Chronic tobacco smoke exposure increases cough to capsaicin in awake guinea pigs

doi:10.1016/S0034-5687(01)00193-1

Respiration Physiology

Volume 126, Issue 2, June 2001, Pages 127-140

Respiration Physiolo...

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Abstract

Chronic exposure to irritants such as tobacco smoke (TS) can induce spontaneous and enhanced irritant-induced coughing, especially in asthma. To determine if the mechanism of enhanced coughing involves activation of capsaicin-sensitive sensory receptors (C-fibers), we exposed both non-sensitized (NS) and ovalbumin-sensitized guinea pigs to TS (5 mg/L air, 30 min exposure, and 7 days/week). Similar groups were exposed to compressed air. After 90 days of exposure, we challenged the airways with capsaicin, bradykinin, histamine and methacholine. Capsaicin induced coughing as well as bronchoconstriction in guinea pigs exposed to TS. In ovalbumin (OA) guinea pigs coughing and bronchoconstriction were enhanced. Tachykinin receptor antagonists attenuated coughing to both capsaicin and acute TS challenge. Bradykinin also induced coughing and bronchoconstriction in guinea pigs exposed to TS. There was no statistical separation between the two TS groups however. Histamine and methacholine induced similar bronchoconstriction but fewer coughs in all four experimental groups. In conclusion, chronic TS exposure induced coughing to capsaicin and bradykinin challenge. The effect of capsaicin was further enhanced in OA guinea pigs. Enhanced coughing induced by TS exposure likely involves activation of capsaicin-sensitive sensory C-fibers and neuropeptide release with possible subsequent activation of rapidly-adapting receptors.

Introduction

Cough is an important defense reflex that occurs during inhalation of irritant substances and is often the first symptom of airway disease (Karlsson et al., 1988). The treatment of chronic coughing is difficult in part because its etiology is poorly understood (Irwin et al., 1981). Enhanced coughing has been reported in asthmatic individuals following inhalation of airway irritants such as acetic acid (Mitsuhashi et al., 1985) and capsaicin (Doherty et al., 2000). On the other hand, Collier and Fuller (1984) found no hypersensitivity to capsaicin challenge in asthmatic compared to healthy individuals. Further investigation is warranted.

Tobacco smoke (TS) is a common inhaled irritant that induces bronchoconstriction in asthmatic individuals (Dahms et al., 1981). Chronic TS exposure enhances symptoms of asthma including cough, especially in children (Joad, 2000). Acute TS challenge activates both airway rapidly adapting receptors (RARs) (Bergren and Sampson, 1982) and C-fiber endings (Lee et al., 1989). Both RARs and C-fibers are thought to initiate cough (Forsberg and Karlsson, 1986, Forsberg et al., 1988). It is possible that chronic TS exposure or airway sensitization alters the cough threshold by inducing hyperirritability of either or both category of sensory receptor in the airways.

Recent studies in guinea pigs report that chronic TS exposure enhances bronchoconstriction to capsaicin challenge (Bergren, 2001, Wu and Lee, 1999). Furthermore, chronic TS exposure increases C-fiber reactivity to capsaicin challenge in guinea pigs (Mutoh et al., 1999; Bergren, unpublished data). C-fiber activation is thought to induce cough in at least some conditions (Karlsson et al., 1988). It is, therefore, possible that chronic TS exposure may either lower the cough threshold or increase the cough response to inhaled irritants through C-fiber sensitization.

Guinea pigs are animals that cough. Agents such as TS and capsaicin that induce cough in man also induce cough in guinea pigs (Collier and Fuller, 1984, Karlsson et al., 1991, Laude et al., 1993). In addition, guinea pig airways can easily be sensitized to foreign proteins such as ovalbumin (Andersson, 1980). This guinea pigs model of airway hyperirritability has been widely used for the study of mechanisms and treatment of asthma.

We, therefore, tested the hypothesis that chronic exposure to TS enhances coughing to airway irritants through sensitization and activation of capsaicin sensitive sensory receptors. These sensory receptors are likely to be C-fiber endings as it appears that RARs are activated by mechanical mechanisms after capsaicin challenge in guinea pigs (Bergren, 1997). We also tested the hypothesis that the combination chronic TS exposure and airway sensitization lowers the cough threshold as well as enhances coughing in guinea pigs to inhaled agents through C-fiber activation. Supportive of this hypothesis is that chronic exposure to TS enhanced airway reactivity (AR) to both capsaicin and bradykinin as well as increase release of tachykinins into the pulmonary circulation during acute TS challenge in guinea pigs (Bergren, 2001).

Section snippets

Animals

Hartley guinea pigs (Harlan, Minneapolis, MN) weighing approximately 300 g at delivery were housed in the Creighton University School of Medicine Animal Resource Facility with food and water ad libitum. The study was performed with the approval of the Creighton University Animal Use Committee.

Airway sensitization by ovalbumin

Two days after their arrival, 32 guinea pigs were injected intraperitoneally with ovalbumin-sensitized (OA) (10 μg) and aluminum hydroxide (100 mg) in distilled water (0.5 ml). A booster injection of OA

Results

A qualitative summary of data concerning cough and bronchoconstriction from the present study is presented in Table 1.

Discussion

The present study demonstrates that chronic TS exposure enhances coughing in guinea pigs challenged with capsaicin, bradykinin or acute TS exposure. Coughing induced by capsaicin and acute TS challenge is further enhanced by OA-sensitization. In addition, a cocktail of NK1 and NK2 antagonists attenuated both capsaicin- and acute TS-induced coughing. This suggests that enhanced coughing induced by chronic TS exposure involved tachykinin release. The source of the tachykinins is likely the airway

Acknowledgements

This study was funded by a grant from the State of Nebraska's Department of Health and Human Service Cancer and Smoking Disease Program. Douglas Lassiter and Quenton Tanko expertly provided technical assistance. This study has been presented in part at the 1998 Experimental Biology meetings (FASEB Journal 12(5), A792).

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Chronic tobacco smoke exposure increases cough to capsaicin in awake guinea pigs

Abstract

Introduction

Section snippets

Animals

Airway sensitization by ovalbumin

Results

Discussion

Acknowledgements

Lancet

Respir. Physiol.

Respir. Physiol.

Pharmac. Ther.

Chest

Pulm. Pharmacol.

Clin. Chest Med.

Pulm. Pharmacol.

Gen. Pharmacol.

Respir. Physiol.

Antigen-induced bronchial anaphylaxis in actively sensitized guinea pigs. Pattern of response in relation to immunization regimen

Allergy

Chronic tobacco smoke exposure increases airway reactivity to capsaicin in awake guinea pigs

J. Appl. Physiol.

Sidestream smoke exposure enhances rapidly adapting receptor responses to substance P in young guinea pigs

J. Appl. Physiol.

Capsaicin inhalation in man and the effects of sodium cromoglycate

Br. J. Pharmacol.

Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease

Thorax

Cigarette smoke induces bronchoconstrictor hyperresponsiveness to substance P and inactivates airway neutral endopeptidase in the guinea pig: possible role of free radicals

J. Clin. Invest.

Alteration in osmolarity of inhaled aerosols cause bronchoconstriction and cough, but absence of a permeant anion causes cough alone

Am. Rev. Respir. Dis.

Cough induced by stimulation of capsaicin-sensitive neurons in conscious guinea pigs

Acta Physiol. Scand.