Innate Immunity and Cardiovascular Function in Sepsis
脓毒症的先天免疫和心血管功能
基本信息
- 批准号:9927632
- 负责人:
- 金额:$ 33.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdult Respiratory Distress SyndromeAttenuatedCardiomyopathiesCardiovascular PhysiologyCardiovascular systemCell Adhesion MoleculesCell NucleusCell physiologyCellsCessation of lifeComplexComplicationCritical IllnessCritical PathwaysDataDiseaseEndothelial CellsEndotheliumEndotoxemiaEventExhibitsFunctional disorderGoalsGrantHeartHeat shock proteinsHeat-Shock Proteins 70ImmuneImmune System DiseasesImmune responseInfectionInfiltrationInflammatoryInflammatory ResponseInnate Immune ResponseKnockout MiceKnowledgeMaintenanceMediatingMicroRNAsMolecularMorbidity - disease rateMultiple Organ FailureMusMyocardial dysfunctionMyocardiumNatural ImmunityNuclear TranslocationOrganPatientsPatternPattern recognition receptorPhosphatidylinositolsPhosphotransferasesPlayProductionRegulationResearchRoleSepsisSepsis SyndromeSeptic ShockSignal PathwaySignal TransductionSystemic Inflammatory Response SyndromeTestingTherapeutic EffectTransgenic MiceTraumaUnited Statesangiogenesisattenuationbasecytokineeffective therapyexosomeheart functionimprovedmacrophagemembermortalitynovelnovel therapeutic interventionnovel therapeuticsorgan injurypathogenpolymicrobial sepsispreservationpreventresponsesepticsurvival outcome
项目摘要
The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory
distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or
septic shock and multiple organ dysfunction syndrome (MODS)(1). In the United States ~750,000
patients/year develop sepsis syndrome(2). Cardiovascular dysfunction is a major complication associated
with MODS morbidity and mortality. However, the mechanisms by which cardiovascular dysfunction occurs
during sepsis/septic shock remain unclear. Endothelial cell dysfunction contributes to sepsis-induced MODS
and high mortality. Endothelial cells express pattern recognition receptors (PRRs). PRRs recognize pathogen
associated molecular patterns (PAMPs), initiate innate immune and inflammatory responses, and upregulate
adhesion molecule expression, thus promoting immune cell infiltration and organ injury. Therefore,
preservation of endothelial cell function is an important approach for attenuating sepsis-inducedmorbidity and
mortality. During the last grant period, we discovered a novel role for endothelial specific HSPA12B in the
regulation of endothelial cell function and innate immune response during CLP sepsis. HSPA12B is a newly
discovered member of the HSP70 family. It is predominantly expressed in endothelial cells, and plays an
important role in the induction of angiogenesis. We found that endothelial cell specific deficiency of
HSPA12B (HSPA12B-/-) exacerbates mortality and worsens cardiac function in sepsis. In contrast, transgenic
mice that over express endothelial HSPA12B exhibit significantly improved survival outcome and cardiac
function in endotoxemia. Our findings raise an important question, i.e. how does endothelial HSPA12B have
such a profound effect on the mortality and cardiovascular dysfunction associated with polymicrobial sepsis?
We have made a novel observation that HSPA12B can translocate into the nucleus in endothelial cells. We
also discovered that HSPA12B can be released from endothelial cells and transmitted into macrophages via
exosomes where it downregulates inflammatory cytokine production. Our findings suggest that endothelial
HSPA12B has an important role not only for endothelial cell function but also for inflammatory responses by
immune cells during sepsis. Thus, endothelial HSPA12B could be an important effector that mediates
crosstalk between endothelial cells and immune cells during sepsis. Based on the preliminary data, we
hypothesize that “ endothelial HSPA12B is a novel endogenous effector which protects against sepsis
induced cardiomyopathy by differentially regulating endothelial cell function and innate immune inflammatory
responses”. To test these hypotheses, we propose three specific aims. Specific aim 1. Investigate whether
HSPA12B induced protection against septic cardiomyopathy is mediated via regulation of endothelial
function. Specific aim 2. Determine whether the protection against septic cardiomyopathy by endothelial
HSPA12B is mediated by regulation of inflammatory cell responses. Specific aim 3. Evaluate the therapeutic
effect of HSPA12B in sepsis induced cardiomyopathy. The long term goals of this research are to elucidate
the cellular and molecular mechanisms of septic cardiomyopathy and to develop new and novel therapies to
ameliorate the morbidity and mortality associated with sepsis induced cardiac dysfunction.
危重患者经常会出现一系列复杂的疾病,其中可能包括急性呼吸道疾病
窘迫综合征 (ARDS)、全身炎症反应综合征 (SIRS)、败血症综合征和/或
感染性休克和多器官功能障碍综合征 (MODS)(1) 在美国约 750,000 例。
患者/年出现脓毒症综合征(2) 心血管功能障碍是相关的主要并发症。
然而,心血管功能障碍发生的机制。
脓毒症/感染性休克期间内皮细胞功能障碍是否导致脓毒症诱发的 MODS 仍不清楚。
内皮细胞表达识别病原体的模式识别受体(PRR)。
相关分子模式 (PAMP),启动先天免疫和炎症反应,并上调
粘附分子表达,从而促进免疫细胞浸润和器官损伤。
保护内皮细胞功能是减少脓毒症引起的发病率的重要方法
在上一次资助期间,我们发现了内皮特异性 HSPA12B 在死亡率中的新作用。
HSPA12B 在 CLP 脓毒症期间调节内皮细胞功能和先天免疫反应。
发现的 HSP70 家族成员,它主要在内皮细胞中表达,并发挥重要作用。
我们发现内皮细胞特异性缺陷。
HSPA12B (HSPA12B-/-) 会恶化脓毒症患者的死亡率并恶化心脏功能。
过度表达内皮 HSPA12B 的小鼠表现出显着改善的生存结果和心脏功能
我们的研究结果提出了一个重要问题,即内皮 HSPA12B 是如何发挥作用的。
对与多种微生物败血症相关的死亡率和心血管功能障碍有如此深远的影响吗?
我们发现 HSPA12B 可以易位到内皮细胞的细胞核中。
还发现 HSPA12B 可以从内皮细胞释放并通过
我们的研究结果表明,外泌体可以下调炎症细胞因子的产生。
HSPA12B 不仅对内皮细胞功能具有重要作用,而且对炎症反应也具有重要作用
因此,内皮 HSPA12B 可能是介导脓毒症期间的重要效应器。
根据初步数据,我们研究了脓毒症期间内皮细胞和免疫细胞之间的串扰。
提出“内皮 HSPA12B 是一种新型内源性效应器,可预防脓毒症
通过差异调节内皮细胞功能和先天免疫炎症诱导心肌病
为了检验这些假设,我们提出了三个具体目标 1. 调查是否。
HSPA12B 诱导的针对脓毒症心肌病的保护作用是通过内皮细胞的调节介导的
具体目标 2. 确定内皮细胞是否对脓毒症心肌病具有保护作用。
HSPA12B 通过炎症细胞反应的调节介导。 具体目标 3. 评估治疗效果。
HSPA12B 在脓毒症引起的心肌病中的作用本研究的长期目标是阐明。
脓毒症心肌病的细胞和分子机制,并开发新的治疗方法
改善与脓毒症引起的心功能障碍相关的发病率和死亡率。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Chuanfu Li其他文献
Chuanfu Li的其他文献
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{{ truncateString('Chuanfu Li', 18)}}的其他基金
Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis
乳酸对脓毒症心血管功能障碍的新作用
- 批准号:
10397654 - 财政年份:2020
- 资助金额:
$ 33.3万 - 项目类别:
Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis
乳酸对脓毒症心血管功能障碍的新作用
- 批准号:
10609873 - 财政年份:2020
- 资助金额:
$ 33.3万 - 项目类别:
Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis
乳酸对脓毒症心血管功能障碍的新作用
- 批准号:
10027071 - 财政年份:2020
- 资助金额:
$ 33.3万 - 项目类别:
Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis
乳酸对脓毒症心血管功能障碍的新作用
- 批准号:
10192825 - 财政年份:2020
- 资助金额:
$ 33.3万 - 项目类别:
Novel Role of Lactate for Cardiovascular Dysfunction in Sepsis
乳酸对脓毒症心血管功能障碍的新作用
- 批准号:
10192825 - 财政年份:2020
- 资助金额:
$ 33.3万 - 项目类别:
Innate Immunity and Cardiovascular Function in Sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
8628995 - 财政年份:2009
- 资助金额:
$ 33.3万 - 项目类别:
Innate immunity and cardiovascular function in sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
7901577 - 财政年份:2009
- 资助金额:
$ 33.3万 - 项目类别:
Innate immunity and cardiovascular function in sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
8118998 - 财政年份:2009
- 资助金额:
$ 33.3万 - 项目类别:
Innate Immunity and Cardiovascular Function in Sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
8792849 - 财政年份:2009
- 资助金额:
$ 33.3万 - 项目类别:
Innate Immunity and Cardiovascular Function in Sepsis
脓毒症的先天免疫和心血管功能
- 批准号:
10166858 - 财政年份:2009
- 资助金额:
$ 33.3万 - 项目类别:
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