Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India.
Liver Int. 2021 Jul;41(7):1614-1628. doi: 10.1111/liv.14875. Epub 2021 Apr 1.
Sepsis is common in cirrhosis and is often a result of immune dysregulation. Specific stimuli and pathways of inter-cellular communications between immune cells in cirrhosis and sepsis are incompletely understood. Immune cell-derived extracellular vesicles (EV) were studied to understand mechanisms of sepsis in cirrhosis.
Immune cell-derived EV were measured in cirrhosis patients [Child-Turcotte-Pugh (Child) score A, n = 15; B n = 16; C n = 43 and Child-C with sepsis (n = 38)], and healthy controls (HC, n = 11). In vitro and in vivo functional relevance of EV in cirrhosis and associated sepsis was investigated.
Monocyte, neutrophil and hematopoietic stem cells associated EV progressively increased with higher Child score (P < .001)and correlated with liver disease severity indices (r > 0.3, P < .001), which further increased in Child C sepsis than without sepsis(P < .001); monocyte EV showing the highest association with disease stage [P = .013; Odds ratio-4.14(1.34-12.42)]. A threshold level of monocyte EV of 53/µl predicted mortality in patients of Child C with sepsis [Odds ratio-6.2 (2.4-15.9), AUROC = 0.76, P < .01]. In vitro EV from cirrhotic with sepsis compared without sepsis, induced mobilization arrest in healthy monocytes within 4 hours (P = .004), reduced basal oxygen consumption rate (P < .001) and induced pro-inflammatory genes (P < .05). The septic-EV on adoptive transfer to C57/BL6J mice, induced sepsis-like condition within 24 h with leukocytopenia (P = .005), intrahepatic inflammation with increased CD11b + cells (P = .03) and bone marrow hyperplasia (P < .01).
Extracellular vesicles induce functional impairment in circulating monocytes and contribute to the development and perpetuation of sepsis. High levels of monocyte EV correlate with mortality and can help early stratification of sicker patients.
肝硬化中常发生脓毒症，且常由免疫失调引起。免疫细胞间特定的刺激和细胞间通讯通路在肝硬化和脓毒症中的作用尚不完全清楚。本研究通过检测免疫细胞衍生的细胞外囊泡（EV）来探讨肝硬化中脓毒症的发病机制。
检测肝硬化患者（Child-Turcotte-Pugh 评分 A 级 n=15；B 级 n=16；C 级 n=43 和伴有脓毒症的 Child-C 级 n=38）和健康对照者（HC，n=11）的免疫细胞衍生的 EV。研究了 EV 在肝硬化及相关脓毒症中的体外和体内功能相关性。
单核细胞、中性粒细胞和造血干细胞相关 EV 随 Child 评分的增加而逐渐升高（P<.001），且与肝功能严重程度指数呈正相关（r>0.3，P<.001），在伴有脓毒症的 Child-C 级中进一步增加（P<.001）；单核细胞 EV 与疾病分期的相关性最高（P=.013；优势比-4.14（1.34-12.42））。单核细胞 EV 水平为 53/µl 时可预测伴有脓毒症的 Child-C 级患者的死亡率[优势比 6.2（2.4-15.9），AUROC=0.76，P<.01]。与无脓毒症的肝硬化患者相比，伴有脓毒症的肝硬化患者的 EV 在体外可诱导健康单核细胞在 4 小时内发生迁移阻滞（P=.004），基础耗氧量降低（P<.001），并诱导促炎基因表达（P<.05）。将脓毒症 EV 过继转移至 C57/BL6J 小鼠，可在 24 小时内引起类脓毒症状态，表现为白细胞减少（P=.005）、肝内炎症伴 CD11b+细胞增加（P=.03）和骨髓增生（P<.01）。
细胞外囊泡可诱导循环单核细胞功能障碍，并促进脓毒症的发生和持续存在。单核细胞 EV 水平与死亡率相关，有助于对病情较重患者进行早期分层。
