Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*.
Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*.
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DOI：
10.1097/ccm.0b013e31825fdc31
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发表时间：
2012-11
影响因子：
8.8
通讯作者：
Parikh SM
中科院分区：
文献类型：
--
作者：
David S;Mukherjee A;Ghosh CC;Yano M;Khankin EV;Wenger JB;Karumanchi SA;Shapiro NI;Parikh SM
在脓毒症中，静止的血管由于不完全理解的机制而变得渗漏和发炎。我们假设血管生成素-2（Angpt-2），一种内皮细胞分泌的内皮稳定受体Tie-2的部分拮抗剂，有助于这种疾病的不良结局。实验室和动物研究Beth Israel Deaconess Medical Center，Boston，MA的研究实验室和急诊部Angpt-2杂合子小鼠，急诊部患者与野生型对应物相比，具有一个功能性Angpt-2等位基因的小鼠发展出更轻的肾和肺损伤、更少的组织炎症和更少的血管渗漏。在两种不同的脓毒症模型后，杂合子经历了>40%的绝对生存优势（p = 0.004和0.018）。在因疑似感染就诊于我们急诊科的人类受试者中（n = 270），循环Angpt-2在临床护理的第一个小时内显著升高。在原始队列和独立验证组中，第一小时的Angpt-2浓度与当前疾病严重程度成比例（p <0.0001），在最终非存活者中随时间进一步升高（p <0.0001），并预测未来发生休克（p <0.0001）或死亡（p < 0.0001）。最后，脓毒症的人血清破坏微血管内皮细胞的屏障功能，这种作用被Angpt-2单克隆抗体完全中和。我们得出结论，Angpt-2诱导先于脓毒症的不良结果，并有助于脓毒症的不良结果，为治疗研究开辟了新的途径。
In sepsis, quiescent blood vessels become leaky and inflamed by mechanisms that are incompletely understood. We hypothesized that Angiopoietin-2 (Angpt-2), a partial antagonist of the endothelium-stabilizing receptor Tie-2 secreted by endothelium, contributes to adverse outcomes in this disease. Laboratory and animal research Research laboratories and Emergency Department of Beth Israel Deaconess Medical Center, Boston, MA Angpt-2 heterozygous mice, Emergency Department patients Mice with one functional Angpt-2 allele developed milder kidney and lung injury, less tissue inflammation, and less vascular leakage compared to wildtype counterparts. Heterozygotes experienced >40% absolute survival advantage following two different models of sepsis (p = 0.004 and 0.018). In human subjects presenting to our emergency department with suspected infection (n = 270 combined), circulating Angpt-2 was markedly elevated within the first hour of clinical care. First-hour Angpt-2 concentrations were proportional to current disease severity (p < 0.0001), rose further over time in eventual non-survivors (p < 0.0001), and predicted the future occurrence of shock (p < 0.0001) or death (p < 0.0001) in the original cohort and an independent validation group. Finally, septic human serum disrupted the barrier function of microvascular endothelial cells, an effect fully neutralized by an Angpt-2 monoclonal antibody. We conclude that Angpt-2 induction precedes and contributes to the adverse outcomes in sepsis, opening a new avenue for therapeutic investigation.