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1 Center of Excellence for the study of Inflammation, Pharmacology section, University of Ferrara, Ferrara, Italy
2 Surgery and Physiology, University of California, San Francisco, California, United States
3 Allergie-Zentrum Charite, Charite-Universitatsmedizin Berlin, Berlin, Germany
4 Critical Care Medicine and Surgery, University of Florence, Florence, Italy
* To whom correspondence should be addressed. E-mail: tvm{at}unife.it.
A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including, capsaicin, resiniferatoxin and citric acid elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease activated receptor 2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a protein kinase C (PKC)-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide (AP) and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist, capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor, GF109203X, the PKA inhibitor, H-89, and the cyclooxygenase inhibitor, indomethacin, did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA and prostanoid release. PAR2 activation, likely by an indirect mechanism of sensitization of TRPV1, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.
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