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

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Τίτλος: Airway sensory neurobiology and TRP channels in chronic cough: mechanisms, cough hypersensitivity, and therapeutic translation.
Συγγραφείς: Yang X; Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China. Electronic address: yangxinyue@mail.nwpu.edu.cn., Duan X; Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China. Electronic address: duanxianglong@nwpu.edu.cn.
Πηγή: Life sciences [Life Sci] 2026 Sep 15; Vol. 401, pp. 124499. Date of Electronic Publication: 2026 May 28.
Τύπος έκδοσης: Journal Article; Review
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0375521 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0631 (Electronic) Linking ISSN: 00243205 NLM ISO Abbreviation: Life Sci Subsets: MEDLINE
Imprint Name(s): Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.
Ιατρικοί όροι (MeSH): Chronic Cough*/physiopathology , Chronic Cough*/metabolism , Chronic Cough*/drug therapy , Transient Receptor Potential Channels*/metabolism , Cough*/physiopathology , Cough*/metabolism, TRPV Cation Channels/metabolism ; Sensory Receptor Cells/metabolism ; Humans ; Animals ; Chronic Disease
Περίληψη: 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.
(Copyright © 2026. Published by Elsevier Inc.)
Competing Interests: Declaration of competing interest We, the undersigned authors of the review article entitled “Airway sensory neurobiology and TRP channels in chronic cough: mechanisms, cough hypersensitivity, and therapeutic translation” submitted to Life Sciences, hereby declare that we have no financial, personal, or professional relationships with any individuals or organizations that could inappropriately influence or bias the content of this work.
Contributed Indexing: Keywords: Airway Hyperresponsiveness; Chronic cough; Sensory neurons; Transient receptor potential (TRP) channels
Substance Nomenclature: 0 (Transient Receptor Potential Channels)
0 (TRPV Cation Channels)
Entry Date(s): Date Created: 20260529 Date Completed: 20260702 Latest Revision: 20260702
Update Code: 20260703
DOI: 10.1016/j.lfs.2026.124499
PMID: 42214607
Βάση Δεδομένων: MEDLINE
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  Data: Airway sensory neurobiology and TRP channels in chronic cough: mechanisms, cough hypersensitivity, and therapeutic translation.
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  Data: &lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Yang+X%22&quot;&gt;Yang X&lt;/searchLink&gt;; Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi&#39;an, Shaanxi, 710072, China. Electronic address: yangxinyue@mail.nwpu.edu.cn.&lt;br /&gt;&lt;searchLink fieldCode=&quot;AU&quot; term=&quot;%22Duan+X%22&quot;&gt;Duan X&lt;/searchLink&gt;; Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi&#39;an, Shaanxi, 710072, China. Electronic address: duanxianglong@nwpu.edu.cn.
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  Data: 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.&lt;br /&gt;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.&lt;br /&gt;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.&lt;br /&gt;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.&lt;br /&gt; (Copyright &#169; 2026. Published by Elsevier Inc.)
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  Data: Declaration of competing interest We, the undersigned authors of the review article entitled “Airway sensory neurobiology and TRP channels in chronic cough: mechanisms, cough hypersensitivity, and therapeutic translation” submitted to Life Sciences, hereby declare that we have no financial, personal, or professional relationships with any individuals or organizations that could inappropriately influence or bias the content of this work.
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        Value: 10.1016/j.lfs.2026.124499
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        Text: English
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        Type: general
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        Type: general
      – SubjectFull: Cough physiopathology
        Type: general
      – SubjectFull: Cough metabolism
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