Kashiwagi Hitoshi, Yuhki Koh-Ichi, Imamichi Yoshitaka, Kojima Fumiaki, Kumei Shima, Higashi Tsunehito, Horinouchi Takahiro, Miwa Soichi, Narumiya Shuh, Ushikubi Fumitaka
Department of Pharmacology, Asahikawa Medical University, Asahikawa, Japan.
Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
TH Open. 2017 Oct 30;1(2):e122-e129. doi: 10.1055/s-0037-1607979. eCollection 2017 Jul.
The results of studies that were performed to determine whether cigarette smoking affects platelet function have been controversial, and the effects of nicotine- and tar-free cigarette smoke extract (CSE) on platelet function remain to be determined. The aim of this study was to determine the effect of CSE on platelet aggregation and to clarify the mechanism by which CSE affects platelet function. CSE inhibited murine platelet aggregation induced by 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U-46619), a thromboxane (TX) A receptor agonist, and that induced by collagen with respective IC values of 1.05 ± 0.14% and 1.34 ± 0.19%. A similar inhibitory action of CSE was also observed in human platelets. CSE inhibited arachidonic acid-induced TXA production in murine platelets with an IC value of 7.32 ± 2.00%. Accordingly, the inhibitory effect of CSE on collagen-induced aggregation was significantly blunted in platelets lacking the TXA receptor compared with the inhibitory effect in control platelets. In contrast, the antiplatelet effects of CSE in platelets lacking each inhibitory prostanoid receptor, prostaglandin (PG) I receptor and PGE receptor subtypes EP and EP , were not significantly different from the effects in respective control platelets. Among the enzymes responsible for TXA production in platelets, the activity of cyclooxygenase (COX)-1 was inhibited by CSE with an IC value of 1.07 ± 0.15% in an uncompetitive manner. In contrast, the activity of TX synthase was enhanced by CSE. The results indicate that CSE inhibits COX-1 activity and thereby decreases TXA production in platelets, leading to inhibition of platelet aggregation.
为确定吸烟是否影响血小板功能而开展的研究结果一直存在争议，不含尼古丁和焦油的香烟烟雾提取物（CSE）对血小板功能的影响仍有待确定。本研究的目的是确定CSE对血小板聚集的影响，并阐明CSE影响血小板功能的机制。CSE抑制了由血栓素（TX）A受体激动剂9,11-二脱氧-9α,11α-甲环氧-前列腺素-5Z,13E-二烯-1-酸（U-46619）诱导的小鼠血小板聚集以及由胶原诱导的血小板聚集，其半数抑制浓度（IC）值分别为1.05±0.14%和1.34±0.19%。在人血小板中也观察到了CSE类似的抑制作用。CSE抑制小鼠血小板中花生四烯酸诱导的TXA生成，IC值为7.32±2.00%。因此，与对照血小板中的抑制作用相比，在缺乏TXA受体的血小板中，CSE对胶原诱导的聚集的抑制作用明显减弱。相比之下，CSE在缺乏每种抑制性前列腺素受体、前列腺素（PG）I受体和前列腺素E受体亚型EP和EP的血小板中的抗血小板作用与各自对照血小板中的作用没有显著差异。在负责血小板中TXA生成的酶中，环氧合酶（COX）-1的活性被CSE以非竞争性方式抑制，IC值为1.07±0.15%。相反，TX合酶的活性被CSE增强。结果表明，CSE抑制COX-1活性，从而减少血小板中TXA的生成，导致血小板聚集受到抑制。
