Effect of Smoking on Cough Reflex Sensitivity in Humans

Despite the importance of cigarette smoking as a cause of respiratory symptoms and disease, until recently there has been little attention on the effect of smoking on cough reflex sensitivity. Recent studies have shown that in otherwise healthy smokers, cough reflex sensitivity is diminished relative to that of nonsmokers. One proposed mechanism, chronic cigarette smoke-induced desensitization of airway cough receptors, is supported by the demonstration that smoking cessation leads to prompt enhancement of cough reflex sensitivity, even after many years of smoking. Furthermore, resumption of cigarette smoking promptly results in suppression of cough reflex sensitivity. These observations have introduced the concept that cough reflex sensitivity in humans is a dynamic phenomenon, able to be modulated by the presence or absence of stimuli such as cigarette smoke, even after prolonged exposure.     

Effect of Taste Sensation on Cough Reflex Sensitivity

Cough is among the most common symptoms with which people present for medical attention, but evidence-based treatments remain limited. One issue compromising interpretation of clinical trials of cough preparations is that control formulations often are nearly as effective as those that contain active ingredients. This observation has caused some researchers to propose that one or more nominally inactive ingredients may have some physiological effects. For example, most liquid cough preparations are highly sweetened, and it has been suggested that sweet taste might modulate cough sensitivity. The fact that honey has been used for thousands of years as a cough remedy is consistent with this idea. However, empirical evidence for modulation of cough sensitivity by taste was lacking. Evidence is still sparse, but relevant experiments have now been published: rinsing the mouth with a sweet sucrose solution increased cough thresholds in a single-inhalation capsaicin challenge. Furthermore, rinsing the mouth with a bitter solution did not affect thresholds, an important demonstration of specificity. The underlying mechanisms of cough suppression by sweet taste are still unclear. However, extant data suggest that modulation of cough sensitivity by taste is a promising area for further investigation. Such work may lead to greater understanding of apparent placebo effects in clinical trials and provide empirical support for therapies based on stimulation of taste nerves.     

Influence of Smoking Status on Cough Reflex Sensitivity in Subjects with COPD

Cough reflex sensitivity has not been studied extensively in patients with chronic obstructive pulmonary disease (COPD). The aim of the study was to evaluate cough reflex sensitivity to capsaicin in current and former smokers with COPD and examine its association with potentially protussive mediators. Fifteen active smokers and 18 ex-smokers with moderate to severe COPD, 14 healthy active smokers, and 13 healthy never smokers were enrolled. Capsaicin aerosol was administered in order of ascending concentration until the concentrations inducing two or more coughs (C₂) and five or more coughs (C₅) were attained. The concentrations of leukotriene E₄ (LTE₄), leukotriene B₄ (LTB₄), and interleukin-8 (IL-8) in bronchoalveolar lavage (BAL) fluid were analyzed by ELISA. Cough reflex sensitivity in COPD smokers [mean log C₂ = 1.20 ± 0.23 (SEM) μM; log C₅ = 1.85 ± 0.21 μM] did not differ from that in COPD ex-smokers (log C₂ = 1.15 ± 0.14 μM; log C₅ = 2.10 ± 0.19 μM; p > 0.05). Mean C₂ and C₅ in both COPD groups were significantly lower than in healthy active smokers, but higher compared with the healthy never-smokers. BAL fluid concentrations of LTE₄ and LTB₄ were similar in all groups. IL-8 concentrations did not differ between COPD smokers, COPD ex-smokers, and healthy active smokers, but were significantly higher in all three groups compared with healthy never smokers. Cough reflex sensitivity to capsaicin does not differ between smokers and ex-smokers with COPD.     

Effect of Tiotropium on Cough Reflex Sensitivity in Acute Viral Cough

Study Objectives Cough is the most common complaint for which patients in the United States seek medical attention. Few, if any, effective therapies exist for the most common form of acute cough, that due to viral upper respiratory tract infection (URI). The aim of this study was to evaluate the effect of the anticholinergic agent tiotropium bromide on cough reflex sensitivity in subjects with acute viral URI. Patients Otherwise healthy adult nonsmokers with acute viral URI were randomized to receive inhaled tiotropium, 18 μg once daily, or matched placebo, for 7 days. A control group of healthy volunteers underwent an identical protocol. Measurements and Results Cough reflex sensitivity to inhaled capsaicin was measured at baseline (Day 0), and 1 h after the first (Day 1) and seventh (Day 7) dose of tiotropium or placebo. Concentrations of capsaicin inducing two or more (C ₂) and five or more coughs (C ₅) were determined. In subjects with URI, tiotropium (n = 11) demonstrated inhibition of cough reflex sensitivity relative to baseline (increased log C ₂ [p = 0.004] and log C ₅ [p = 0.0004]) after the first dose. No change occurred in the placebo group (n = 10). After 7 days, mean log C ₂ was significantly increased in the tiotropium group relative to placebo (p = 0.03). Although FEF_25–75 was also increased in the tiotropium group (p = 0.016), there was no significant correlation between changes in cough reflex sensitivity and FEF_25–75. Tiotropium had no effect in healthy volunteers (n = 24). Conclusions Tiotropium inhibits cough reflex sensitivity to capsaicin in subjects with acute viral URI. The antitussive effect of tiotropium may occur through a mechanism other than bronchodilation.     

Effect of Zafirlukast on Cough Reflex Sensitivity in Asthmatics

In patients with asthma, increased sensitivity of airway sensory nerves may be involved in producing bronchospasm and cough. To evaluate the effect of a leukotriene-modifying agent on cough reflex sensitivity, we measured the cough response to inhaled capsaicin before and after a 14-day course of therapy with zafirlukast, a cysteinyl leukotriene receptor antagonist, in a group of stable asthmatics. The concentration of capsaicin inducing two or more (C₂) and five or more (C₅) coughs was not altered by zafirlukast, even in those subjects demonstrating a significant change (increment or decrement) in forced expiratory volume in 1 sec (FEV₁). These findings support previous evidence that cough and bronchoconstriction are modulated by distinct neural pathways.     

Preclinical Assessment of Novel Therapeutics on the Cough Reflex: Cannabinoid Agonists as Potential Antitussives

Cough, a reflex defense mechanism, is a common symptom of many airway inflammatory diseases. At present there are no satisfactory treatments for cough that have an acceptable side effect profile. Recent data have described the inhibitory effect of selective cannabinoid CB₂ receptor agonists on sensory nerve activity in vitro and the cough reflex in a guinea pig model. CB₂ receptor expression is limited in the central nervous system (CNS) and hence the development of selective agonists may provide a new therapeutic strategy for treatment of cough devoid of the CNS-mediated side effects that are normally associated with nonselective cannabinoid agonists.     

Preclinical Assessment of Novel Therapeutics on the Cough Reflex: Cannabinoid Agonists as Potential Antitussives

Cough, a reflex defense mechanism, is a common symptom of many airway inflammatory diseases. At present there are no satisfactory treatments for cough that have an acceptable side effect profile. Recent data have described the inhibitory effect of selective cannabinoid CB₂ receptor agonists on sensory nerve activity in vitro and the cough reflex in a guinea pig model. CB₂ receptor expression is limited in the central nervous system (CNS) and hence the development of selective agonists may provide a new therapeutic strategy for treatment of cough devoid of the CNS-mediated side effects that are normally associated with nonselective cannabinoid agonists.

     

Prostanoids and the Cough Reflex

Prostanoids such as prostaglandin (PG) D₂, PGE₂, PGF_2α, prostacyclin (PGI₂), and thromboxane (Tx) A₂ act via five classes of receptors named DP, EP, FP, IP, and TP, respectively, and mediate a diverse range of physiological effects. Prostanoids are commonly associated with many diseases as a proinflammatory mediator; however, in the lung, prostanoids, particularly PGE₂, seem to have a protective role. Inhaled PGE₂ has been shown to be anti-inflammatory and a bronchodilator but causes cough. This has hindered the development of prostanoids for the treatment of airway inflammatory diseases. We discuss here the extensive research into the role of prostanoids in the airways and their modulation of the cough reflex.     

Deep Inspiration-Provoked Cough: A Sign of Cough Reflex Arc Hypersensitivity

Deep inspiration-provoked cough (DIPC) is a form of allotussia. Allotussia is thought to be a manifestation of cough reflex arc hypersensitivity but objective evidence about this is lacking. 36 subjects with chronic cough and 25 healthy subjects underwent mannitol and citric acid cough provocation tests. DIPC was defined as two or more coughs after deep inhalation of an empty mannitol capsule. Citric acid was administered utilizing a dosimetric nebulizer during controlled tidal breathing. Nine subjects demonstrated DIPC, 8/36 subjects with chronic cough and 1/25 healthy subjects (p = 0.048). The concentration of citric acid to provoke five or more coughs (C5) was 23.4 (63.8) mM among subjects with DIPC and 750 (2941) mM among the subjects without it (p = 0.006). The number of deep inspiration-provoked coughs correlated with the citric acid C5 (Rs -0.38, p = 0.002). In conclusion, DIPC, a form of allotussia, is associated with cough reflex arc hypersensitivity.

Trial Registration Number.

ClinicalTrials.gov database KUH5801136.

     

The Cough Reflex in Animals: Relevance to Human Cough Research

All mammalian species studied cough or display some similar respiratory reflex upon aerosol challenge with tussigenic stimuli such as citric acid or capsaicin. Animals cough to the same stimuli that evoke coughing in humans, and therapeutic agents that display antitussive effects in human studies also prevent coughing in animals. The many invasive procedures and complementary in vitro studies possible in animals but not readily reproduced in human subjects, along with the proven predictive value of cough studies in animals, provide the rationale for animal modeling of human cough. The advantages and disadvantages of studying cough in animals are discussed.

     

The Cough Reflex in Animals: Relevance to Human Cough Research

All mammalian species studied cough or display some similar respiratory reflex upon aerosol challenge with tussigenic stimuli such as citric acid or capsaicin. Animals cough to the same stimuli that evoke coughing in humans, and therapeutic agents that display antitussive effects in human studies also prevent coughing in animals. The many invasive procedures and complementary in vitro studies possible in animals but not readily reproduced in human subjects, along with the proven predictive value of cough studies in animals, provide the rationale for animal modeling of human cough. The advantages and disadvantages of studying cough in animals are discussed.     

咳嗽反射调控机制的研究进展

咳嗽反射是机体重要的防御性反射,通过外周神经和中枢神经共同调控保持平衡,其刺激信号主要是通过迷走神经介导.咳嗽反射不仅受脑干水平影响,且大脑中枢在咳嗽反射调控过程中也发挥着重要作用.针对咳嗽反射,目前周围神经潜在的调控靶点包括瞬时受体电位香草酸受体1(TRPV1)、瞬时受体电位锚蛋白1(TRPA1)及P2X3受体,而关...     

Basic Mechanisms of Cough: Current Understanding and Remaining Questions

Considerable effort in many laboratories has gone into describing the afferent nerve subtypes that initiate cough, and the ionic mechanisms the activation and modulation of these nerves. In this brief overview, we have attempted to summarize some of what is understood in these areas. In addition, we have tried to highlight many of the important basic questions that remain to be answered.     

Basic Mechanisms of Cough: Current Understanding and Remaining Questions

Considerable effort in many laboratories has gone into describing the afferent nerve subtypes that initiate cough, and the ionic mechanisms the activation and modulation of these nerves. In this brief overview, we have attempted to summarize some of what is understood in these areas. In addition, we have tried to highlight many of the important basic questions that remain to be answered.

     

Studies on the Defecation Reflex in Man

In patients with cecostomies and in patients with urinary bladder substitutes obtained from either the sigmoid colon or the cecum, the motor activity in different parts of the large bowel was recorded with the aid of open tip tubes and a pressure-recording apparatus after administration of a contact laxative (Dulcolax®). Administration of Dulcolax® into the cecum of patients with cecostomy produced motor activity locally as well as in the transverse colon and in the sigmoid. When the drug was administered into the cecum of patients with isolated cecal bladder replacements, motor activity was recorded in the cecum but not in the sigmoid. Rectal application of Dulcolax® initiated motor activity in the intact sigmoid as well as in the isolated sigmoid bladder substitute but not in the cecum in patients with cecostomies nor in the cecal bladder replacements. The experiments indicate that only the left colon is engaged in the defecation mechanism elicited by rectal stimulation. The motor response in the left colon after rectal stimulation is mediated by a reflex with its afferent limb from the rectal ampulla. The motor response in the sigmoid after cecal stimulation is elicited by impulses mediated by intrinsic nervous pathways in the intestinal wall.     

Cough,Basic Science,and the Clinician

Cough is a major cause of disability and distress worldwide. In June 2007, the First American Cough Conference was held in New York City and covered a spectrum of topics of interest to the basic scientist as well as the clinician. The conference was organized by Dr. Peter Dicpinigaitis and its proceedings are published in the February Supplement of LUNG. This supplement consists of a series of articles that provide a valuable overview of recent advances in our understanding of mechanism, etiology, and treatment of cough and constitute an adjunct to the guidelines recently published by the American College of Chest Physicians, the British Thorax Society, the European Respiratory Society, and the Japanese Respiratory Society.     

Neuroprotective Effects of Statins: Evidence from Preclinical and Clinical Studies

OPINION STATEMENT: The benefits of statins for both primary and secondary prevention of ischemic stroke are clearly established. Evidence is accumulating that statin withdrawal after ischemic stroke may lead to worse outcome and that initiation of statins after ischemic stroke may reduce mortality and improve outcome. Current treatment guidelines recommend starting statins before discharge in patients with stroke related to atherosclerosis or who have elevated cholesterol. The primary treatment question then is not if to start statins in most ischemic stroke patients, but when. Our recommendation would be start a statin as soon as the patient passes a dysphagia screen and can safely take oral medication. Based on the results of the Heart Protection Study and the SPARCL trial, either simvastatin 40?mg or atorvastatin 80?mg are appropriate alternatives. Clinical trials are needed to demonstrate unequivocal efficacy of improved outcome and to determine if lower doses may have this effect. Additionally, improved outcome needs to be established in cardioembolic stroke patients before routine use of statins in this stroke subtype can be recommended.     

Alcohol Sensitivity and Smoking History in Men and Women

Many studies have found genetic effects to contribute to alcoholism risk in both men and women. Based on preliminary evidence for shared genetic risk between smoking and drinking problems, a re-analysis of alcohol challenge data on 412 Australian twins was performed to explore the possibility that smoking may diminish or moderate the intoxicating effects of alcohol. We found history of smoking to be strongly associated with self-reported intoxication after alcohol challenge in women (women: r = -0.44 ± 0.08; men: r = -0.21 ±0.08), comparable with self-reported average weekly consumption of alcohol, which was more strongly associated in men (women: r = -0.37 ±0.07; men: r = -0.54 ±0.06). Structural equation model-fitting indicated a strong association between heavy drinking and smoking, but the association between smoking and postalcohol intoxication remained even when the effects of heavy drinking were controlled for. These results prompt the question of whether smoking cigarettes directly influences the transition from moderate to excessive use of alcohol by diminishing feelings of alcohol intoxication.