The Role of Pericytes in the Vascular Dysfunction of Sepsis

周细胞在脓毒症血管功能障碍中的作用

• 批准号: 10246356
• 负责人: Hongkuan Fan
• 金额: $ 28.41万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246356
• 关键词: Address; Adherens Junction; Apoptosis; Basement membrane; Blood Vessels; Blood capillaries; Caring; Cause of Death; Cell physiology; Cells; Coculture Techniques; Complication; Data; Disease; Drug or chemical Tissue Distribution; Endothelial Cells; Endothelium; Exhibits; Extravasation; FLI1 Transcription Factor; FLI1 gene; Functional disorder; Genes; Goals; Health; Homeostasis; Inflammation Mediators; Injury to Kidney; Intensive Care Units; Kidney; Knockout Mice; Knowledge; Label; Lead; Life; Luciferases; Lung; Mediating; Microcirculation; Multiple Organ Failure; Mus; Organ failure; Outcome; Paracrine Communication; Pathogenesis; Pericytes; Permeability; Plasma; Play; Process; Research; Role; Sepsis; Septic Shock; Signal Transduction; System; TNF gene; Therapeutic; Tight Junctions; Transgenic Mice; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; cadherin 5; cecal ligation puncture; claudin-1 protein; endothelial dysfunction; exosome; experience; improved; in vivo imaging; kidney vascular structure; liver injury; lung injury; nanovesicle; novel; novel therapeutic intervention; occludin; preservation; protein expression; targeted treatment; therapeutic target; treatment strategy

PROJECT SUMMARY/ABSTRACT Septic shock with multiple organ failure is the leading cause of death in non-coronary intensive care units and remains a major health problem in the US. Endothelial cell (EC) dysfunction, manifested by increases in vascular permeability, is an important hallmark of septic shock and plays a critical role in the pathogenesis of multi-organ failure. Pericytes maintain endothelial barrier function and represent a potential therapeutic target in sepsis. However, the processes that govern pericyte viability and their role in barrier function in sepsis have not yet been fully elucidated. Pericytes are specialized cells embedded in the capillary basement membrane that wrap around endothelial cells of the microcirculation throughout the body and are thought to be important regulators of microcirculatory homeostasis. However, the role of pericytes in the endothelial dysfunction of sepsis is largely unknown. Our data demonstrated that pericytes are depleted in the mouse lung and kidney microvasculature during cecal ligation and puncture (CLP)-induced sepsis and pericyte depletion results in vascular leakage. The transcription factor friend leukemia virus integration 1 (Fli-1), is critical to pericyte dysfunction and viability in sepsis by mediating pericyte programmed cell death through pyroptosis. MiR-145 inhibits Fli-1 expression and is abundantly expressed in pericytes; however, during sepsis, miR-145 expression decreases with a concomitant increase in Fli-1 expression. This suggests that miR-145 may play an important role in pericyte viability and, therefore, be an important regulator of vascular permeability. A clearer understanding of how the miR-145/Fli-1 axis regulates pericyte viability in sepsis in a critical gap in knowledge that may lead to novel therapeutic approaches for sepsis. Furthermore, understanding the mechanisms by which pericytes support the vascular barrier integrity in sepsis may also have therapeutic implications. One potential mechanism whereby pericytes communicate with endothelial cells is through paracrine signaling via exosomes. Intriguingly, we have demonstrated that pericyte-derived exosomes but not fibroblast-derived exosomes improve survival in mice subjected to CLP-induced sepsis and that pericyte exosomes contain abundant miR-145. The long-term goal of our research is to identify novel treatment strategies to maintain endothelial barrier function in sepsis. The overall objective for this proposal is to identify the determinants of pericyte viability in sepsis and the mechanisms by which pericytes maintain endothelial barrier function. We hypothesize that pericyte viability regulated by the miR-145/Fli-1 axis is a critical determinant of sepsis outcomes through pericyte- mediated stabilization of endothelial permeability. Three specific aims address this hypothesis: Aim 1: Determine the mechanisms by which the miR-145/Fli-1 axis regulates pericyte function and viability in sepsis. Aim 2: Define the mechanisms by which pericytes and pericyte exosomes regulate EC function. Aim 3: Elucidate the therapeutic potential of pericyte-derived exosomes in CLP-induced sepsis.

项目概要/摘要 脓毒性休克合并多器官衰竭是非冠心病重症监护病房中死亡的主要原因 仍然是美国的一个主要健康问题。内皮细胞 (EC) 功能障碍，表现为 血管通透性是感染性休克的重要标志，在感染性休克的发病机制中起着至关重要的作用。 多器官衰竭。周细胞维持内皮屏障功能，是潜在的治疗靶点 败血症。然而，控制周细胞活力的过程及其在脓毒症屏障功能中的作用尚未得到证实。 尚未得到充分阐明。周细胞是嵌入毛细血管基底膜中的特殊细胞， 包裹着全身微循环的内皮细胞，被认为很重要 微循环稳态的调节剂。然而，周细胞在脓毒症内皮功能障碍中的作用 很大程度上是未知的。我们的数据表明，小鼠肺和肾中的周细胞已耗尽 盲肠结扎穿刺 (CLP) 诱导的败血症和周细胞耗竭期间的微血管 血管渗漏。转录因子朋友白血病病毒整合 1 (Fli-1) 对周细胞至关重要 通过焦亡介导周细胞程序性细胞死亡来治疗脓毒症的功能障碍和活力。米尔-145 抑制 Fli-1 表达并在周细胞中大量表达；然而，在脓毒症期间，miR-145 表达 随着 Fli-1 表达的增加而减少。这表明 miR-145 可能发挥重要作用 在周细胞活力中发挥作用，因此是血管通透性的重要调节剂。更清晰 了解 miR-145/Fli-1 轴如何调节脓毒症中的周细胞活力，目前是知识的关键空白 这可能会带来脓毒症的新治疗方法。此外，了解其机制 周细胞支持脓毒症中血管屏障的完整性也可能具有治疗意义。一种潜力 周细胞与内皮细胞沟通的机制是通过外泌体的旁分泌信号传导。 有趣的是，我们已经证明，周细胞衍生的外泌体而非成纤维细胞衍生的外泌体可以改善 遭受 CLP 诱导的败血症的小鼠的存活率以及周细胞外泌体含有丰富的 miR-145。这 我们研究的长期目标是确定新的治疗策略来维持内皮屏障功能 败血症。该提案的总体目标是确定败血症中周细胞活力的决定因素以及 周细胞维持内皮屏障功能的机制。我们假设周细胞活力 由 miR-145/Fli-1 轴调节是脓毒症结果的关键决定因素 介导内皮通透性的稳定。针对这一假设的三个具体目标： 目标 1： 确定 miR-145/Fli-1 轴调节脓毒症中周细胞功能和活力的机制。 目标 2：定义周细胞和周细胞外泌体调节 EC 功能的机制。目标 3：阐明 周细胞衍生的外泌体在 CLP 诱导的脓毒症中的治疗潜力。