Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
J Leukoc Biol. 2019 Jul;106(1):187-192. doi: 10.1002/JLB.4MIR1118-425R. Epub 2019 Mar 1.
In this mini review, we describe the molecular mechanisms in polymicrobial sepsis that lead to a series of adverse events including activation of inflammatory and prothrombotic pathways, a faulty innate immune system, and multiorgan dysfunction. Complement activation is a well-established feature of sepsis, especially involving generation of C5a and C5b-9, along with engagement of relevant receptors for C5a. Activation of neutrophils by C5a leads to extrusion of DNA, forming neutrophil extracellular traps that contain myeloperoxidase and oxidases, along with extracellular histones. Generation of the distal complement activation product, C5b-9 (known as the membrane attack complex, MAC), also occurs in sepsis. C5b-9 activates the NLRP3 inflammasome, which damages mitochondria, together with appearance in plasma of IL-1β and IL-18. Histones are strongly proinflammatory as well as being prothrombotic, leading to activation of platelets and development of venous thrombosis. Multiorgan dysfunction is also a feature of sepsis. It is well known that septic cardiomyopathy, which if severe, can lead to death. This complication in sepsis is linked to reduced levels in cardiomyocytes of three critical proteins (SERCA2, NCX, Na /K -ATPase). The reductions in these three key proteins are complement- and histone-dependent. Dysfunction of these ATPases is linked to the cardiomyopathy of sepsis. These data suggest novel targets in the setting of sepsis in humans.
在这篇迷你综述中，我们描述了微生物群失调导致一系列不良事件的分子机制，包括炎症和促血栓形成途径的激活、先天免疫系统的缺陷以及多器官功能障碍。补体激活是脓毒症的一个既定特征，特别是涉及 C5a 和 C5b-9 的产生，以及 C5a 相关受体的参与。C5a 激活中性粒细胞导致 DNA 挤出，形成含有髓过氧化物酶和氧化酶以及细胞外组蛋白的中性粒细胞细胞外陷阱。补体激活的远端产物 C5b-9（称为膜攻击复合物，MAC）也会在脓毒症中产生。C5b-9 激活 NLRP3 炎性体，破坏线粒体，同时在血浆中出现 IL-1β 和 IL-18。组蛋白具有很强的促炎和促血栓形成作用，导致血小板激活和静脉血栓形成。多器官功能障碍也是脓毒症的一个特征。众所周知，严重的败血症性心肌病可导致死亡。这种败血症的并发症与心肌细胞中三种关键蛋白（SERCA2、NCX 和 Na+/K+-ATPase）水平降低有关。这三种关键蛋白的减少与补体和组蛋白依赖性有关。这些 ATP 酶的功能障碍与败血症性心肌病有关。这些数据表明在人类脓毒症中存在新的靶点。
