Acrolein relaxes mouse isolated tracheal smooth muscle via a TRPA1-dependent mechanism
Acrolein relaxes mouse isolated tracheal smooth muscle via a TRPA1-dependent mechanism
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DOI：
10.1016/j.bcp.2014.02.009
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发表时间：
2014-05-01
影响因子：
5.8
通讯作者：
Henry, Peter J.
中科院分区：
文献类型：
--
作者：
Cheah, Esther Y.;Burcham, Philip C.;Henry, Peter J.
气道感觉C纤维表达TRPA 1通道，该通道最近被确定为丙烯醛（烟雾中有毒且高度普遍的成分）的关键化学感觉受体。TRPA 1可能在引发丙烯醛诱导的一系列效应（包括咳嗽和神经源性炎症）中发挥中介作用。目前，尚不清楚丙烯醛诱导的TRPA 1激活是否产生其他气道效应，包括小鼠气道平滑肌的松弛。本研究的目的是研究丙烯醛对小鼠离体气管平滑肌张力的影响，并阐明丙烯醛作用的细胞和分子机制。在小鼠离体气管节段上进行了等长张力记录研究，以记录丙烯醛诱导的舒张反应。通过EIA测量松弛剂PGE（2）的释放，以检查其在响应中的作用。选择性拮抗剂/抑制剂的使用允许对这种放松反应的分子和细胞机制进行药理学表征。丙烯醛诱导小鼠离体气管段的剂量依赖性舒张反应。重要的是，这些舒张反应被TRPA 1拮抗剂AP-18和HC-030031、NK 1受体拮抗剂RP-67580和EP 2受体拮抗剂PF-04418948显著抑制，而被非选择性考克斯抑制剂吲哚美辛完全消除。丙烯醛还引起PGE（2）快速释放，HC-030031可抑制该释放。总之，丙烯醛在小鼠气道中诱导了一种新型支气管扩张反应。药理学研究表明，丙烯醛诱导的松弛可能涉及TRPA 1表达气道感觉C纤维，NK 1受体表达上皮细胞和EP 2受体表达气道平滑肌细胞之间的相互作用。(C)2014 Elsevier Inc. All rights reserved.
Airway sensory C-fibres express TRPA1 channels which have recently been identified as a key chemosensory receptor for acrolein, a toxic and highly prevalent component of smoke. TRPA1 likely plays an intermediary role in eliciting a range of effects induced by acrolein including cough and neurogenic inflammation. Currently, it is not known whether acrolein-induced activation of TRPA1 produces other airway effects including relaxation of mouse airway smooth muscle. The aims of this study were to examine the effects of acrolein on airway smooth muscle tone in mouse isolated trachea, and to characterise the cellular and molecular mechanisms underpinning the effects of acrolein. Isometric tension recording studies were conducted on mouse isolated tracheal segments to characterise acrolein-induced relaxation responses. Release of the relaxant PGE(2) was measured by EIA to examine its role in the response. Use of selective antagonists/inhibitors permitted pharmacological characterisation of the molecular and cellular mechanisms underlying this relaxation response. Acrolein induced dose-dependent relaxation responses in mouse isolated tracheal segments. Importantly, these relaxation responses were significantly inhibited by the TRPA1 antagonists AP-18 and HC-030031, an NK1 receptor antagonist RP-67580, and the EP2 receptor antagonist PF-04418948, whilst completely abolished by the non-selective COX inhibitor indomethacin. Acrolein also caused rapid PGE(2) release which was suppressed by HC-030031. In summary, acrolein induced a novel bronchodilator response in mouse airways. Pharmacologic studies indicate that acrolein-induced relaxation likely involves interplay between TRPA1-expressing airway sensory C-fibres, NK1 receptor-expressing epithelial cells, and EP2-receptor expressing airway smooth muscle cells. (C) 2014 Elsevier Inc. All rights reserved.