Lin Yi-Wen, Huang Chun-Yao, Shih Chun-Min, Tsai Yi-Ting, Lin Chin-Sheng, Lin Chih-Yuan, Li Chi-Yuan, Loh Shih-Hurng, Lin Cheng-Yen, Lin Feng-Yen, Tsai Chien-Sung
Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center Taipei, Taiwan.
Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital Taipei, Taiwan.
Am J Transl Res. 2018 Oct 15;10(10):3133-3149. eCollection 2018.
Cardiopulmonary bypass (CPB) induces cytokine production and causes postoperative monocytic inflammatory responses, which are associated with patient outcomes. In fact, monocytes regulate immunity through dynamic networks of survival and cellular apoptosis as well as thrombomodulin (TM)-associated differenciiation. Whether CPB affects the plasma level of eotaxin-2, a potent chemoattractant, or stimulates monocyte apoptosis among patients undergoing elective coronary artery bypass graft (CABG) surgery is also unknown. Thus, we aimed to investigate this subject and explored the feasible roles of TM in the phenomena. Firstly, clinical data showed that after CABG surgery, patients with lower plasma eotaxin-2 levels and higher TM expression levels exhibited reduced monocytic apoptosis, compared with that in patients with lower TM expression levels. Subsequently, to explore the hypothesis that eotaxin-2 induces monocytic apoptosis mediation by TM expression, we used monocytic THP-1 cells. The results indicated that treatment of THP-1 cells with eotaxin-2 markedly increased apoptosis. Knockdown of TM significantly increased, and overexpression of TM significantly reversed eotaxin-2-induced monocyte apoptosis, which was compared with that of only eotaxin-2-treated THP-1 cells. TM may regulate mitochondria-mediated apoptosis by its PI3K/Akt axis signaling pathway, which acts as an extinguisher for p53 and BAX activation, as well as limit further downstream release of cytochrome c and cleavage of caspases 8 and 3; we suggest that TM interacts with the cofilin cytoskeleton, which further supports a role for TM in eotaxin-induced THP-1 cell apoptosis. Based on clinical observation and study, we conclude that TM expression on monocytes is associated with their apoptosis. The above mechanisms may be relevant to clinical phenomena in which patients exhibiting more monocytic apoptosis are complicated by higher plasma levels of eotaxin-2 and lower TM expression on monocytes after CABG surgery.
体外循环（CPB）可诱导细胞因子产生并引发术后单核细胞炎症反应，这与患者预后相关。事实上，单核细胞通过生存和细胞凋亡的动态网络以及与血栓调节蛋白（TM）相关的分化来调节免疫。CPB是否会影响强效趋化因子嗜酸性粒细胞趋化因子-2的血浆水平，或刺激择期冠状动脉旁路移植术（CABG）患者的单核细胞凋亡也尚不清楚。因此，我们旨在研究这一课题，并探讨TM在这些现象中的可能作用。首先，临床数据显示，CABG术后，与TM表达水平较低的患者相比，血浆嗜酸性粒细胞趋化因子-2水平较低且TM表达水平较高的患者单核细胞凋亡减少。随后，为了探究嗜酸性粒细胞趋化因子-2通过TM表达诱导单核细胞凋亡介导作用的假说，我们使用了单核细胞THP-1细胞。结果表明，用嗜酸性粒细胞趋化因子-2处理THP-1细胞可显著增加细胞凋亡。TM基因敲低显著增加了细胞凋亡，而TM过表达则显著逆转了嗜酸性粒细胞趋化因子-2诱导的单核细胞凋亡，这与仅用嗜酸性粒细胞趋化因子-2处理的THP-1细胞相比。TM可能通过其PI3K/Akt轴信号通路调节线粒体介导的凋亡，该通路可作为p53和BAX激活的抑制剂，并限制细胞色素c的进一步下游释放以及半胱天冬酶8和3的裂解；我们认为TM与丝切蛋白细胞骨架相互作用，这进一步支持了TM在嗜酸性粒细胞趋化因子诱导的THP-1细胞凋亡中的作用。基于临床观察和研究，我们得出结论，单核细胞上的TM表达与其凋亡相关。上述机制可能与临床现象相关，即CABG术后表现出更多单核细胞凋亡的患者伴有血浆嗜酸性粒细胞趋化因子-2水平升高和单核细胞上TM表达降低。
