Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, PR China; Key Laboratory of Non-resolving Inflammation and Cancer of Hunan Province, The 3rd Xiangya Hospital, Central South University, Changsha, PR China.
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, PR China; State Key Laboratory of Medical Genetics, School of Biological Science and Technology, Central South University, Changsha, Hunan Province, PR China.
Thromb Res. 2019 Jun;178:26-33. doi: 10.1016/j.thromres.2019.03.019. Epub 2019 Mar 28.
Sepsis is frequently complicated by disseminated intravascular coagulation (DIC), which promotes multiple organ dysfunctions and significantly increase the mortality of patients with sepsis. How bacteria cause DIC is not fully understood. Outer membrane vesicles (OMVs) are membrane-enclosed microvesicles released by variety of bacteria. The aim of this study is to determine whether OMVs contribute to the pathogenesis of DIC during bacterial infection.
Wild-type (WT) or Toll-like receptor 4 (TLR4) knock-out mice were intraperitoneally injected with purified Escherichia coli (E.coli) derived OMVs, or with either wild type E.coli or E.coli with genetic deletion of ypjA, which is critical for OMV's production. Blood samples, liver and lung tissues were collected. The development of DIC was assessed in terms of the occurrence of coagulopathy, the thrombi deposition in livers and lungs, the multiple organ injuries, and the lethality.
Genetic deletion of ypjA significantly attenuated E.coli-induced coagulopathy, intravascular thrombi deposition, multiple organ injuries and mortality, whereas injection of purified E.coli-derived OMVs resulted in the development of DIC in a TLR4-dependent manner.
OMVs importantly contribute to the pathogenesis of DIC during Gram-negative bacterial infection. These findings might open a new avenue to prevent infection-associated coagulopathy by targeting OMVs production.
败血症常伴有弥散性血管内凝血（DIC），这会促进多个器官功能障碍，并显著增加败血症患者的死亡率。但目前尚不完全清楚细菌如何导致 DIC。外膜囊泡（OMVs）是多种细菌释放的一种膜包裹的微囊泡。本研究旨在确定 OMVs 是否有助于细菌感染时 DIC 的发病机制。
野生型（WT）或 Toll 样受体 4（TLR4）敲除小鼠经腹腔内注射纯化的大肠杆菌（E.coli）来源的 OMVs，或注射野生型 E.coli 或 E.coli 中 ypjA 的基因缺失株，ypjA 对 OMV 的产生至关重要。收集血液样本、肝脏和肺组织。通过凝血功能障碍的发生、肝脏和肺部血管内血栓形成、多器官损伤和死亡率来评估 DIC 的发展。
ypjA 的基因缺失显著减弱了 E.coli 诱导的凝血功能障碍、血管内血栓形成、多器官损伤和死亡率，而纯化的 E.coli 衍生的 OMVs 的注射则以 TLR4 依赖的方式导致 DIC 的发展。
OMVs 对革兰氏阴性菌感染期间 DIC 的发病机制有重要贡献。这些发现可能为通过靶向 OMVs 产生来预防感染相关的凝血功能障碍开辟了新途径。
