Hepatic Surgical Stress Promotes Systemic Immunothrombosis That Results in Distant Organ Injury
Hepatic Surgical Stress Promotes Systemic Immunothrombosis That Results in Distant Organ Injury
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肝脏手术应激促进全身免疫血栓形成，导致远处器官损伤
DOI：
10.3389/fimmu.2020.00987
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发表时间：
2020-05
影响因子：
7.3
通讯作者：
Huang Hai
中科院分区：
文献类型：
--
作者：
Zhang Hongji;Goswami Julie;Varley Patrick;van der Windt Dirk J.;Ren Jinghua;Loughran Patricia;Yazdani Hamza;Neal Matthew D.;Simmons Richard L.;Zhang Jinxiang;Tsung Allan;Huang Hai
先天免疫可在血栓形成过程中启动血小板活化，称为免疫血栓形成。中性粒细胞形成中性粒细胞胞外陷阱(Net)，已被证明直接与血小板相互作用，并在各种感染和无菌炎症环境中发挥促凝作用。由缺血/再灌注(I/R)损伤引发的肝脏外科应激对远隔器官有广泛的全身影响。然而，这种远程损伤现象的机制还不是很清楚。在此，我们试图确定Nets在肝脏I/R局部炎性损伤后引起全身免疫血栓形成和远端器官损伤中的作用。术后血栓弹性图显示，在接受肝切除的患者中，凝块形成速度(α角)显著增加，凝块形成时间(R-time)缩短，表明术后处于高凝状态。小鼠肝脏I/R后，循环中的血小板活化和血小板-中性粒细胞聚集率显著增加。肝I/R后远隔器官如肺、肾等微血管内可见Net和富含血小板的微血栓，DNase抑制Net后免疫血栓和脏器损伤明显减少。去除血小板表面TLR4可抑制Net诱导的血小板活化，但对Net的形成无影响。此外，与对照组相比，血小板特异性TLR4KO小鼠在肝脏I/R后显著减少了远隔器官的损伤，降低了循环中的血小板活化和血小板-中性粒细胞聚集。这些数据证实，在急性局部炎症过程后，净激活的血小板可导致全身促凝状态，从而导致免疫血栓形成的远程器官损伤。
Innate immunity can initiate platelet activation during the development of thrombosis through a process, termed immunothrombosis. Neutrophils form neutrophil extracellular traps (NETs) that have been shown to interact directly with platelets and play pro-coagulant roles in a variety of infectious and sterile inflammatory settings. Hepatic surgical stress initiated by ischemia/reperfusion (I/R) injury has wide systemic consequences on distant organs. However, the mechanisms of this remote injury phenomenon are not well-understood. Here, we sought to determine the role of NETs in causing systemic immunothrombosis and distant organ injury following a local inflammatory insult with liver I/R. Postoperative thromboelastographic revealed that the speed of clot formation (alpha-angle) was significantly increased whereas time to clot formation (R-time) were decreased by in patients undergoing liver resection, indicating a hypercoagulable state after surgery. In mice subjected to liver I/R, circulating platelet activation and platelet-neutrophil aggregates were significantly increased. Injured distant organs such as the lung and kidney displayed NETs and platelet-rich micro-thrombi in the microvasculature following liver I/R. The immune-thrombi and organ damage were dramatically decreased when NETs were inhibited by DNase treatment. Depletion of Tlr4 on platelets limited NET-induced activation of platelets but had no effect on NET formation. Furthermore, platelet-specific TLR4 KO mice had significantly reduced distant organ injury with decreased circulating platelet activation, platelet-neutrophil aggregates following liver I/R in comparison to their control counterparts. These data establish that after an acute local inflammatory process, NET-activated platelets can lead to a systemic pro-coagulant state with resultant remote organ injury by immunothrombosis.
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影响因子：
5.5
作者：
Stoiber W;Obermayer A;Steinbacher P;Krautgartner WD
通讯作者：
Krautgartner WD
中性粒细胞胞外陷阱促进手术应激后肝转移的发生和进展。
影响因子：
11.2
作者：
Tohme S;Yazdani HO;Al-Khafaji AB;Chidi AP;Loughran P;Mowen K;Wang Y;Simmons RL;Huang H;Tsung A
通讯作者：
Tsung A
DOI：
10.1038/nrgastro.2012.225
发表时间：
2013-02
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Kirchner T;Möller S;Klinger M;Solbach W;Laskay T;Behnen M
通讯作者：
Behnen M
影响因子：
3
作者：
Louis, Scott G.;Barton, Jeffrey S.;Billingsley, Kevin G.
通讯作者：
Billingsley, Kevin G.