Inflammasome Activation Triggers Systemic Coagulation in Sepsis

脓毒症中炎症小体激活引发全身凝血

基本信息

批准号：
10645452
负责人：
ZHENYU Li
金额：
$ 42.95万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10645452
关键词：
Apoptosis Bacteria Bacterial Infections Blood Coagulation Disorders Blood Coagulation Factor Bone Marrow Burkholderia CASP1 gene Cells Cessation of life Clinical Coagulation Process Complication Consumption Data Development Disease Disseminated Intravascular Coagulation Escherichia coli Family Fibrinogen Flagellin Functional disorder Goals Gram-Negative Bacteria In Vitro Infection Inflammasome Infusion procedures Injections Intervention Knockout Mice Lead Link Modeling Molecular Morbidity - disease rate Mus Myelogenous Needles Organ Outcome Pathway interactions Patients Peripheral Phagocytosis Physiological Plasma Play Proteins Prothrombin time assay Pseudomonas aeruginosa Reagent Research Project Grants Rod Role Salmonella Sepsis Septic Shock Testing Thrombocytopenia Thromboplastin Thrombosis Thrombus Tissues Type III Secretion System Pathway Work antithrombin III-protease complex base cecal ligation puncture driving force in vivo insight intravenous injection macrophage monocyte mortality mouse model multidisciplinary new therapeutic target protein E release factor septic patients targeted treatment

项目摘要

Abstract Septic shock is invariably associated with systemic coagulation leading to thrombus formation. Sepsis-related organ dysfunction has been attributed to microvascular thrombosis. Mortality rate doubles in septic patients with disseminated intravascular coagulation (DIC). DIC is even considered as a sign that “death is coming”. Previous studies have demonstrated the important roles of tissue factor (TF) in sepsis-associated DIC. However, the mechanism leading to TF release, which triggers systemic coagulation in sepsis, is unknown. Recent in vitro studies revealed that bacterial components (flagellin, the rod protein of the type III secretion system (T3SS), or LPS) induce programmed cell death (called pyroptosis) of macrophages through activation of inflammasome pathways. We show that intravenous injection of a T3SS rod protein E. coli, EprJ, induced depletion of peripheral monocytes and macrophages in tissues. Importantly, injection of EprJ or LPS, which elicit canonical and noncanonical inflammasome activation, respectively, induced systemic coagulation activation, as evident by prolonged prothrombin time (PT) due to increased consumption of coagulation factors, thrombocytopenia, increased plasma levels of thrombin-antithrombin complex (TAT), and reduced plasma fibrinogen levels. Thus, our findings made connections between the in vitro and in vivo observations and suggested monocyte/macrophage pyroptosis as a trigger of DIC in sepsis. The goal of this application is to delineate the underlying mechanisms by which inflammasome activation and pyroptosis trigger DIC in sepsis. Specific Aim 1 will establish inflammasome activation and pyroptosis as a common mechanism for DIC induced by bacterial infection. The working hypothesis is that bacteria and bacterial components from different strains elicit DIC through Inflammasome activation and pyroptosis. We will use a combination of various deficient mice to elucidate the role of inflammasome activation and pyroptosis in DIC elicited by Gram-negative bacteria. Specific Aim 2 is to identify the molecular mechanism of TF release from macrophages following inflammasome activation. We will also use the myeloid-specific TF knockout mice and a low TF mouse model to elucidate whether DIC elicited by the bacterial components depends on release of TF from macrophages. Specific Aim 3 will demonstrate the role of inflammasome activation in sepsis-associated coagulopathy. We will use the cecal ligation and puncture (CLP) sepsis model and bacterial infusion sepsis model to investigate the role of inflammasome activation and pyroptosis in coagulation. Completion of the proposed studies will demonstrate the molecular mechanism of systemic coagulation is sepsis. Such findings would have profound ramifications for the identification of new drug targets for DIC, the deadly complication of sepsis.

抽象的脓毒性休克总是与导致脓毒症相关血栓形成的全身凝血有关。器官功能障碍归因于微血管血栓形成，脓毒症患者的死亡率加倍。弥散性血管内凝血（DIC）甚至被认为是“死亡即将来临”的征兆。先前的研究已经证明了组织因子（TF）在脓毒症相关 DIC 中的重要作用。然而，导致 TF 释放并引发脓毒症全身凝血的机制尚不清楚。最近的体外研究表明，细菌成分（鞭毛蛋白，III 型分泌物的杆蛋白）系统（T3SS）或 LPS）通过激活诱导巨噬细胞程序性细胞死亡（称为细胞焦亡）我们发现静脉注射大肠杆菌 T3SS 杆状蛋白 EprJ 可诱导炎症小体途径的发生。重要的是，注射 EprJ 或 LPS，消除组织中的外周单核细胞和巨噬细胞。分别引发典型和非典型炎症小体激活，诱导全身凝血激活，如由于凝血因子消耗增加而导致凝血酶原时间（PT）延长，血小板减少症、血浆凝血酶-抗凝血酶复合物 (TAT) 水平升高以及血浆水平降低因此，我们的研究结果将体外和体内观察结果联系起来。建议单核细胞/巨噬细胞焦亡作为败血症中 DIC 的触发因素。描述脓毒症中炎症小体激活和细胞焦亡触发 DIC 的潜在机制。具体目标 1 将确定炎症小体激活和细胞焦亡作为 DIC 的常见机制由细菌感染引起的工作假设是细菌和细菌成分来自不同的细菌。菌株通过炎症小体激活和细胞焦亡引发 DIC。我们将使用各种组合。缺陷小鼠阐明炎症小体激活和细胞焦亡在革兰氏阴性菌引起的 DIC 中的作用具体目标 2 是确定巨噬细胞释放 TF 的分子机制。我们还将使用骨髓特异性 TF 敲除小鼠和低 TF 小鼠模型。阐明细菌成分引起的 DIC 是否依赖于巨噬细胞释放 TF。具体目标 3 将证明炎症小体激活在脓毒症相关凝血病中的作用。使用盲肠结扎穿刺（CLP）脓毒症模型和细菌输注脓毒症模型来研究炎症体激活和焦亡在凝血中的作用将完成拟议的研究。证明败血症是全身性凝血的分子机制，这样的发现将具有深远的意义。确定 DIC 新药物靶点的影响，DIC 是脓毒症的致命并发症。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Donnan Potential across the Outer Membrane of Gram-Negative Bacteria and Its Effect on the Permeability of Antibiotics.

穿过革兰氏阴性菌外膜的唐南电位及其对抗生素渗透性的影响。

DOI：
发表时间：
2021-06-11
期刊：
影响因子：
0
作者：
Alegun, Olaniyi;Pandeya, Ankit;Cui, Jian;Ojo, Isoiza;Wei, Yinan
通讯作者：
Wei, Yinan

Calcium Ion Chelation Preserves Platelet Function During Cold Storage.

钙离子螯合可在冷藏期间保留血小板功能。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Xiang, Binggang;Zhang, Guoying;Zhang, Yan;Wu, Congqing;Joshi, Smita;Morris, Andrew J;Ware, Jerry;Smyth, Susan S;Whiteheart, Sidney W;Li, Zhenyu
通讯作者：
Li, Zhenyu

Insight into the AcrAB-TolC Complex Assembly Process Learned from Competition Studies.

从竞争研究中深入了解 AcrAB-TolC 复杂的组装过程。

DOI：
发表时间：
2021-07-08
期刊：
影响因子：
0
作者：
Rajapaksha, Prasangi;Ojo, Isoiza;Yang, Ling;Pandeya, Ankit;Abeywansha, Thilini;Wei, Yinan
通讯作者：
Wei, Yinan

Inflammasome activation and pyroptosis mediate coagulopathy and inflammation in Salmonella systemic infection.

炎性小体激活和细胞焦亡介导沙门氏菌全身感染中的凝血病和炎症。

DOI：
发表时间：
2023-10
期刊：
影响因子：
6.7
作者：
Pandeya, Ankit;Zhang, Yan;Cui, Jian;Yang, Ling;Li, Jeffery;Zhang, Guoying;Wu, Congqing;Li, Zhenyu;Wei, Yinan
通讯作者：
Wei, Yinan

Pyroptosis-Induced Inflammation and Tissue Damage.

焦亡引起的炎症和组织损伤。