Book Review

A SUPREME COURT JUSTICE Is APPOINTED. By David I. Danelski. Pp. 242. Random House, New York, New York, 1964

Voluntary suppression of cough induced by inhalation of capsaicin in healthy volunteers

AbstractThe aim of the present study was to investigate the voluntary suppression of cough in response to capsaicin inhalation in healthy volunteers, and to determine if the dose-response curve to capsaicin was significantly altered when volunteers were asked to suppress their cough response. The quantification of the degree of voluntary suppression of induced cough could provide a new methodology for screening antitussive agents as antitussives may act by influencing voluntary control of cough.Cough was induced by inhalation of capsaicin. Two challenges were given 5 min apart, each comprising five ascending concentrations of capsaicin (1 × 10−5m−3·33 × 10−4m). During one of these challenges the volunteer was allowed to cough when required, and during the other they were asked to suppress cough. These two conditions were given in random order. The cough response was recorded by means of a microphone with the integrated sound trace displayed on a chart recorder.A dose-response relationship was obtained on administration of ascending concentrations of capsaicin. In the non-suppressed challenge 2324 subjects coughed on inhalation of capsaicin (3·33 × 10−4m) with a mean number of coughs of 2·92 ± 0·34, whereas in the suppressed challenge only 324 subjects coughed with a mean number of coughs of 0·29 ± 0·18 (P < 0·001).These results demonstrate that cough induced by inhalation of capsaicin can be voluntarily suppressed. The mechanism of voluntary suppression of cough is discussed in relation to capsaicin challenge and the screening of antitussive medications

Modulation of transient receptor potential (TRP) channels by plant derived substances used in over-the-counter cough and cold remedies

Background: Upper respiratory tract infections (URTIs) impact all age groups and have a significant economic and social burden on society, worldwide. Most URTIs are mild and self-limiting, but due to the wide range of possible causative agents, including Rhinovirus (hRV), Adenovirus, Respiratory Syncytial Virus (RSV), Coronavirus and Influenza, there is no single and effective treatment. Over-the-counter (OTC) remedies, including traditional medicines and those containing plant derived substances, help to alleviate symptoms including inflammation, pain, fever and cough. Purpose: This systematic review focuses on the role of the major plant derived substances in several OTC remedies used to treat cold symptoms, with a particular focus on the transient receptor potential (TRP) channels involved in pain and cough. Methods: Literature searches were done using Pubmed and Web of Science, with no date limitations, using the principles of the PRISMA statement. The search terms used were ‘TRP channel AND plant compound’, ‘cough AND plant compound’, ‘cough AND TRP channels AND plant compound’, ‘cough AND P2X3 AND plant compound’ and ‘P2X3 AND plant compound’ where plant compound represents menthol or camphor or eucalyptus or turpentine or thymol.Results: The literature reviewed showed that menthol activates TRPM8 and may inhibit respiratory reflexes reducing irritation and cough. Menthol has a bimodal action on TRPA1, but inhibition may have an analgesic effect. Eucalyptus also activates TRPM8 and inhibits TRPA1 whilst down regulating P2X3, aiding in the reduction of cough, pain and airway irritation. Camphor inhibits TRPA1 and the activation of TRPM8 may add to the effects of menthol. Activation of TRPV1 by camphor, may also have an analgesic effect. Conclusions: The literature suggests that these plant derived substances have multifaceted actions and can interact with the TRP ‘cough’ receptors. The plant derived substances used in cough and cold medicines have the potential to target multiple symptoms experienced during a cold

Rhinovirus-16 increases ATP release in A549 cells without concomitant increase in production

Human rhinovirus (RV) is the most common cause of upper respiratory tract infection (URTI) and chronic airway disease exacerbation. Cough is present in 50–80% of URTI cases, accompanied by heightened airway hypersensitivity, yet no effective treatment currently exists for this infectious cough. The mechanism by which RV causes cough and airway hypersensitivity in URTI is still unknown despite recent advances in potential therapies for chronic cough.The effect of RV-16 infection (MOI 1) on intracellular ATP stores and ATP release in A549 alveolar epithelial cells was measured.RV-16 infection was found to significantly increase (by 50% from basal at 24 h) followed by decrease (by 50% from basal at 48 and 72 h) intracellular ATP concentrations, while increasing ATP release (from 72 h) independently of secondary stimulation. This effect was mimicked by intercellular adhesion molecule 1 receptor binding alone through ultraviolet-inactivated sham control. In addition, RV-16-infected cells became more sensitive to secondary stimulation with both hypotonic and isotonic solutions, suggestive of a hypersensitive response. These responses were not mediated via increased TRPV4 or pannexin-1 whole-cell expression as determined by Western blotting. Interestingly, the increased ATP release seen was not a result of increased mitochondrial ATP production.Thus, this is the first report demonstrating that RV-16 infection of airway epithelial cells causes hypersensitivity by increasing ATP release. These finding provide a novel insight into the process by which viruses may cause cough and identify a potential target for treatment of viral and post-viral cough

Palmitoylation of human proteinase-activated receptor-2 differentially regulates receptor-triggered ERK1/2 activation, calcium signalling and endocytosis

hPAR2 (human proteinase-activated receptor-2) is a member of the novel family of proteolytically activated GPCRs (G-protein-coupled receptors) termed PARs (proteinase-activated receptors). Previous pharmacological studies have found that activation of hPAR2 by mast cell tryptase can be regulated by receptor N-terminal glycosylation. In order to elucidate other post-translational modifications of hPAR2 that can regulate function, we have explored the functional role of the intracellular cysteine residue Cys361. We have demonstrated, using autoradiography, that Cys361 is the primary palmitoylation site of hPAR2. The hPAR2C361A mutant cell line displayed greater cell-surface expression compared with the wt (wild-type)-hPAR2-expressing cell line. hPAR2C361A also showed a decreased sensitivity and efficacy (intracellular calcium signalling) towards both trypsin and SLIGKV. In stark contrast, hPAR2C361A triggered greater and more prolonged ERK (extracellular-signal-regulated kinase) phosphorylation compared with that of wt-hPAR2 possibly through Gi, since pertussis toxin inhibited the ability of this receptor to activate ERK. Finally, flow cytometry was utilized to assess the rate and extent of receptor internalization following agonist challenge. hPAR2C361A displayed faster internalization kinetics following trypsin activation compared with wt-hPAR2, whereas SLIGKV had a negligible effect on internalization for either receptor. In conclusion, palmitoylation plays an important role in the regulation of PAR2 expression, agonist sensitivity, desensitization and internalization

ATP, an attractive target for the treatment of refractory chronic cough

Chronic cough is the most common complaint in respiratory clinics. Most of them have identifiable causes and some may respond to common disease-modifying therapies. However, there are many patients whose cough lacks effective aetiologically targeted treatments or remains unexplained after thorough assessments, which have been described as refractory chronic cough. Current treatments for refractory chronic cough are limited and often accompanied by intolerable side effects such as sedation. In recent years, various in-depth researches into the pathogenesis of chronic cough have led to an explosion in the development of drugs for the treatment of refractory chronic cough. There has been considerable progress in the underlying mechanisms of chronic cough targeting ATP, and ongoing or completed clinical studies have confirmed the promising antitussive efficacy of P2X3 antagonists for refractory cough. Herein, we review the foundation on which ATP target was developed as potential antitussive medications and provide an update on current clinical progresses

Lipid laden macrophages in respiratory disease

Letter to the edito

Chronic cough—the limitation and advances in assessment techniques

Accurate and consistent assessments of cough are essential to advance the understanding of the mechanisms of cough and individualised the management of patients. Considerable progress has been made in this work. Here we reviewed the currently available tools for subjectively and objectively measuring both cough sensitivity and severity. We also provided some opinions on the new techniques and future directions. The simple and practical Visual Analogue Scale (VAS), the Leicester Cough Questionnaire (LCQ), and the Cough Specific Quality of Life Questionnaire (CQLQ) are the most widely used self-reported questionnaires for evaluating and quantifying cough severity. The Hull Airway Reflux Questionnaire (HARQ) is a tool to elucidate the constellation of symptoms underlying the diagnosis of chronic cough. Chemical excitation tests are widely used to explore the pathophysiological mechanisms of the cough reflex, such as capsaicin, citric acid and adenosine triphosphate (ATP) challenge test. Cough frequency is an ideal primary endpoint for clinical research, but the application of cough counters has been limited in clinical practice by the high cost and reliance on aural validation. The ongoing development of cough detection technology for smartphone apps and wearable devices will hopefully simplify cough counting, thus transitioning it from niche research to a widely available clinical application