Innate Immunity and Cardiovascular Function in Sepsis

脓毒症的先天免疫和心血管功能

• 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
• 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

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.

危重病人经常出现复杂的疾病谱，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)、脓毒症综合征和/或 感染性休克并多器官功能障碍综合征(MODS)(1例)。在美国约有750,000人 患者/年发生败血症综合征(2例)。心血管功能障碍是相关的主要并发症。 有MODS的发病率和死亡率。然而，心血管功能障碍发生的机制 脓毒症/感染性休克期间的情况仍不清楚。血管内皮细胞功能障碍在脓毒症致多器官功能障碍中的作用 和高死亡率。内皮细胞表达模式识别受体(PRRs)。PRRS识别病原体 相关分子模式(PAMP)，启动先天免疫和炎症反应，并上调 黏附分子的表达，从而促进免疫细胞的渗透和器官损伤。因此， 保存内皮细胞功能是减轻脓毒症致残率和死亡率的重要途径 死亡率。在上一次授予期间，我们发现了内皮特异性HSPA12B在 CLP脓毒症时内皮细胞功能和天然免疫反应的调节。HSPA12B是一种新的 发现了HSP70家族的成员。它主要在内皮细胞中表达，并发挥一种 在诱导血管生成中起重要作用。我们发现血管内皮细胞特异性缺陷 HSPA12B(HSPA12B-/-)可加重脓毒症患者的死亡率，恶化心功能。相比之下，转基因 过度表达内皮细胞HSPA12B的小鼠显著改善了生存结果和心脏 在内毒素血症中的作用。我们的发现提出了一个重要的问题，即内皮细胞HSPA12B是如何 多菌败血症对死亡率和心血管功能障碍有如此深远的影响？ 我们做了一项新的观察，发现HSPA12B可以移位到内皮细胞的细胞核中。我们 还发现HSPA12B可以从内皮细胞释放，并通过 外体，它下调炎性细胞因子的产生。我们的发现表明内皮细胞 HSPA12B不仅对内皮细胞功能有重要作用，而且对炎症反应也有重要作用。 脓毒症期间的免疫细胞。因此，内皮细胞HSPA12B可能是一种重要的效应分子 脓毒症时内皮细胞和免疫细胞之间的串扰。根据初步数据，我们 内皮细胞HSPA12B是一种新型内源性抗脓毒症效应物的假设 内皮细胞功能与先天免疫性炎症的差异性调控诱导心肌病 答复“。为了检验这些假设，我们提出了三个具体目标。具体目标1.调查是否 HSPA12B对感染性心肌病的保护作用是通过调节内皮细胞介导的 功能。特定目的2.确定内皮细胞对感染性心肌病的保护作用 HSPA12B是通过调节炎症细胞反应而介导的。具体目标3.评估治疗方法 热休克蛋白12B在败血症所致心肌病中的作用这项研究的长期目标是阐明 感染性心肌病的细胞和分子机制及开发新的治疗方法 改善脓毒症引起的心功能不全的发病率和死亡率。