Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
Thromb Res. 2020 Dec;196:159-166. doi: 10.1016/j.thromres.2020.08.013. Epub 2020 Aug 9.
Disseminated intravascular coagulation (DIC), a severe complication of sepsis, promotes multiple organ dysfunctions and lethality. Bacterial infection is the most common cause of sepsis. We previously show an important role of bacteria-released outer membrane vesicles (OMVs) in bacterial infection-induced DIC. In the light of recent advance that activation of caspase-11 and its enzymatic substrate gasdermin D (GSDMD) is able to trigger coagulation, we postulate that OMVs might induce DIC through the caspase-11-GSDMD pathway.
Caspase-11- or GSDMD-deficient mice and their wild-type (WT) controls were injected with purified Escherichia coli-derived OMVs. Blood samples were then collected. The development of DIC was assessed in terms of the occurrence of coagulopathy, the organ injuries and the lethality. Peritoneal macrophages derived from WT, Caspase-11- or GSDMD-deficient mice were stimulated with OMVs. Then the cell surface tissue factor (TF) activity and thrombin generation were assessed.
Genetic deletion of Caspase-11 or GSDMD or pharmacological inhibition of caspase-11 markedly attenuated OMVs-induced coagulopathy, multiple organ injuries and mortality. Caspase-11- or GSDMD-deficient macrophages exhibited markedly reduced TF activity after OMVs stimulation.
OMVs induce DIC through the caspase-11-GSDMD pathway. These findings might open a new avenue to prevent or treat bacterial infection-induced DIC.
弥散性血管内凝血（DIC）是脓毒症的一种严重并发症，可导致多器官功能障碍和死亡。细菌感染是脓毒症最常见的原因。我们之前的研究表明，细菌释放的外膜囊泡（OMVs）在外膜囊泡诱导的 DIC 中起重要作用。鉴于最近的一项进展，即半胱氨酸蛋白酶-11（caspase-11）及其酶底物 GSDMD 的激活能够引发凝血，我们推测 OMVs 可能通过 caspase-11-GSDMD 途径诱导 DIC。
用纯化的大肠杆菌来源的 OMVs 注射 caspase-11 或 GSDMD 缺陷型小鼠及其野生型（WT）对照小鼠。然后收集血液样本。通过凝血功能障碍、器官损伤和死亡率评估 DIC 的发生。用 OMVs 刺激 WT、Caspase-11 或 GSDMD 缺陷型小鼠来源的腹腔巨噬细胞。然后评估细胞表面组织因子（TF）活性和凝血酶生成。
Caspase-11 或 GSDMD 的基因缺失或 caspase-11 的药理学抑制显著减轻了 OMVs 诱导的凝血功能障碍、多器官损伤和死亡率。在 OMVs 刺激后，Caspase-11 或 GSDMD 缺陷型巨噬细胞的 TF 活性明显降低。
OMVs 通过 caspase-11-GSDMD 途径诱导 DIC。这些发现可能为预防或治疗细菌感染诱导的 DIC 开辟新途径。
