title: Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs.
abstract: 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 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 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 GF-109203X, 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, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.
authors.affiliation: Center of Excellence for the study of Inflammation, Dept. of Clinical & Experimental Medicine, Pharmacology Section, Univ. of Ferrara, 44100 Ferrara, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Gatti
authors.forename: Eunice
authors.initials: E
authors.lastname: Andre
authors.forename: Silvia
authors.initials: S
authors.lastname: Amadesi
authors.forename: Thai Q
authors.initials: TQ
authors.lastname: Dinh
authors.forename: Axel
authors.initials: A
authors.lastname: Fischer
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Selena
authors.initials: S
authors.lastname: Harrison
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Marcello
authors.initials: M
authors.lastname: Trevisani
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D019343:Citric Acid / Q000009:adverse effects; D003371:Cough / Q000139:chemically induced / Q000503:physiopathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004224:Diterpenes / Q000009:adverse effects; D006168:Guinea Pigs / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009475:Neurons, Afferent / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000502:physiology*; D012462:Saline Solution, Hypertonic / Q000009:adverse effects; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000502:physiology*; D014357:Trypsin / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D004224:Diterpenes; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D044464:Receptor, PAR-2; D012462:Saline Solution, Hypertonic; D013449:Sulfonamides; D050916:TRPV Cation Channels; D019343:Citric Acid; C024353:resiniferatoxin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D014357:Trypsin; C071423:capsazepine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002211:Capsaicin; D007213:Indomethacin