Gatti Raffaele, Andre Eunice, Amadesi Silvia, Dinh Thai Q, Fischer Axel, Bunnett Nigel W, Harrison Selena, Geppetti Pierangelo, Trevisani Marcello
Center of Excellence for the study of Inflammation, Dept. of Clinical & Experimental Medicine, Pharmacology Section, Univ. of Ferrara, 44100 Ferrara, Italy.
J Appl Physiol (1985). 2006 Aug;101(2):506-11. doi: 10.1152/japplphysiol.01558.2005. Epub 2006 Apr 20.
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.
咳嗽反应阈值降低常伴随慢性气道炎症性疾病。然而，慢性炎症导致咳嗽阈值降低的机制尚不清楚。包括辣椒素、树脂毒素和柠檬酸在内的刺激剂通过激活瞬时受体电位香草酸受体1（TRPV1）在人和实验动物中引发咳嗽。蛋白酶激活受体-2（PAR2）的激活在炎症中起作用，并通过PKC依赖途径使培养的感觉神经元中的TRPV1敏感化。在此，我们研究了PAR2激活是否会加剧豚鼠中TRPV1依赖的咳嗽，以及蛋白激酶是否参与PAR2诱导的咳嗽调节。雾化的PAR2激动剂（PAR2激活肽和胰蛋白酶）本身不会引起任何咳嗽。然而，它们增强了柠檬酸和树脂毒素诱导的咳嗽，TRPV1受体拮抗剂辣椒平可完全阻止这种作用。相反，高渗盐水诱导的咳嗽（一种以TRPV1非依赖方式引发咳嗽的刺激）不受雾化PAR2激动剂的影响。PKC抑制剂GF-109203X、PKA抑制剂H-89和环氧化酶抑制剂吲哚美辛不影响TRPV1激动剂诱导的咳嗽，但减弱了PAR2激动剂引起的这种反应的增强。总之，PAR2刺激通过激活包括PKC、PKA和前列腺素释放在内的多种机制加剧TRPV1依赖的咳嗽。PAR2激活通过使初级感觉神经元中的TRPV1敏感化，可能在某些气道炎症性疾病如哮喘和慢性阻塞性肺疾病中观察到的咳嗽加剧中起作用。
