Disseminated intravascular coagulation phenotype is regulated by the TRPM7 channel during sepsis.
Disseminated intravascular coagulation phenotype is regulated by the TRPM7 channel during sepsis.
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DOI：
10.1186/s40659-023-00419-4
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发表时间：
2023-03-03
影响因子：
6.7
通讯作者：
Simon F
中科院分区：
文献类型：
--
作者：
Jiménez-Dinamarca I;Prado Y;Tapia P;Gatica S;Alt C;Lin CP;Reyes-Martínez C;Feijóo CG;Aravena C;González-Canacer A;Correa S;Varela D;Cabello-Verrugio C;Simon F
脓毒症是一种针对全身感染的不受控制的炎症反应，其导致死亡率升高，主要由称为内毒素的细菌产物引起，产生内毒素血症。弥散性血管内凝血（DIC）是脓毒症患者常见的并发症，与器官衰竭和死亡有关。脓毒症激活内皮细胞（EC），促进促血栓形成表型，导致DIC。离子通道介导的钙渗透性参与凝血。瞬时接收电位melastatin 7（TRPM 7）非选择性二价阳离子通道也含有α-激酶结构域，可渗透包括Ca 2+在内的二价阳离子，调节内皮细胞内毒素刺激的钙渗透性，并与脓毒症患者死亡率增加相关。然而，内皮TRPM 7是否介导内毒素血症诱导的凝血尚不清楚。因此，我们的目的是检查TRPM 7是否在内毒素血症期间介导凝血。结果表明，TRPM 7调节内毒素诱导的血小板和中性粒细胞与EC的粘附，这依赖于TRPM 7离子通道活性和α-激酶功能。内毒素动物显示TRPM 7介导中性粒细胞在血管上滚动和血管内凝血。TRPM 7介导粘附蛋白、血管性血友病因子（vWF）、细胞间粘附分子1（ICAM-1）和P-选择素的表达增加，这些蛋白也由TRPM 7 α-激酶功能介导。值得注意的是，内毒素诱导的vWF，ICAM-1和P-选择素的表达所需的内毒素诱导的血小板和中性粒细胞粘附到内皮细胞。内毒素血症大鼠显示内皮TRPM 7表达增加，与促凝血表型、肝肾功能障碍、死亡事件增加和死亡相对风险增加相关。有趣的是，来自感染性休克患者（SSP）的循环EC（CEC）显示TRPM 7表达增加，与DIC评分增加和存活时间减少相关。此外，CEC中TRPM 7高表达的SSP显示死亡率和相对死亡风险增加。值得注意的是，来自SSP的CEC显示出AUROC分析预测SSP死亡率的显著结果，优于急性生理学和慢性健康评估II（APACHE II）和序贯器官衰竭评估（SOFA）评分。我们的研究表明，脓毒症诱导的DIC是由TRPM 7介导的EC。TRPM 7离子通道活性和α-激酶功能是DIC介导的脓毒症诱导的器官功能障碍所必需的，其表达与脓毒症期间死亡率增加相关。TRPM 7作为一种新的预后生物标志物，可预测SSP中与DIC相关的死亡率，并作为感染性炎症疾病期间针对DIC的药物开发的新靶点。 在线版本包含补充材料，可通过10.1186/s40659-023-00419-4获得。
Sepsis is an uncontrolled inflammatory response against a systemic infection that results in elevated mortality, mainly induced by bacterial products known as endotoxins, producing endotoxemia. Disseminated intravascular coagulation (DIC) is frequently observed in septic patients and is associated with organ failure and death. Sepsis activates endothelial cells (ECs), promoting a prothrombotic phenotype contributing to DIC. Ion channel-mediated calcium permeability participates in coagulation. The transient reception potential melastatin 7 (TRPM7) non-selective divalent cation channel that also contains an α-kinase domain, which is permeable to divalent cations including Ca2+, regulates endotoxin-stimulated calcium permeability in ECs and is associated with increased mortality in septic patients. However, whether endothelial TRPM7 mediates endotoxemia-induced coagulation is not known. Therefore, our aim was to examine if TRPM7 mediates coagulation during endotoxemia. The results showed that TRPM7 regulated endotoxin-induced platelet and neutrophil adhesion to ECs, dependent on the TRPM7 ion channel activity and by the α-kinase function. Endotoxic animals showed that TRPM7 mediated neutrophil rolling on blood vessels and intravascular coagulation. TRPM7 mediated the increased expression of the adhesion proteins, von Willebrand factor (vWF), intercellular adhesion molecule 1 (ICAM-1), and P-selectin, which were also mediated by the TRPM7 α-kinase function. Notably, endotoxin-induced expression of vWF, ICAM-1 and P-selectin were required for endotoxin-induced platelet and neutrophil adhesion to ECs. Endotoxemic rats showed increased endothelial TRPM7 expression associated with a procoagulant phenotype, liver and kidney dysfunction, increased death events and an increased relative risk of death. Interestingly, circulating ECs (CECs) from septic shock patients (SSPs) showed increased TRPM7 expression associated with increased DIC scores and decreased survival times. Additionally, SSPs with a high expression of TRPM7 in CECs showed increased mortality and relative risk of death. Notably, CECs from SSPs showed significant results from the AUROC analyses for predicting mortality in SSPs that were better than the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores. Our study demonstrates that sepsis-induced DIC is mediated by TRPM7 in ECs. TRPM7 ion channel activity and α-kinase function are required by DIC-mediated sepsis-induced organ dysfunction and its expression are associated with increased mortality during sepsis. TRPM7 appears as a new prognostic biomarker to predict mortality associated to DIC in SSPs, and as a novel target for drug development against DIC during infectious inflammatory diseases. The online version contains supplementary material available at 10.1186/s40659-023-00419-4.
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DOI：
10.12938/bmfh.2019-054
发表时间：
2020
期刊：
Bioscience of microbiota, food and health
影响因子：
--
作者：
Aihara Y;Fukuda Y;Takizawa A;Osakabe N;Aida T;Tanaka K;Yoshikawa S;Karasuyama H;Adachi T
通讯作者：
Adachi T
影响因子：
7.1
作者：
Akatsuka M;Masuda Y;Tatsumi H;Sonoda T
通讯作者：
Sonoda T
影响因子：
3
作者：
Barrionuevo, Nathaly;Gatica, Sebastian;Simon, Felipe
通讯作者：
Simon, Felipe
影响因子：
3.7
作者：
Echeverría C;Montorfano I;Hermosilla T;Armisén R;Velásquez LA;Cabello-Verrugio C;Varela D;Simon F
通讯作者：
Simon F
影响因子：
30.8
作者：
Bridge, AJ;Pebernard, S;Iggo, R
通讯作者：
Iggo, R