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Mechanisms of chronic cough
Abstract
Chronic and uncontrollable cough is one of the most common and debilitating symptoms found in patients with chronic airway diseases. The physical trauma and stresses of chronic cough on the airway mucosa and respiratory muscles can further worsen the deteriorating process of the airway diseases. The articles presented in this section focus primarily on the effect of chronic cough on the cell structure and protective function of the airway mucosa, the mechanisms underlying the hypersensitivity of chronic cough, and new target areas for antitussive drug development. A major emphasis has been placed on the neuronal plasticity found at the peripheral and central sites of the neural pathway mediating the cough reflex, and its potential role in the development of chronic cough is discussed. A number of new and important questions concerning the physiological and pharmacological mechanisms underlying chronic cough have emerged in these presentations. Further studies are required to answer these questions, which should bring a better understanding of the pathogenic mechanisms of chronic cough and lead to the development of new therapeutic strategies.
... However, although the expression of NKA and NKB in the airway of rats increased after inhaling residual sevoflurane for 14 d, the difference was not statistically significant. It was speculated that neutral endopeptidase in airway epithelium and angiotensin converting enzyme in blood could rapidly degrade NKA and NKB (Lee LY, et al., 2004), which does not rule out the possibility that NKA and NKB have been partially degraded in the process of sampling and preservation of 14d rats. Besides, since 21 d rats are in puberty, gonadotropins produced at this developmental stage play a positive role in regulating the synthesis of NKA and NKB (Navarro V, 2020), under the synergistic efect of gonadotropins, residual sevolurane may be more likely to increase the expression of NKA and NKB in late developmental stage (puberty) rats. ...
Background
Neurogenic inflammation caused by sevoflurane may not only limite to the nervous system, but also expand to the respiratory system. The purpose of this study was to investigate the expression changes of transient receptor potential vanilloid 1 (TRPV1), neurokinin A (NKA), neurokinin B (NKB), calcitonin gene related peptide (CGRP) and substance P (SP) in 14, 21 and 42-day-old rats after inhaling 0.4% sevoflurane, in order to evaluate whether the residual sevoflurane be harmful to the respiratory system through neurogenic inflammation.
Methods
The anesthetic inhalation device was designed to allow 14, 21 and 42-day-old rats inhale 0.4% sevoflurane, while rats in the control group inhaled 40% O2 for 1h. Rats in the antagonist group inhaled 0.4% sevoflurane or 40% O2 for 1 h after Capsazepine (CPZ) pretreatment. The expression of TRPV1 in lung tissue was detected by western blot, and the expression of NKA, NKB, CGRP and SP in trachea was detected by immunohistochemistry.
Results
After inhaling 0.4% sevoflurane, the expression of TRPV1 in lung tissue of 14 and 21-day-old rats was significantly higher than that of the control group, as well as increased the expression of CGRP and SP in the trachea of 14-day-old rats and NKA, NKB, CGRP and SP in the trachea of 21-day-old rats. CPZ pretreatment could antagonize these effects.
Conclusion
Residual sevoflurane during resuscitation of inhalation anesthesia could induce neurogenic inflammation by activating TRPV1, which damaged to the developing respiratory system, but has no significant effect on the respiratory system in adulthood.
... The stimulation of CSLV afferents is well documented to elicit various reflex responses, such as cough, bronchoconstriction, and airway hypersecretion (7,22). Once the afferents are sensitized by mediators, this result might in turn exaggerate these respiratory reflexes (7,15,23,26). Accordingly, during lung inflammation, we propose that H 2 S might contribute to the pathogenesis of airway hypersensitivity such as chronic cough. However, whether the endogenous H 2 S and its sensitizing effect on CSLV afferents play any part in the regulation of airway functions during lung inflammation remains to be determined. ...
The sensitization of capsaicin-sensitive lung vagal (CSLV) afferents by inflammatory mediators is important in the development of airway hypersensitivity. Hydrogen sulfide (H2S) is an endogenous mediator inducing hyperalgesia through transient receptor potential ankyrin 1 (TRPA1) receptors located on nociceptors. We conducted this study to determine whether H2S elevates the sensitivity of rat CSLV afferents. In anesthetized, artificially ventilated rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a H2S donor) caused no significant changes in the baseline activity of CSLV afferents. However, the afferent responses to right atrial injection of capsaicin or phenylbiguanide and to lung inflation were all markedly potentiated after NaHS inhalation. By contrast, the inhalation of its vehicle or NaOH (with a similar pH to NaHS) failed to enhance the afferent responses. Additionally, the potentiating effect on the afferent responses was found in rats inhaling L-cysteine (a substrate of H2S synthase) that slowly releases H2S. The potentiating effect of NaHS on the sensitivity of CSLV afferents was completely blocked by pretreatment of HC-030031 (a TRPA1 receptor antagonist), but was unaffected by its vehicle. In isolated rat CSLV neurons, the perfusion of NaHS alone did not influence the intracellular Ca(2+) concentration but markedly potentiated the Ca(2+) transients evoked by capsaicin. The NaHS-caused effect was totally abolished by HC-030031 pretreatment. These results suggest that H2S induces a nonspecific sensitizing effect on CSLV fibers to both chemical and mechanical stimulation in rat lungs, which appears mediated through an action on the TRPA1 receptors expressed on the nerve endings of CSLV afferents.
... These lung afferent fibers, mainly C fibers and some A-␦ fibers, can be stimulated by a variety of chemical mediators (Lee and Pisarri, 2001;Lin and Lee, 2002;Ruan et al., 2005;Taylor-Clark and Undem, 2006;Yu et al., 2007) or inhaled irritants (Lai and Kou, 1998;Lee et al., 1989;Lee and Pisarri, 2001) leading to elicitation of various airway reflexes including coughing and bronchoconstriction (Lee and Pisarri, 2001;Widdicombe, 2003). Thus, the sensitization of CSLVA fibers was implicated in the pathogenesis of hyperreactive airway diseases such as chronic cough and asthma (Kuo and Lai, 2008;Lee and Undem, 2004;Widdicombe, 2003;Zhang et al., 2008a,b). ...
We investigated the effect of N-arachidonyl dopamine (NADA), an endogenous agonist of both transient receptor potential vanilloid 1 (TRPV1) and cannabinoid CB1 receptors, on the sensitivity of rat capsaicin-sensitive lung vagal afferent (CSLVA) fibers. In artificially ventilated rats, an intravenous infusion of NADA (400 microg/kg/ml, 0.5 ml/min for 2 min) mildly elevated the baseline CSLVA fiber activity, whereas it markedly potentiated CSLVA fiber responses to a right atrial injection of capsaicin or adenosine, and to lung inflation. The potentiating effect on CSLVA fiber sensitivity to an adenosine injection or lung inflation was blocked by capsazepine pretreatment (a TRPV1 receptor antagonist), but was unaffected by AM251 pretreatment (a CB1 receptor antagonist). In spontaneously breathing rats, a NADA infusion similarly potentiated the CSLVA fiber-mediated apneic response evoked by an adenosine injection, and this potentiating effect was also prevented by capsazepine pretreatment. We concluded that NADA at the dose tested non-specifically increases CSLVA fiber sensitivity to chemical and mechanical stimulation via activation of TRPV1 receptors.
... These lung afferent fibers can be stimulated by a variety of chemical mediators (30,34,40,45) or inhaled irritants (6,26,27,30), leading to elicitation of various airway reflexes including cough and bronchoconstriction (6,30). Thus the sensitization of CSLVA fibers by inflammatory mediators has been implicated in the pathogenesis of hyperreactive airway diseases such as chronic cough and asthma (31,50). ...
Anandamide (AEA), an arachidonic acid derivative produced during inflammatory conditions, is an endogenous agonist of both transient receptor potential vanilloid 1 (TRPV1) receptors and cannabinoid CB1 receptors. Sensitization of capsaicin-sensitive lung vagal afferent (CSLVA) fibers by chemical mediators is important in the pathogenesis of hyperreactive airway diseases. We investigated the effect of the intravenous infusion of AEA (2 mg x kg(-1) x ml(-1), 0.5 ml/min for 2 min) on the sensitivity of CSLVA fibers to chemical and mechanical stimulation in anesthetized rats. In artificially ventilated rats, AEA infusion only mildly elevated the baseline activity of CSLVA fibers. However, CSLVA fiber responses to right atrial injection of capsaicin, AEA, or adenosine and to lung inflation (tracheal pressure = 30 cmH(2)O) were all markedly potentiated during AEA infusion, which reverted 20 min after termination of the infusion. The potentiating effect on the sensitivity of CSLVA fibers to adenosine injection or lung inflation was completely blocked by pretreatment with capsazepine (a TRPV1 receptor antagonist) but was unaffected by pretreatment with AM281 (a CB1 receptor antagonist). In spontaneously breathing rats, right atrial injection of adenosine evoked an apneic response that is presumably mediated through CSLVA fibers. Similarly, the adenosine-evoked apneic response was potentiated during AEA infusion, and this potentiating effect was also completely prevented by pretreatment with capsazepine. These results suggest that AEA infusion at the dose tested produces a mild activation of TRPV1 receptors and this nonspecifically increases CSLVA fiber sensitivity to chemical and mechanical stimulation.
... Acute stimulation of peripheral chemoreceptors and nasal sensory afferents upregulates the cough reflex, while stimulation of bronchopulmonary C-fiber, cardiac, and abdominal afferent nerve endings may downregulate it. More recent studies have expanded on different phenotypes of sensory afferent fibers, including those associated with the cough reflex, on the basis of ganglionic location, ionic composition, specific chemosensitivity, mechanosensitivity, and neuropeptide content of the cell bodies of the afferent fibers and expression of receptors in their peripheral terminal endings (Lee and Undem 2004). It seems likely that the input signals monitored by the second-order neurons will vary still more with the differences in the phenotypes of the vagal synaptic partners. ...
Cough is the most common symptom for which individuals seek medical attention and spend health-care dollars. Despite the burden induced by cough, the current treatments for cough are only partially effective. Delineating the sites and mechanisms in the cough central network for changes in the cough reflex could lead to new therapeutic strategies and drug target sites for more effective treatments. The first synaptic target in the CNS for the cough-related sensory input is the second-order neurons in the nucleus tractus solitarius (NTS); these neurons reorganize the primary sensory information into a coherent output. The NTS neurons have been shown to undergo neuroplasticity under a variety of conditions, such as respiratory disorders, stress, and exposures to environmental pollutants. The NTS contains a rich innervation of substance P immunoreactive nerve terminals, suggesting that substance P might be important in altered cough reflex response. This chapter summarizes our current findings on the role of substance P in enhanced cough reflex as well as the potential NTS targets for the action of substance P.
... " Urge to cough " is one of the common respiratory discomforts and symptoms found in patients with various airway diseases, and its association with activation of bronchopulmonary C-fibers has been suggested (Canning et al. 2004; Mazzone et al. 2007). Because various physiological and pathophysiological mechanisms underlying acute and chronic coughs have been reviewed in details recently (Lee and Undem 2004; Page et al. 2004; Widdicombe and Undem 2006), they will not be included in the discussion here. ...
C-fibers represent the majority of vagal afferents innervating the airways and lung, and can be activated by inhaled chemical irritants and certain endogenous substances. Stimulation of bronchopulmonary C-fibers with selective chemical activators by either inhalation or intravenous injection evokes irritation, burning and choking sensations in the throat, neck and upper chest (mid-sternum region) in healthy human subjects. These irritating sensations are often accompanied by bouts of coughs either during inhalation challenge or when a higher dose of the chemical activator is administered by intravenous injection. Dyspnea and breathless sensation are not always evoked when these afferents are activated by different types of chemical stimulants. This variability probably reflects the chemical nature of the stimulants, as well as the possibility that different subtypes of C-fibers encoded by different receptor proteins are activated. These respiratory sensations and reflex responses (e.g., cough) are believed to play an important role in protecting the lung against inhaled irritants and preventing overexertion under unusual physiological stresses (e.g., during strenuous exercise) in healthy individuals. More importantly, recent studies have revealed that the sensitivity of bronchopulmonary C-fibers can be markedly elevated in acute and chronic airway inflammatory diseases, probably caused by a sensitizing effect of certain endogenously released inflammatory mediators (e.g., prostaglandin E(2)) that act directly or indirectly on specific ion channels expressed on the sensory terminals. Normal physiological actions such as an increase in tidal volume (e.g., during mild exercise) can then activate these C-fiber afferents, and consequently may contribute, in part, to the lingering respiratory discomforts and other debilitating symptoms in patients with lung diseases.
The parasympathetic nervous system is a key regulator of the human organism involved in the pathophysiology of various disorders through cholinergic mechanisms. In the lungs, acetylcholine (ACh) released by vagal nerve endings stimulates muscarinic receptors thereby increasing airway smooth muscle tone. Contraction of airway smooth muscle cells leads to increased respiratory resistance and dyspnea. An additional branch of the cholinergic system is the non-neuronal cholinergic system expressed in nearly all cell types present in the airways. Activation of this system may contribute to an increased cholinergic tone in the lungs, inducing pathophysiological processes like inflammation, remodeling, mucus hypersecretion and chronic cough. Selective muscarinic receptor antagonists specifically inhibit acetylcholine at the receptor inducing bronchodilation in patients with obstructive airway diseases. This paper reviews preclinical pharmacological research activities on anticholinergics including experimental models of asthma and chronic obstructive pulmonary disease, COPD. It discloses various options to follow up the non-neuronal cholinergic system as a novel drug target for the treatment of key aspects of obstructive airway diseases, in particular those of a chronic nature.
Chronic cough remains a challenge to many clinicians because there is often no diagnostic link to causation, and because indirect antitussives are largely ineffective. Chronic cough can also be a predominant symptom associated with many chronic respiratory diseases such as COPD, asthma and pulmonary fibrosis. Chronic cough itself does impair the quality of life and is associated with psychological impairment. The symptoms associated with chronic cough include persistent tickling or irritating sensation in the chest or throat, hoarse voice, dysphonia or vocal cord dysfunction. Currently, the clinical diagnosis of cough is associated with chronic cough caused by airway eosinophilic conditions such as asthma, gastrooesophageal reflux disease or post-nasal drip (or upper airway syndrome), which implies cause and effect, or with chronic cough associated with other diseases such as COPD, cancer or heart failure, that does not necessarily imply cause and effect. A recently-recognised category is idiopathic cough, with no associated or causative diagnosis. We suggest that there is a better label needed for chronic cough, that includes the common association with a hypersensitive cough response to tussive stimuli such as capsaicin or citric acid. This would invoke a hypersensitive syndrome, and there are good reasons to use a new label that would encompass the problem of chronic cough: the chronic 'cough hypersensitivity syndrome'. This would focus the problem on the cough symptomatology and lead to greater focus on understanding the mechanisms of cough sensitisation, with the ultimate aim of obtaining more effective antitussives.
A successful, systematic, anatomic, diagnostic protocol for evaluating patients with chronic cough was presented in 1981. To determine whether it was still valid, we prospectively evaluated, over a 22-month interval, 102 consecutive and unselected immunocompetent patients complaining of cough an average of 53 +/- 97 months (range, 3 wk to 50 yr). Utilizing the anatomic, diagnostic protocol modified to include prolonged esophageal pH monitoring (EPM), the causes of cough were determined in 101 of 102 (99%) patients, leading to specific therapy that was successful in 98%. Cough was due to one condition in 73%, two in 23%, and three in 3%. Postnasal drip syndrome was a cause 41% of the time, asthma 24%, gastroesophageal reflux (GER) 21%, chronic bronchitis 5%, bronchiectasis 4%, and miscellaneous conditions 5%. Cough was the sole presenting manifestation of asthma and GER 28 and 43% of the time, respectively. While history, physical examination, methacholine inhalational challenge (MIC), and EPM yielded the most frequent true positive results, MIC was falsely positive 22% of the time in predicting that asthma was the cause of cough. Laboratory testing was particularly useful in ruling out suspected possibilities. We conclude that the anatomic diagnostic protocol is still valid and that it has well-defined strengths and limitations.
1. Cough can (a) be an important defense mechanism to help clear excessive secretions and foreign material from airways; (b) be an important factor in the spread of infection; (c) maintain consciousness during potentially lethal arrhythmias and/or convert arrhythmias to more normal cardiac rhythms; and (d) present as one of the most common symptoms for which patients seek medical attention and spend health-care dollars. 2. Cough involves a complex reflex are that begins with the stimulation of an irritant receptor. Most receptors are probably located in the respiratory system; the existence of a discrete central cough center has not been demonstrated. Evidence to date suggests that the cough center is diffusely located in the medulla. An effective cough depends on the ability to achieve high gas flows and intrathoracic pressures, enhancing the removal of mucus adhering to the airway wall. Cough ineffectiveness may occur when respiratory muscles are weakened or when the surface adhesive properties of mucus are altered. While a variety of nonpharmacologic protussive treatment modalities may improve cough mechanics, clinical studies documenting improvement in patient morbidity and mortality are lacking. 3. It is the complications of cough that lead patients to seek medical attention. The most common complications are subjective perceptions of exhaustion and self-consciousness, and symptoms of insomnia, hoarseness, musculoskeletal pain: sweating, and urinary incontinence. The pressures produced during vigorous coughing can cause a variety of complications in nearly all organ systems. 4. The two categories of cough, are acute, lasting less than 3 weeks, and chronic, lasting 3 to 8 weeks or longer; they are not mutually exclusive (Grade II-2, III-3). Acute cough is most frequently due to the common cold (Grade III). Chronic cough is often simultaneously due to more than one condition (Grade II-2, II-3), but can be the sole clinical manifestation of asthma and gastroesophageal reflux disease (GERD) (Grade II-2). The most common causes of chronic cough in nonsmokers are postnasal drip syndrome (PNDS), asthma, and/or GERD (Grade II-2, II-3), whether or not the cough is described as dry or productive (Grade II-2). PNDS, asthma, and/or GERD are likely to be causes(s) of chronic cough approximately 100% of the time in nonsmokers who are not taking angiotensin-converting enzyme inhibitor (ACEI) drugs and who have normal or nearly normal chest radiographs showing no more than stable inconsequential scars (Grade II-2). 5. PNDS, either singly or in combination with other conditions, is the single most common cause of chronic cough for which patients seek medical attention (Grade II-2). The symptoms and signs of PNDS are nonspecific (Grade II-2); therefore, a definitive diagnosis of PNDS-induced cough cannot be made from history and physical examination alone. A favorable response to specific therapy for PNDS, with resolution of cough, is a crucial step in confirming that PNDS is present and is the etiology of cough. The combination of a first-generation antihistamine and a decongestant is considered to be the most consistently effective sole form of therapy in treating most patients with PNDS-induced cough not due to sinusitis (Grade II-2). In most patients, some improvement in cough will be seen within 1 week of initiation of therapy. Newer generation, relatively nonsedating antihistamines have been found ineffective in treating acute cough associated with the common cold (Grade I) and are not as effective as first-generation antihistamines in treating PNDS secondary to nonallergic conditions. The first-generation antihistamines should be used preferentially to treat PNDS-induced cough that is nonhistamine-mediated (Grade I, II-2). 6. Asthma is a common cause of chronic cough. A diagnosis of cough-variant asthma is suggested by the presence of airway hyperresponsiveness, and confirmed only when the cough resolves with asthma medications. The treatment of cough-variant asthma is the same as for asthma presenting with other symptoms. Inhaled medications prescribed for asthma may worsen the cough. 7. GERD can cause cough by aspiration, but it most likely causes chronic cough in patients with normal radiographs by a vagally mediated reflex mechanism (Grade II, II-2). When GERD is the cause of chronic cough, GI symptoms are often absent (Grade II-2). Twenty-four-hour esophageal pH monitoring is the most sensitive and specific test For GERD. In interpreting the test, it is important to assess the duration and frequency of reflux episodes, and the temporal relationship between reflux and cough episodes. Patients with normal standard reflux parameters may still have reflux as a cause of cough if a temporal relationship exists (Grade II-2). When 24-h esophageal pH monitoring cannot be done, an empiric trial of antireflux medication is appropriate when GERD is suspected as a cause of cough. However, if empiric treatment fails, GERD cannot be ruled out until objective studies are conducted (Grade III) because the empiric therapy may not have been intensive enough or medical therapy may have failed. Because minimum consistently effective therapy for GERD-induced chronic cough is not known, initial treatment should include diet and lifestyle changes in addition to drugs. Cough due to GERD has been reported to resolve with medical therapy in 70 to 100% of patients; mean time to recovery may take as long as 169 to 179 days (Grade II-2). Antireflux surgery may be considered after intensive medical therapy has been documented to have failed. 8. Cough is a principal feature of chronic bronchitis (CB) and its treatment should chiefly be directed to reduction of sputum production and airway inflammation (eg, by smoking cessation and removal of environmental irritants) (Grade II-2). While CB is among tie most frequent causes of chronic cough in the community, it is the cause in only about 5% in series of patients who Seek medical attention for cough. Ipratropium can decrease sputum production and cough (Grade I). Nonspecific cough suppressants should be avoided, and mucolytics are of uncertain benefit. Although the effectiveness systemic corticosteroids and antibiotics on cough have not been specifically studied, they are likely to be helpful in decreasing cough during exacerbations of COPD (Grade III). 9. Bronchiectasis is a cause of chronic cough in a relatively small number of patients: the diagnosis is established by clinical history, chest radiograph, high-resolution CT scan of the thorax, and cough disappearance with specific therapy. Cough associated with flares of the disease can be treated with a combination of chest physiotherapy, drugs to stimulate mucociliary clearance, and systemic antibiotics (Grade II-2). Inhaled antibiotics are recommended only in cystic fibrosis (CF) patients with bronchiectasis (Grade I). 10. Postinfectious cough is a diagnosis of exclusion; it should be considered when a patient complains only of cough after a respiratory tract infection and has normal chest radiograph. Postinfectious cough ultimately resolves over time; oral corticosteroids (Grade II-3), inhaled corticosteroids (Grade III), or ipratropium bromide (Grade II may attenuate the cough. 11. Coughs that develop for the first time and last for months in susceptible groups are suggestive of bronchogenic cat-cinema. Bronchogenic carcinoma is not a common cause of chronic cough (Grade II-2), and is very unlikely in never-smokers (Grade II-2). Present or prior cigarette smoking or occupational exposures increase the risk. Chest radiographs, sputum cytology, and flexible bronchoscopy are the most important initial tests for evaluating bronchogenic carcinoma as a cause of chronic cough. 12. Cough due to ACEIs is a class effect of these drugs and is not dose-related. The cough is typically nonproductive and is associated with an irritating, tickling, or scratchy sensation in the throat. ACEI-induced cough may appear hours to weeks or months after ACEI is started (Grade Iii. Because no laboratory test predicts who will have ACEI-induced cough, the diagnosis should be considered in any patient who has a cough while taking an ACEI (Grade IIII. Cough due to ACEIs will disappear or substantially improve within 4 weeks of discontinuing the drug (Grade I); definitive treatment of ACEI-induced cough is discontinuation of the drug. 13. Habit cough and psychogenic cough are diagnoses of exclusion (Grade III). The character of the cough (eg; honking or barking) is not diagnostically helpful in adults (Grade II-2). However, the pediatric literature suggests that honking and barking coughs are consistent with psychogenic cough (Grade III). After exclusion of other causes, psychological counseling and short-term antitussive therapy may be appropriate for psychogenic cough (Grade III). 14. Chronic interstitial pulmonary disease is an uncommon cause of cough; treatment of such cough is based on treatment of the underlying condition. If this treatment fails to resolve the cough, the cough may still be treatable with specific therapy for other comet-bid conditions. The most common causes of chronic cough should be investigated before antitussives are prescribed (Grade III). 15. In children, asthma, upper and lower respiratory tract infections, and GERD are the most common causes of acute and chronic cough. Less common causes of cough in children are congenital anomalies, aspiration and environmental exposures. The approach to managing chronic cough in children is similar to the approach in adults (Grade III). Diagnostic testing may be limited because many children are unable to cooperate in testing, and positive tests do not necessarily establish diagnosis or predict a favorable response to specific therapy (Grade III). A chest radiograph should be obtained in nearly all children with chronic cough to rule out lower respiratory tract and cardiac pathology (Grade III). A sweat test for CF may be considered when no clear etiology for cough is established. The recommended diagnostic approach to cough in children is history, physical examination, and determination of a most likely etiology (Grade III). 16. The cause of chronic cough can be determined in most patients; specific therapy will be successful in the majority of patients when chronic cough is evaluated in a systematic manner. Guidelines and algorithms for evaluating acute and chronic cough in immunocompetent and immunocompromised adults, and children, with diagnostic caveats, are presented in the body of this report. 17. Pharmacologic treatment of cough is either (a) antitussive, to prevent, control, or eliminate cough, or (b) protussive, to make cough more effective. Antitussive therapy is indicated when cough serves no useful function such as clearing the airways. Specific antitussive therapy is directed at the etiology or mechanism causing cough leg, cigarette smoking, postnasal drip). Nonspecific antitussive therapy is directed at the symptom rather than the etiology or mechanism. Because of the high probability of being able to determine the causes of cough and prescribe specific treatment that can be successful, there is a limited role for nonspecific antitussive treatment (Grade II-2, II-3). It is indicated (Grade III) when specific therapy has not had a chance to work or will not work leg, inoperable lung cancer). Protussive therapy is indicated when cough performs a useful function and needs to be encouraged leg, in bronchiectasis, CF). Although hypertonic saline, amiloride, and terbutaline by aerosol following chest physiotherapy have been shown to increase cough clearance (Grade I), or cough clearability in the case of amiloride, their clinical utility remains to be determined in future studies that assess short-term and long-term effects of these agents on the patient's condition. Hypertonic saline in CF appears promising.
This study tests the hypothesis that the bronchial hyperreactivity induced by chronic cigarette smoke (CS) exposure involves the increased expression and release of tachykinins and calcitonin gene-related peptide (CGRP) from afferent nerve fibers innervating the airways. In guinea pigs chronically exposed to CS (20 min twice daily for 14-17 d), peak response in total lung resistance to capsaicin (1.68 microg/kg, intravenously) was significantly greater than that evoked by the same dose of capsaicin in control (air-exposed) animals. This augmented response in CS-exposed animals was abolished after treatment with CP-99994 and SR-48968, the neurokinin (NK)-1 and NK-2 receptor antagonists, suggesting the involvement of tachykinins in chronic CS-induced airway hyperresponsiveness (AHR). Further, substance P (SP)-like immunoreactivity (LI) and CGRP-LI in the airway tissue were significantly greater in the CS animals than in the control animals. Finally, beta-preprotachykinin (PPT, a splice variant from the PPT A gene encoding tachykinins including SP and NKA) messenger RNA levels as measured by in situ hybridization histochemistry displayed a significant increase in jugular ganglion neurons but not in dorsal root or nodose ganglion neurons. These data suggest that chronic CS-induced AHR is related to an increase in SP synthesis and release in jugular ganglion neurons innervating the lungs and airways.
In the vagal-sensory system, neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) are synthesized nearly exclusively in small-diameter nociceptive type C-fiber neurons. By definition, these neurons are designed to respond to noxious or tissue-damaging stimuli. A common feature of visceral inflammation is the elevation in production of sensory neuropeptides. Little is known, however, about the physiological characteristics of vagal sensory neurons induced by inflammation to produce substance P. In the present study, we show that allergic inflammation of guinea pig airways leads to the induction of substance P and CGRP production in large-diameter vagal sensory neurons. Electrophysiological and anatomical evidence reveals that the peripheral terminals of these neurons are low-threshold Adelta mechanosensors that are insensitive to nociceptive stimuli such as capsaicin and bradykinin. Thus inflammation causes a qualitative change in chemical coding of vagal primary afferent neurons. The results support the hypothesis that during an inflammatory reaction, sensory neuropeptide release from primary afferent nerve endings in the periphery and central nervous system does not require noxious or nociceptive stimuli but may also occur simply as a result of stimulation of low-threshold mechanosensors. This may contribute to the heightened reflex physiology and pain that often accompany inflammatory diseases.
Immunohistochemistry was combined with retrograde labeling to characterize the effect of respiratory infection with Sendai virus on the number of Substance P/Neurokinin A-containing vagal afferent neurons whose cell bodies resided in the nodose ganglia and whose receptive fields were located in guinea pig trachea. Of the neurons labeled from the trachea of vehicle-inoculated guinea pigs, few stained positively for Substance P/Neurokinin A (approximately 3% of total labeled neurons). These neurons had small diameter cell bodies (mode = 16-20 microm), a feature of nociceptive-like C-fibers. Viral infection (Day 4 after inoculation) was associated with a significantly greater number of labeled neurons containing Substance P/Neurokinin A (approximately 20% of total labeled neurons). The majority of these had a relatively large cell body diameter (mode = 36- 40 microm), a feature of nonnociceptive afferent neurons. This induction appeared to be reversible as there were significantly fewer Substance P/Neurokinin A positive neurons in nodose ganglia from virus-inoculated guinea pigs at Day 28 after inoculation, a time point when virus-induced airway inflammation had all but resolved. These findings support the hypothesis that viral infection leads to a qualitative change in the vagal afferent innervation of guinea pig airways such that both small diameter nociceptive-like neurons and large diameter nonnociceptive neurons express tachykinins.
Cough is among the most common complaints for which patients seek medical attention. Consequently, enormous expenditures are made worldwide on prescription and non-prescription cough remedies. Multiple prospective studies have shown that specific antitussive therapy aimed at the underlying aetiology of cough is highly successful. The greatest current need therefore is for more effective nonspecific antitussive therapy, whose purpose is to suppress the cough reflex and provide symptomatic relief regardless of the underlying mechanism. Such therapy is particularly required for prolonged cough following upper respiratory tract infection, cough whose underlying aetiology is not easily treated, and idiopathic cough. Many areas of inquiry are currently ongoing that may lead to the development of novel and effective antitussive drugs.
Cough is associated with plasticity of putative cough afferent fibres, but whether plasticity in the brainstem network contributes is less well understood. A key site in the CNS network is the nucleus tractus solitarius (NTS), the first synaptic contact of the primary afferent fibres. We sought to develop a conscious guinea pig model to detect enhanced cough, to focus on the NTS as a potential site for plasticity, and to test a role for substance P in the NTS since the neuropeptide has been implicated in plasticity of the vagal afferent fibres. Guinea pigs were exposed to second-hand tobacco smoke (SHS) or filtered air (FA) from 1-6 weeks of age. At 5 weeks, cannulae were implanted in the NTS. At 6 weeks, either vehicle or a neurokinin 1 (NK-1) receptor antagonist was injected into the NTS of the conscious guinea pigs who were then exposed to citric acid aerosol. SHS exposure significantly enhanced citric acid-induced cough (56%, P<0.05), an effect attenuated by NTS NK-1 receptor blockade (P<0.05). The findings suggest that one possible mechanism for plasticity in cough is related to substance P effects in the NTS. Future studies will be required to investigate the possible mechanisms underlying the role of substance P as well as other mechanisms in generating SHS-induced cough.
Increased sensitivity of cough pathways has been demonstrated in numerous studies. The underlying mechanisms of this sensitization are largely unknown; however, a burgeoning body of evidence suggests that vagal primary afferent neurones that innervate the airways are likely to be involved. This plasticity includes changes in anatomy, neurochemistry and function. PGE2 is an example of an inflammatory mediator that increases responsiveness to tussive stimuli. Electrophysiological studies of neurone cell bodies isolated from afferent ganglia have revealed that prostanoids modulate the function of a variety of distinct ion channels including those that carry TTX-insensitive voltage-gated sodium currents, slow post-spike hyperpolarizations and a hyperpolarization-activated cation current. Mediator-induced modulation of the function of various voltage-gated currents operating at the peripheral terminals of airway afferent neurons would probably influence input from the airways into the central nervous system and contribute to the urge to cough and increased responsiveness to tussive stimuli.
Airway mucosal changes have been reported in chronic cough. In cough variant asthma and in eosinophilic bronchitis, there is evidence of eosinophil infiltration and sub-basement membrane thickening. In non-asthmatic cough, an increase of bronchoalveolar mast cells, mucosal mononuclear cells, and epithelial shedding have been reported. In a more recent study, evidence of airway wall remodelling has been observed in both asthmatic and non-asthmatic cough, such as an increase in sub-basement membrane thickness, goblet cell area, vascularity and vessel size. Smooth muscle area was increased in non-asthmatic coughers. Heightened cough sensitivity in non-asthmatic coughers was related to the degree of goblet cell hyperplasia and epithelial shedding. Cough reflex may be heightened by increased production of growth factors that might be further enhanced by the physical effects of cough on the airways. Mast cells may participate in the cough pathophysiology through release of growth factors as well as tussive mediators. Changes in the airway wall mucosa and epithelium may be important in the pathogenesis of cough receptor sensitization.
Coughing is a highly coordinated reflex that serves to protect the airways from a variety of potentially harmful stimuli. However, in airways disease the cough reflex threshold is lowered and coughing can become exaggerated and inappropriate. Excessive coughing not only affects an individual's quality of life, but may contribute to the pathology of the disease. Understanding the neural components of the cough reflex is essential for establishing new treatments for cough disorders. This review will summarize the current understanding of the afferent neural pathways mediating cough, including how interactions between airway afferent nerve fibre subtypes may modulate the cough reflex pathway and underlie the manifestation of cough disorders.