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：
Chuanfu Li
金额：
$ 33.3万
依托单位：
EAST TENNESSEE STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/9927632
关键词：
Acute Adult Respiratory Distress Syndrome Attenuated Cardiomyopathies Cardiovascular Physiology Cardiovascular system Cell Adhesion Molecules Cell Nucleus Cell physiology Cells Cessation of life Complex Complication Critical Illness Critical Pathways Data Disease Endothelial Cells Endothelium Endotoxemia Event Exhibits Functional disorder Goals Grant Heart Heat shock proteins Heat-Shock Proteins 70 Immune Immune System Diseases Immune response Infection Infiltration Inflammatory Inflammatory Response Innate Immune Response Knockout Mice Knowledge Maintenance Mediating MicroRNAs Molecular Morbidity - disease rate Multiple Organ Failure Mus Myocardial dysfunction Myocardium Natural Immunity Nuclear Translocation Organ Patients Pattern Pattern recognition receptor Phosphatidylinositols Phosphotransferases Play Production Regulation Research Role Sepsis Sepsis Syndrome Septic Shock Signal Pathway Signal Transduction Systemic Inflammatory Response Syndrome Testing Therapeutic Effect Transgenic Mice Trauma United States angiogenesis attenuation base cytokine effective therapy exosome heart function improved macrophage member mortality novel novel therapeutic intervention novel therapeutics organ injury pathogen polymicrobial sepsis preservation prevent response septic survival 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.

重症患者经常发展出复杂的疾病频谱，其中可能包括急性呼吸系统遇险综合征（ARDS），全身性炎症反应综合征（SIRS），败血症综合征和/或败血性休克和多器官功能障碍综合征（MODS）（1）。在美国约75万患者/年发育脓毒症综合征（2）。心血管功能障碍是与主要并发症相关的主要并发症具有国防部的发病率和死亡率。但是，心血管功能障碍的机制在败血症/败血症期间，休克尚不清楚。内皮细胞功能障碍有助于败血症引起的mod 和高死亡率。内皮细胞表达模式识别受体（PRR）。 PRR识别病原体相关的分子模式（PAMP），启动先天免疫和炎症反应，并更新粘附分子的表达，从而促进免疫球浸润和器官损伤。所以，保存内皮细胞功能是减弱败血症诱导症和的重要方法死亡。在最后一个赠款期间，我们发现了内皮特异性HSPA12B的新作用 CLP败血症期间内皮细胞功能和先天免疫反应的调节。 HSPA12B是新的发现了HSP70家族的成员。它主要在内皮细胞中表达在诱导血管生成中的重要作用。我们发现内皮细胞特异性缺陷 HSPA12B（HSPA12B - / - ）加剧了死亡率并恶化败血症。相反，转基因超出表示内皮HSPA12B暴露的小鼠显着改善了生存结果和心脏内毒素血症的功能。我们的发现提出了一个重要的问题，即内皮HSPA12B如何对与多数型败血症相关的死亡率和心血管功能障碍的深远影响？我们已经做出了一个新的观察结果，即HSPA12B可以在内皮细胞中转移到核中。我们还发现HSPA12B可以从内皮细胞释放，并通过外泌体下调炎性细胞因子的产生。我们的发现表明内皮 HSPA12B不仅在内皮细胞功能中具有重要作用，而且对于通过败血症期间的免疫细胞。那就是，内皮HSPA12B可能是培养的重要效应子败血症期间内皮细胞和免疫细胞之间的串扰。根据初步数据，我们假设“内皮HSPA12B是一种新型的内源性效应子，可防止败血症通过不同调节内皮细胞功能和先天免疫炎症引起的心肌病诱导心肌病回答”。为了检验这些假设，我们提出了三个具体目标。具体目的1。 HSPA12B通过调节内皮调节诱导败血性心肌病的保护功能。具体目的2。确定内皮对败血性心肌病的保护是否 HSPA12B是通过调节炎症细胞反应介导的。特定目标3。评估治疗 HSPA12B在败血症诱导的心肌病中的影响。这项研究的长期目标是阐明败血性心肌病的细胞和分子机制，并开发出新的和新颖的疗法改善与败血症诱导心脏功能障碍相关的发病率和死亡率。