Abstract：
Exposure to aerosolized citric acid (CA, 150 mM) and prostaglandin E2 (PGE2, 0.43 mM) for 10 min in guinea pigs reportedly produces the distinct cough patterns (Type I vs. II) and ventilatory responses (long-lasting hyperventilation vs. brief tachypnea) even though triggering the same cough numbers. Type I and II coughs are primarily mediated by activation of TRPV1 and EP3 receptors (a PGE2 receptor) of vagal C-fibers respectively. Substance P (SP) and neurokinin A (NKA) released by vagal pulmonary sensory fibers peripherally are capable of affecting CA-induced cough and ventilation via preferentially activating neurokinin 1 and 2 receptors (NK1R and NK2R) respectively. This study aimed to define the impacts of CA- and PGE2-exposure on pulmonary SP and NKA levels and the roles of NK1R and NK2R in modulating CA- and PGE2-evoked cough and ventilatory responses. In unanesthetized guinea pigs, we determined: (1) pulmonary SP and NKA contents induced by the CA- or PGE2-exposure; (2) effects of CP-99994 and SR-48968 (a NK1R and a NK2R antagonist respectively) given by intraperitoneal injection (IP) or aerosol inhalation (IH) on the CA- and PGE2-evoked cough and ventilatory responses; and (3) immunocytochemical expressions of NK1R/NK2R in vagal C-neurons labeled by TRPV1 or EP3 receptors. We found that CA- and PGE2-exposure evoked Type I and II cough respectively associated with different degrees of increases in pulmonary SP and NKA. Applications of CP-99994 and SR-48968 via IP and IH efficiently suppressed the cough responses to CA with less impact on the cough response to PGE2. These antagonists inhibited or blocked the ventilatory response to CA and caused hypoventilation in response to PGE2. Moreover, NK1R and NK2R were always co-expressed in vagal C-neurons labeled by TRPV1 or EP3 receptors. These results suggest that SP and NKA endogenously released by CA- and PGE2-exposure play important roles in generating the cough and ventilatory responses to CA and PGE2, at least in part, via activation of NK1R and NK2R expressed in vagal C-neurons (pulmonary C-neurons).
摘要：
暴露于雾化柠檬酸(CA，据报道，豚鼠中150mM）和前列腺素E2（PGE2，0.43mM）持续10分钟会产生不同的咳嗽模式（I型与II)和通气反应(持久换气过度与短暂的呼吸急促），即使触发相同的咳嗽数字。I型和II型咳嗽主要分别由迷走神经C-纤维的TRPV1和EP3受体(PGE2受体)的活化介导。迷走神经肺感觉纤维外周释放的P物质（SP）和神经激肽A（NKA）能够分别通过优先激活神经激肽1和2受体（NK1R和NK2R）影响CA引起的咳嗽和通气。本研究旨在确定CA和PGE2暴露对肺SP和NKA水平的影响，以及NK1R和NK2R在调节CA和PGE2诱发的咳嗽和通气反应中的作用。在未麻醉的豚鼠中，我们确定：（1）由CA或PGE2暴露诱导的肺SP和NKA含量；（2）通过腹膜内注射（IP）或雾化吸入（IH）给予CP-99994和SR-48968（分别为NK1R和NK2R拮抗剂）对CA和PGE2引起的咳嗽和通气反应的影响；（3）NKVagaR-1VagR或Vagal标记的NKcy我们发现CA和PGE2暴露分别引起I型和II型咳嗽，与肺SP和NKA的不同程度增加有关。CP-99994和SR-48968经由IP和IH的应用有效地抑制了对CA的咳嗽反应,而对对PGE2的咳嗽反应的影响较小。这些拮抗剂抑制或阻断了对CA的通气反应，并导致对PGE2的通气不足。此外，NK1R和NK2R总是在由TRPV1或EP3受体标记的迷走神经C-神经元中共表达。这些结果表明，通过CA和PGE2暴露内源性释放的SP和NKA在产生对CA和PGE2的咳嗽和通气反应中起重要作用，至少部分地，通过激活迷走神经C神经元（肺C神经元）中表达的NK1R和NK2R。
