Inflammasome activation in trauma-hemorrhagic shock

创伤失血性休克中的炎症小体激活

• 批准号: 10700054
• 负责人: Melanie J. Scott
• 金额: $ 33.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700054
• 关键词: Binding; Biochemical; Biochemical Markers; Bleeding time procedure; Blood Coagulation Disorders; Blood Platelets; Blood flow; CD14 Antigen; Cardiolipins; Caspase; Cell Death; Cell Line; Cells; Cessation of life; Coagulation Process; Data; Deposition; Diffuse; Dose; Effectiveness; Endothelial Cells; Fibrin; Future; Goals; Grant; HMGB1 gene; Hemorrhage; Hemorrhagic Shock; Hepatocyte; Histologic; Human; Image; In Vitro; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Leukocytes; Liver; Mediating; Microfluidics; Mitochondria; Modeling; Multiple Organ Failure; Multiple Trauma; Mus; Organ; Organ failure; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Platelet Activation; Platelet aggregation; Proteins; Research; Resuscitation; Role; Safety; Sampling; Sepsis; Shock; Stress; Supportive care; System; Thromboplastin; Thrombus; Tissues; Trauma; Trauma patient; Treatment Failure; Work; cell injury; cell type; cytochrome c; cytotoxicity; effectiveness evaluation; extracellular vesicles; improved; in vivo; inflammatory marker; inhibitor; intravital imaging; mouse model; neutrophil; novel; novel therapeutics; organ injury; prevent; public health relevance; severe injury; systemic inflammatory response; therapeutic target; translational potential; vesicular release

PROJECT SUMMARY/ABSTRACT Controlling inflammation and cellular damage is key to preventing and treating multiple organ failure (MOF) following trauma. However, many of the mechanisms that regulate inflammation and cell death in specific organs remain unknown. So despite advances in supportive care for MOF patients, there have been few advances in MOF treatments, or in our ability to adequately prevent MOF onset. Our overarching goal is to ultimately develop new therapeutics for trauma patients based on regulating inflammatory responses and effects on cell death following trauma and hemorrhagic shock with resuscitation (HS/R). In this proposal we will continue to investigate downstream cell and tissue-specific effects of caspase-4 (human)/11 (mouse) activation after HS/R. We will also assess the ability of a novel caspase-4/11 inhibitor to reduce HS/R- mediated effects on systemic inflammation, cell death and end-organ injury. Understanding the multiple effects of caspase-11 on inflammation and organ damage will enable us to assess the translational potential of targeted caspase-11-inhibition for improved patient outcomes after trauma and hemorrhage. The most recent work on this grant defined a novel mechanism of caspase-4/11 activation (non- canonical inflammasome) in trauma/HS/R. Caspase-4/11 is the intracellular receptor for lipopolysaccharide (LPS) and is an important mediator of inflammation during infection and sepsis. Our work showed activation of caspase-4/11 in non-LPS-driven models of inflammation, and we defined a novel mechanism of activation of caspase-11 by endogenous oxidized cardiolipin (CLox) on the outside of stressed mitochondria. CLox is regulated by cytochrome c, and specific inhibition of cytochrome c inhibits caspase-11 activation and is highly organ protective in a mouse model of HS/R. However, the mechanistic basis of detrimental effects of caspase- 11 activation in HS/R are not clear, and may be multifactorial given its multiple cell-specific inflammatory effects, including induction of pyroptosis (inflammatory cell death), active release of inflammatory HMGB1 in extracellular vesicles (EV) from hepatocytes after HS/R, and more recently-described effects on coagulation through enhanced binding of tissue factor (TF) on endothelial cells (EC) in sepsis. Therefore, our main hypothesis is that caspase-4/11 activation is detrimental during HS/R through multiple cell-specific effects. In this proposal we will: 1: determine the role of caspase-4/11-mediated inflammation on organ injury during HS/R; 2: determine the effects of caspase-4/11-activation on coagulation and organ injury during HS/R; 3: determine safety and effectiveness of caspase-11-specific inhibition in mouse models of HS/R. We expect to show specific inhibition of caspase-4/11 in HS/R is organ protective and the mechanisms of protection are multi-factorial. We also expect to show inhibition of caspase-4/11 is an attractive therapeutic target to reduce trauma-induced inflammation, coagulopathy and organ damage.

项目总结/摘要 控制炎症和细胞损伤是预防和治疗多器官衰竭的关键 (MOF)创伤后。然而，许多调节炎症和细胞死亡的机制， 具体器官仍不清楚。因此，尽管对MOF患者的支持性治疗取得了进展， 在多器官功能衰竭的治疗方面，或者在我们充分预防多器官功能衰竭发作的能力方面，几乎没有什么进展。我们的首要目标是 最终为创伤患者开发基于调节炎症反应的新疗法， 对创伤和失血性休克复苏（HS/R）后细胞死亡的影响。在本提案中，我们 将继续研究caspase-4（人）/11（小鼠）的下游细胞和组织特异性效应 HS/R后激活。我们还将评估一种新的caspase-4/11抑制剂降低HS/R的能力。 介导对全身炎症、细胞死亡和终末器官损伤的影响。了解多重影响 caspase-11对炎症和器官损伤的作用将使我们能够评估 靶向半胱天冬酶-11抑制，改善创伤和出血后患者的预后。 这项资助的最新工作定义了一种新的caspase-4/11激活机制（非 典型炎性小体）在创伤/HS/R中的作用。Caspase-4/11是脂多糖的细胞内受体 (LPS)并且是感染和脓毒症期间炎症的重要介质。我们的研究显示， caspase-4/11在非LPS驱动的炎症模型中，我们定义了一种新的激活机制， caspase-11通过内源性氧化型心磷脂（CLox）在应激线粒体外表达。Clox是 受细胞色素c调节，细胞色素c的特异性抑制抑制caspase-11的活化， HS/R小鼠模型中的器官保护作用。然而，半胱天冬酶的有害作用的机制基础- 11在HS/R中的激活尚不清楚，并且可能是多因素的，因为其具有多细胞特异性炎症反应。 影响，包括诱导细胞凋亡（炎性细胞死亡），炎症HMGB 1的主动释放， HS/R后肝细胞的细胞外囊泡（EV），以及最近描述的对凝血的影响 通过增强组织因子（TF）与脓毒症中内皮细胞（EC）的结合。因此，我们的主要 假设在HS/R期间，caspase-4/11活化通过多个细胞特异性 方面的影响.本研究拟：1、确定caspase-4/11介导的炎症反应在器官损伤中的作用。 HS/R期间的损伤; 2：确定半胱天冬酶-4/11活化对凝血和器官损伤的影响 HS/R期间; 3：确定小鼠模型中caspase-11特异性抑制的安全性和有效性 HS/R。我们希望在HS/R中特异性抑制caspase-4/11具有器官保护作用， 保护机制是多因素的。我们还期望显示抑制caspase-4/11是一种有吸引力的 治疗靶点，以减少创伤引起的炎症、凝血病和器官损伤。

项目成果

N-tert-butylmethanimine N-oxide is an efficient spin-trapping probe for EPR analysis of glutathione thiyl radical.

• DOI: 10.1038/srep38773
• 发表时间: 2016-12-12
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Scott MJ;Billiar TR;Stoyanovsky DA
• 通讯作者: Stoyanovsky DA

Role of autophagy in intervertebral disc degeneration.

• DOI: 10.1002/jcp.30631
• 发表时间: 2022-03
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Kritschil R;Scott M;Sowa G;Vo N
• 通讯作者: Vo N

The emerging therapeutic potential of extracellular vesicles in trauma.

• DOI: 10.1002/jlb.3mir0621-298r
• 发表时间: 2022-01
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5

The Role of Gasdermin-D-Mediated Pyroptosis in Organ Injury and Its Therapeutic Implications.

• DOI: 10.1080/15476278.2023.2177484
• 发表时间: 2023-12-31
• 期刊: ORGANOGENESIS
• 影响因子: 2.3
• 作者: Mulla, Joud;Katti, Rohan;Scott, Melanie J. J.
• 通讯作者: Scott, Melanie J. J.

Platelet-Monocyte Aggregates: Understanding Mechanisms and Functions in Sepsis.

• DOI: 10.1097/shk.0000000000001619
• 发表时间: 2021-02-01
• 期刊: Shock (Augusta, Ga.)
• 作者: Fu G;Deng M;Neal MD;Billiar TR;Scott MJ
• 通讯作者: Scott MJ