The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction.
The Importance of Pore-Forming Toxins in Multiple Organ Injury and Dysfunction.
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DOI：
10.3390/biomedicines10123256
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发表时间：
2022-12-14
期刊：
影响因子：
4.7
通讯作者：
Wang, Guozheng
中科院分区：
文献类型：
--
作者：
Abrams, Simon T. T.;Wang, Lijun;Yong, Jun;Yu, Qian;Du, Min;Alhamdi, Yasir;Cheng, Zhenxing;Dart, Caroline;Lane, Steven;Yu, Weiping;Toh, Cheng-Hock;Wang, Guozheng
关键词：
背景：多器官损伤和功能障碍常发生在急性危重病中，并对生存产生不利影响。然而，在存活的患者中，器官功能通常会恢复而不会造成永久性损伤。因此，可能存在可逆机制，但在多器官功能障碍综合征（MODS）的发病机制中了解甚少。目的：根据我们对细胞外组蛋白和肺炎球菌溶血素的了解，分别作为内源性和外源性成孔毒素，在这里我们澄清细胞膜破坏和恢复的程度在MODS中是否重要。研究方法：这是对来自三级医院重症监护室（ICU）的98例患者队列的回顾性临床研究与介入动物模型和实验室研究的组合。结果如下：在无感染性休克和/或弥散性血管内凝血（DIC）的患者中，循环组蛋白也与序贯器官衰竭评估（SOFA）评分密切相关，表明其成孔特性可能起重要作用。在体内，组蛋白或肺炎球菌溶血素输注同样引起细胞损伤标志物和多器官损伤的显著升高。在创伤和脓毒症模型中，循环组蛋白与这些标志物密切相关，抗组蛋白试剂显著减少了它们的释放。肺炎链球菌溶血素缺失与其亲本株诱导的脓毒症小鼠模型的比较表明，肺炎链球菌溶血素不是脓毒症发展所必需的，但增加了多器官损害，缩短了生存时间。在体外，组蛋白和肺炎球菌溶血素处理破坏细胞膜的完整性，导致全细胞电流的变化和细胞内Ca 2+升高，导致Ca 2+超载。细胞特异性损伤标志物乳酸脱氢酶（LDH）、丙氨酸氨基转移酶（ALT）和心肌肌钙蛋白I（cTnI）从受损细胞中释放。一旦毒素被清除，细胞膜损伤可以迅速修复，细胞功能恢复。结论：这项工作证实了致孔毒素在MODS发展中的重要性，并提出了一个潜在的机制来解释MODS的可逆性。这可能是开发有效疗法的基础。
Background: Multiple organ injury and dysfunction often occurs in acute critical illness and adversely affects survival. However, in patients who survive, organ function usually recovers without permanent damage. It is, therefore, likely that there are reversible mechanisms, but this is poorly understood in the pathogenesis of multiple organ dysfunction syndrome (MODS). Aims: Based on our knowledge of extracellular histones and pneumolysin, as endogenous and exogenous pore-forming toxins, respectively, here we clarify if the extent of cell membrane disruption and recovery is important in MODS. Methods: This is a combination of retrospective clinical studies of a cohort of 98 patients from an intensive care unit (ICU) in a tertiary hospital, with interventional animal models and laboratory investigation. Results: In patients without septic shock and/or disseminate intravascular coagulation (DIC), circulating histones also strongly correlated with sequential organ failure assessment (SOFA) scores, suggesting their pore-forming property might play an important role. In vivo, histones or pneumolysin infusion similarly caused significant elevation of cell damage markers and multiple organ injury. In trauma and sepsis models, circulating histones strongly correlated with these markers, and anti-histone reagents significantly reduced their release. Comparison of pneumolysin deletion and its parental strain-induced sepsis mouse model showed that pneumolysin was not essential for sepsis development, but enhanced multiple organ damage and reduced survival time. In vitro, histones and pneumolysin treatment disrupt cell membrane integrity, resulting in changes in whole-cell currents and elevated intracellular Ca2+ to lead to Ca2+ overload. Cell-specific damage markers, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and cardiac troponin I (cTnI), were released from damaged cells. Once toxins were removed, cell membrane damage could be rapidly repaired and cellular function recovered. Conclusion: This work has confirmed the importance of pore-forming toxins in the development of MODS and proposed a potential mechanism to explain the reversibility of MODS. This may form the foundation for the development of effective therapies.
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影响因子：
6.7
作者：
Alhamdi Y;Neill DR;Abrams ST;Malak HA;Yahya R;Barrett-Jolley R;Wang G;Kadioglu A;Toh CH
通讯作者：
Toh CH
应对由细胞损伤引起的钙超负荷：ers救援。
影响因子：
6.4
作者：
Chandra G;Mázala DAG;Jaiswal JK
通讯作者：
Jaiswal JK
影响因子：
120.7
作者：
LEVI, M;TENCATE, H;VANDEVENTER, SJH
通讯作者：
VANDEVENTER, SJH
影响因子：
7.2
作者：
Hill-Eubanks, David C.;Werner, Matthias E.;Nelson, Mark T.
通讯作者：
Nelson, Mark T.
DOI：
10.1083/jcb.131.6.1747
发表时间：
1995-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bi GQ;Alderton JM;Steinhardt RA
通讯作者：
Steinhardt RA