Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies

Abstract

Rationale: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets.Objectives: To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms.Methods: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model. Measurements and Main Results:Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E 2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E 2 were decreased by CS exposure.Conclusions: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease.Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).

The emerging role of transient receptor potential channels in chronic lung disease

“…Similar data have been generated in a rat model of asthma with an increase in TRPV1-expressing neurons in the nodose ganglia [45]. In a recent study, patients with COPD had increased cough responses to capsaicin, but reduced responses to PGE 2 compared with healthy volunteers [35]. Consistent with these findings, capsaicin caused a greater number of coughs in cigarette smoke-exposed guinea pigs than in control animals; similar increased responses to capsaicin were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia, although in contrast, PGE 2 responses were decreased by cigarette smoke exposure.…”

“…Interestingly, the threshold for provoking cough by capsaicin (often referred to as the C2 or the C5: concentration of capsaicin required to elicit two or five coughs, respectively) has been found to be lowered in various populations of COPD [33][34][35], asthmatic [33, [35][36][37][38][39], IPF [40] and chronic idiopathic cough [35,41] patients who have chronic cough compared to healthy controls. These data imply that TRPV1 function is increased in a disease setting.…”

“…Interestingly, the same study showed that different patient groups (COPD, healthy smokers, refractory chronic cough and asthma) demonstrated differing patterns of cough response to capsaicin, PGE 2 and citric acid. The different profiles of cough responses support the concept of disease-specific neurophenotypes in chronic lung disease [35]. Interestingly, it is still not clear whether increased sensitivity to various challenge agents acting on particular GPCRs or ion channel targets informs us regarding whether a particular intervention will be useful in a particular disease setting.…”

An update and systematic review on drug therapies for the treatment of refractory chronic cough

“…Stratifying patient groups for disease phenotype is also important. Most cough animal studies use healthy animals to test antitussives in cough challenge tests or do not generate appropriate disease states and treat cohorts with homogeneity [82]. Further, rats and mice do not cough and guinea pigs while being the preferred cough animal model have features driving cough that may not be critical in humans [54].…”

“…Few attempts have been made to generate models displaying the features of CHS [83] or the urge to cough [84], which likely drives behavioral coughing. When specific efforts are made disease-specific neurophenotypes can be encapsulated in animal models and have shown consistent outcomes with human phenotypes [82]. …”