Airway sensory neurobiology and TRP channels in chronic cough: mechanisms, cough hypersensitivity, and therapeutic translation.

AIMS: Chronic cough is increasingly viewed as a heterogeneous clinical syndrome associated with cough hypersensitivity, not simply a symptom defined by duration. This review examines key mechanisms in chronic cough, the reasons why mechanistic insights have translated poorly into therapy, and future directions involving patient stratification and biomarkers.

MATERIALS AND

METHODS

We reviewed and summarized mechanistic, preclinical, and translational studies on TRPA1, TRPV1, TRPV4, and TRPM8 channels, focusing on peripheral and central mechanisms and on how these findings relate to clinical development.

KEY FINDINGS: TRP channels are multimodal sensors in airway sensory nerves and epithelial cells. They respond to irritants, temperature changes, mechanical stress, osmotic stimuli, and inflammatory mediators. Their activation can drive cation influx, neuronal depolarization, neuropeptide release, and ATP-P2X3 signaling, thereby increasing cough reflex sensitivity and neurogenic inflammation. The translational evidence differs across TRP subtypes. TRPV1 has relatively strong support from mechanistic studies and human cough challenge work, whereas TRPA1 is biologically plausible but still has limited human evidence. Evidence for TRPV4 and TRPM8 is more sparse, with TRPV4 mainly linked to ATP-purinergic signaling and TRPM8 less clearly defined in chronic cough. To date, TRP-channel antagonists have produced limited and inconsistent reductions in spontaneous cough frequency.

SIGNIFICANCE: These findings suggest that blocking peripheral TRP channels alone may not be enough to control cough hypersensitivity. Future studies should connect patient selection with biomarkers and clinically relevant endpoints.