activation of these sensory nerves by inhaled cigarette smoke?

Section snippets

Cough and airway irritation evoked by inhaled cigarette smoke in men

This study was performed in healthy young male non-smokers (20–31 yr of age) to determine the role of nicotine in the cigarette smoke-evoked airway irritation; none of them had any symptom or history of pulmonary or cardiovascular disease. The experimental protocols had been approved by the University of Kentucky Institutional Review Board, and informed consent was obtained from each subject. Hexamethonium, nicotine and placebo solutions were prepared daily by the University of Kentucky Hospital

Stimulation of vagal pulmonary C-fiber afferents and rapidly adapting receptors by cigarette smoke in anesthetized dogs

In a series of studies of the reflex responses, we have previously shown that inhalation of high-nicotine cigarette smoke via a tracheostomy tube immediately elicited either an apnoea or an augmented inspiration in both awake and anesthetized dogs; these responses were not present when the same volume of smoke with a lower nicotine content was inhaled [12] and were completely abolished by hexamethonium pretreatment in the same animals [13], indicating a dominant role of nicotine. Since these

Direct effect of nicotine on isolated rat vagal pulmonary sensory neurons

In light of the findings reported above, this study aimed to determine if nicotine exerts a direct stimulatory effect on isolated pulmonary sensory neurons, and if so whether the effect is caused by activation of neuronal nAChRs (NnAChRs) expressed on the membrane of these sensory neurons. One well-documented, characteristic response evoked by activation of NnAChRs is an increase in intracellular calcium concentration ([Ca²⁺]_i) in the neuron by direct passage of calcium through the receptor

Discussion

These studies clearly demonstrate that nicotine is primarily responsible for triggering cough and airway irritation evoked by inhaled cigarette smoke in humans [28]. We suggest that these responses are most likely generated by a stimulatory effect of nicotine on vagal bronchopulmonary C fibers and RARs (irritant receptors) in the airways. Furthermore, our study offers definitive evidence that nicotine exerts a direct stimulatory effect on isolated vagal pulmonary sensory neurons, and this

Acknowledgments

The authors thank Wen-Bin Young, Alan Wang, Robert Morton and Michelle Wiggers for their technical assistances in these studies. These studies were supported in part by grants from the National Institutes of Health (HL-40369 and HL-67379).

The present address of N.K. Burki: Division of Pulmonary Medicine, Department of Medicine, University of Connecticut Health Center, Farmington, CT, 06030, USA; and Y.R. Kou: of Physiology, National Yang-Ming University, Taipei, Taiwan, 112, ROC.

References (36)

L.-Y. Lee et al.
Effect of a single breath of cigarette smoke on slowly adapting receptors in canine lungs
Respir Physiol
(1992)
J. Mortola et al.
Localization of irritant receptors in the airways of the dog
Respir Physiol
(1975)
L.Y. Lee et al.
Hexamethonium aerosol prevents cigarette smoke induced pulmonary reflexes in dogs
Respir Physiol
(1986)
L.Y. Lee et al.
Cigarette smoke-induced bronchoconstriction and release of tachykinins in guinea pig lungs
Respir Physiol
(1995)
L.M. Colquhoun et al.
Pharmacology of neuronal nicotinic acetylcholine receptor subtypes
Adv Pharmacol
(1997)
G. Grynkiewicz et al.
A new generation of Ca²⁺ indicators with greatly improved fluorescence properties
J Biol Chem
(1985)
M. Ray et al.
Involvement of alpha6/alpha3 neuronal nicotinic acetylcholine receptors in neuropsychiatric features of Dementia with Lewy bodies: [(125)I]-alpha-conotoxin MII binding in the thalamus and striatum
Neurosci Lett
(2004)
C.Y. Ho et al.
Sensitivity of vagal afferent endings to chemical irritants in the rat lung
Respir Physiol
(2001)
L.Y. Lee et al.
Afferent properties and reflex functions of bronchopulmonary C-fibers
Respir Physiol
(2001)
M.J. Tobin et al.
Monitoring smoking patterns of low and high tar cigarettes with inductive plethysmography
Am Rev Respir Dis
(1982)

J.N. Diana et al.

Research cigarettes

(1990)

W.B. Wartman et al.

Determination of particulate matter in concentrated aerosols

Application to analysis of cigarette smoke. Anal Chem

(1959)

T.T. Mercer

Production and characterization of aerosols

Arch Intern Med

(1973)

L.-Y. Lee et al.

Stimulation of vagal pulmonary C-fibers by a single breath of cigarette smoke in dogs

J Appl Physiol

(1989)

Y.R. Kou et al.

Stimulation of rapidly adapting receptors in the canine lungs by a single breath of cigarette smoke

J Appl Physiol

(1990)

Y.R. Kou et al.

Mechanisms of cigarette smoke-induced stimulation of rapidly adapting receptors in canine lungs

Respir Physiol

(1991)

B.J. Canning et al.

Identification of the tracheal and laryngeal afferent neurons mediating cough in anesthetized guinea-pigs

J Physiol

(2004)

J.C.G. Coleridge et al.

Afferent vagal C fiber innervation of the lungs and airways and its functional significance

Rev Physiol Biochem Pharmacol

(1984)

Cited by (63)

Drug and alcohol dependence acute effects of pod-style e-cigarettes in vaping-naïve smokers
2021, Drug and Alcohol Dependence
Citation Excerpt :
Compared to NoNic, NicSalt and NicFreebase solutions increased heart rate and were rated as harsher and less smooth among older smokers with moderate nicotine dependence. Stimulation of nicotinic acetylcholine receptors lining the airways by nicotine likely increases sensations of harshness and reduces perceived smoothness from tobacco product aerosol (Lee et al., 2007), and high smoothness and low harshness correlate with perceived product appeal in previous research (Leventhal et al., 2019). Despite that NicSalt generates aerosol that is less harsh than NicFreebase (Leventhal et al., 2021), there were no differences in airway sensations of the two nicotine-containing e-cigarettes among the older, modestly dependent smokers in this study.
This study investigated the acute effects of exposure to pod-style e-cigarettes on subjective, behavioral, and physiological outcomes indicative of the potential to encourage vaping-naïve smokers to switch to e-cigarettes.
In a within-subject experiment, never-vaping adult smokers interested in trying e-cigarettes (n = 24) completed 4 laboratory visits following 16-hr tobacco abstinence. Visits involved controlled puffing from preferred brand cigarettes (OwnCig) or a standardized pod-style e-cigarette with either no nicotine (NoNic), nicotine freebase (NicFreebase; 0.5% nicotine concentration), or nicotine salt (NicSalt E-Cig; 2.8% concentration) solutions. Outcomes included smoking urge, mood, user experience, plasma nicotine, and a behavioral task assessing ability to delay smoking.
NoNic, NicFreebase, and NicSalt pod-style e-cigarettes were significantly less effective than OwnCig at reducing smoking urge and increasing plasma nicotine, positive affect, satisfying user experience ratings, and ability to delay smoking on the behavioral task. Differences among pod-style e-cigarette conditions were limited to: (a) NicFreebase (vs. NoNic) preferentially suppressed participants’ urge to smoke to alleviate negative mood, (b) NicFreebase (vs. NicSalt) slightly preferentially increased plasma nicotine; and (c) NicFreebase and NicSalt (vs. NoNic) produced higher aversive user experience ratings.
In tobacco deprived smokers’ initial vaping experience, controlled administration of certain pod-style e-cigarettes with 0.5% NicFreebase or 2.8% NicSalt may be deficient comparators to cigarettes in terms of their capacity to acutely improve mood, deliver nicotine, suppress smoking motivation, and offer a satisfying user experience. Future research is needed to test pod-style e-cigarettes with higher nicotine doses and confirm whether NicFreebase vs. NicSalt enhances nicotine absorption.
Nicotinic α7 acetylcholine receptor (α7nAChR) in human airway smooth muscle
2021, Archives of Biochemistry and Biophysics
Citation Excerpt :
Given the roles of ASM in airway hyperreactivity [5,6,34–36] and remodeling [5,6,34,54–56], these findings on α7nAChR become important. Nicotine acts on nAChRs of airway-related vagal preganglionic neurons in the central nervous system [57–61]. Cholinergic nerves enhance bronchoconstriction, mucus secretion, and bronchial vasodilation [37–39,41,62], but abnormal cholinergic innervation in asthma has not been definitively proven.
Diseases such as asthma are exacerbated by inflammation, cigarette smoke and even nicotine delivery devices such as e-cigarettes. However, there is currently little information on how nicotine affects airways, particularly in humans, and changes in the context of inflammation or asthma. Here, a longstanding assumption is that airway smooth muscle (ASM) that is key to bronchoconstriction has muscarinic receptors while nicotinic receptors (nAChRs) are only on airway neurons. In this study, we tested the hypothesis that human ASM expresses α7nAChR and explored its profile in inflammation and asthma using ASM of non-asthmatics vs. mild-moderate asthmatics. mRNA and western analysis showed the α7 subunit is most expressed in ASM cells and further increased in asthmatics and smokers, or by exposure to nicotine, cigarette smoke or pro-inflammatory cytokines TNFα and IL-13. In these effects, signaling pathways relevant to asthma such as NFκB, AP-1 and CREB are involved. These novel data demonstrate the expression of α7nAChR in human ASM and suggest their potential role in asthma pathophysiology in the context of nicotine exposure.
Jugular vagal ganglia neurons and airway nociception: A target for treating chronic cough
2021, International Journal of Biochemistry and Cell Biology
Citation Excerpt :
Notably, many stimuli which act on both jugular and nodose airway nociceptors (e.g. capsaicin, bradykinin or protons) readily induce coughing in animals and humans (Chou et al., 2017; Hewitt et al., 2016; Farrell et al., 2020). This is mimicked by cigarette smoke and nicotine (Lee et al., 2007), whereas inhaled serotonin, adenosine and ATP are only weakly tussigenic (Chou et al., 2017; Farrell et al., 2020). In fact, nodose selective nociceptor stimuli may inhibit cough under some circumstances (Chou et al., 2017).
The airways receive a dense supply of sensory nerve fibers that are responsive to damaging or potentially injurious stimuli. These airway nociceptors are mainly derived from the jugular and nodose vagal ganglia, and when activated they induce a range of reflexes and sensations that play an essential role in airway protection. Jugular nociceptors differ from nodose nociceptors in their embryonic origins, molecular profile and termination patterns in the airways and the brain, and recent discoveries suggest that excessive activity in jugular nociceptors may be central to the development of chronic cough. For these reasons, targeting jugular airway nociceptor signaling processes at different levels of the neuraxis may be a promising target for therapeutic development. In this focused review, we present the current understanding of jugular ganglia nociceptors, how they may contribute to chronic cough and mechanisms that could be targeted to bring about cough suppression.
Modeling drug exposure in rodents using e-cigarettes and other electronic nicotine delivery systems
2020, Journal of Neuroscience Methods
Smoking tobacco products is the leading cause of preventable death worldwide. Coordinated efforts have successfully reduced tobacco cigarette smoking in the United States; however, electronic cigarettes (e-cigarette) and other electronic nicotine delivery systems (ENDS) recently have replaced traditional cigarettes for many users. While the clinical risks associated with long-term ENDS use remain unclear, advancements in preclinical rodent models will enhance our understanding of their overall health effects. This review examines the peripheral and central effects of ENDS-mediated exposure to nicotine and other drugs of abuse in rodents and evaluates current techniques for implementing ENDS in preclinical research.
Occupational and Environmental Contributions to Chronic Cough in Adults: Chest Expert Panel Report
2016, Chest
In response to occupational and environmental exposures, cough can be an isolated symptom reflecting exposure to an irritant with little physiological consequence, or it can be a manifestation of more significant disease. This document reviews occupational and environmental contributions to chronic cough in adults, focusing on aspects not previously covered in the 2006 ACCP Cough Guideline or our more recent systematic review, and suggests an approach to investigation of these factors when suspected.
MEDLINE and TOXLINE literature searches were supplemented by articles identified by the cough panel occupational and environmental subgroup members, to identify occupational and environmental aspects of chronic cough not previously covered in the 2006 ACCP Cough Guideline. Based on the literature reviews and the Delphi methodology, the cough panel occupational and environmental subgroup developed guideline suggestions that were approved after review and voting by the full cough panel.
The literature review identified relevant articles regarding: mechanisms; allergic environmental causes; chronic cough and the recreational and involuntary inhalation of tobacco and marijuana smoke; nonallergic environmental triggers; laryngeal syndromes; and occupational diseases and exposures. Consensus-based statements were developed for the approach to diagnosis due to a lack of strong evidence from published literature.
Despite increased understanding of cough related to occupational and environmental triggers, there remains a gap between the recommended assessment of occupational and environmental causes of cough and the reported systematic assessment of these factors. There is a need for further documentation of occupational and environmental causes of cough in the future.
Nicotine and Neurokinin Signaling
2016, Neuropathology of Drug Addictions and Substance Misuse
Substance P (SP) belongs to the family of tachykinins, which also contains neurokinins (NKs) A and B. The three neuropeptides and their respective receptors are expressed in several of the brain regions that regulate stress, anxiety, and addiction-related behaviors. Although there is extensive evidence for a role of the SP/NK1R system in opiate and alcohol dependence, very little is known regarding the role that tachykinins play in the mechanisms of nicotine dependence. This chapter provides an overview of the molecular and circuit-based mechanisms that provide a rationale for the effects of NKs on drug abuse. In particular, we provide a summary of the evidence for the interactions with the nicotinic cholinergic system and how these systems represent a mechanistic link between stress, anxiety, and the symptoms of nicotine withdrawal. More studies are needed to determine whether NK receptors are promising drug targets that might complement current smoking cessation strategies.

View all citing articles on Scopus

View full text

Airway irritation and cough evoked by inhaled cigarette smoke: Role of neuronal nicotinic acetylcholine receptors

Abstract

Introduction

Section snippets

Cough and airway irritation evoked by inhaled cigarette smoke in men

Stimulation of vagal pulmonary C-fiber afferents and rapidly adapting receptors by cigarette smoke in anesthetized dogs

Direct effect of nicotine on isolated rat vagal pulmonary sensory neurons

Discussion

Acknowledgments

Respir Physiol

Respir Physiol

Respir Physiol

Respir Physiol

Adv Pharmacol

J Biol Chem

Neurosci Lett

Respir Physiol

Respir Physiol

Monitoring smoking patterns of low and high tar cigarettes with inductive plethysmography

Am Rev Respir Dis

Research cigarettes

Determination of particulate matter in concentrated aerosols

Application to analysis of cigarette smoke. Anal Chem

Production and characterization of aerosols

Arch Intern Med

Stimulation of vagal pulmonary C-fibers by a single breath of cigarette smoke in dogs

J Appl Physiol

Stimulation of rapidly adapting receptors in the canine lungs by a single breath of cigarette smoke

J Appl Physiol

Mechanisms of cigarette smoke-induced stimulation of rapidly adapting receptors in canine lungs

Respir Physiol

Identification of the tracheal and laryngeal afferent neurons mediating cough in anesthetized guinea-pigs

J Physiol

Afferent vagal C fiber innervation of the lungs and airways and its functional significance

Rev Physiol Biochem Pharmacol