Evidence for acid-sensing ion channel 3 (ASIC3) involvement in cough resulting from aspiration of gastric fluid.

Summary

In guinea-pig models, acidic gastric fluid and citric acid provoke cough by activating vagal airway afferents that express ASIC1/2/3. Pharmacologic ASIC inhibition (diminazene, diclofenac) blocked acid-evoked cough and afferent discharge, whereas TRPV1 blockade did not, implicating ASIC channels—particularly ASIC3—in aspiration-evoked cough and potentially in protection against aspiration pneumonia and ARDS.

Key Findings

• Acidic gastric fluid and citric acid induce cough and activate vagal airway afferents in guinea-pigs.
• Vagal afferent neurons involved in cough express ASIC1, ASIC2 and ASIC3 mRNA.
• ASIC inhibitors (diminazene, diclofenac) block acid-evoked cough and afferent discharge; TRPV1 blockade does not.

Clinical Implications

Suggests targeting ASIC-mediated pathways could enhance airway protective reflexes or identify patients at risk of silent aspiration; translational steps required before clinical use. Supports evaluation of cough reflex integrity in aspiration-risk patients and exploration of ASIC modulators.

Limitations

• Animal model findings may not fully translate to human airway neurophysiology or clinical aspiration syndromes.
• Pharmacologic inhibitors used are not ASIC3-specific; genetic loss-of-function validation (e.g., ASIC3 knockout) was not reported.

Future Directions

Translate findings to human tissues/neurons, test ASIC3-specific genetic models, and evaluate ASIC modulation in preclinical models of aspiration pneumonia and ARDS to assess therapeutic potential.