当前位置: X-MOL 学术Front. Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Thrombomodulin as a Physiological Modulator of Intravascular Injury
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2020-08-19 , DOI: 10.3389/fimmu.2020.575890
Kanako Watanabe-Kusunoki , Daigo Nakazawa , Akihiro Ishizu , Tatsuya Atsumi

Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelial- and blood cell-derived damage-associated molecular patterns (DAMPs), and DAMP-mediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects.



中文翻译:

血栓调节蛋白作为血管内损伤的生理调节剂

主要在内皮上表达的血栓调节蛋白(TM)通过调节凝血系统在维持血管稳态中起着重要作用。血管内损伤和炎症是复杂的生理过程,由受损的内皮介导的促凝血信号,坏死的内皮细胞和血细胞衍生的损伤相关分子模式(DAMPs)以及DAMP介导的炎症诱导。在内皮损伤后的高凝状态期间,通过内皮成分的蛋白水解切割将TM释放到血管内空间。Recombinant TM(rTM)在临床上适用于弥散性血管内凝血的患者,可防止组织损伤。最近的研究表明,rTM通过各种分子机制在止血方面起炎症调节剂的作用。更具体地说,rTM中和DAMPs,包括组蛋白和高迁移率基盒1(HMGB1),抑制补体系统的过度活化,在生理上保护内皮,并影响先天和后天免疫力。中性粒细胞胞外诱捕器(NETs)通过将血小板编排为先天免疫系统的一部分来封闭感染性侵袭者,从而促进免疫血栓形成,但是过度的免疫血栓形成会导致血管内损伤。但是,rTM可以直接和间接调节NET的形成。此外,rTM与获得性免疫的介质相互作用,以解决血管炎症。至今,rTM在包括血栓性微血管病,无菌性炎性疾病,自身免疫性疾病和败血症在内的各种实验模型中均显示出抑制炎症的良好功效。因此,rTM有望成为通过多效性效应调节血管内损伤的新型工具。

更新日期:2020-09-16
down
wechat
bug