The Beneficial Effects of Endothelial Progenitor Cells in the Vascular Dysfunction of Sepsis

 描述（由申请人提供）：脓毒性休克伴多器官衰竭是非冠状动脉重症监护病房的主要死亡原因，在美国仍然是一个主要的健康问题。内皮细胞功能障碍是感染性休克的重要标志，并导致血管通透性增加，在多器官衰竭的发病机制中起关键作用。因此，改善内皮功能是脓毒症的重要潜在治疗靶点。我们研究的长期目标是确定脓毒症内皮损伤的新治疗策略。本提案的总体目标是确定 内皮祖细胞（EPCs）通过其调节脓毒症中的内皮功能障碍。内皮祖细胞是循环的、骨髓来源的内皮前体细胞，其最近与脓毒症相关。具体而言，与健康对照相比，来自脓毒症患者的EPC表现出功能改变，并且EPC增殖与人脓毒症中的器官功能障碍呈负相关。我们的数据表明，在多微生物败血症的小鼠盲肠结扎穿孔（CLP）模型中，用外源性人脐带血来源的EPCs治疗可提高存活率，减弱肺血管渗漏并改善器官损伤。更好地了解EPCs发挥其保护作用的机制对于设计新的治疗策略至关重要。已知内皮细胞（EC）和EPC释放含有调节内皮功能和屏障完整性的微小RNA（miRNA）的外来体和微粒。我们已经表明，用EPCs治疗改变了鼠脓毒症中EC相关miRNA的循环水平，包括miR-126。我们的研究结果提供了强有力的证据表明，miR-126可能在维持EPC/EC功能和屏障完整性方面发挥重要作用。我们提出了两个相关的假设：1）内皮祖细胞通过在脓毒症中释放特异性miRNA来调节内皮功能和屏障完整性，以及2）调节内皮屏障完整性的miRNA的表达改变与人类脓毒症的疾病严重程度和结果相关。两个具体的目的解决这些假设：目的1：确定EPCs影响小鼠败血症血管屏障完整性的机制。目的2：确定已知调节人脓毒症中内皮功能和屏障完整性的miRNAs的表达模式。这项研究将为脓毒症的新治疗策略的设计奠定重要基础。

 DESCRIPTION (provided by applicant): 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 dysfunction is an important hallmark of septic shock and results in increases in vascular permeability that play critical roles in the pathogenesis of multi-organ failure. Thus, improving endothelial function represents an important potential therapeutic target in sepsis. The long-term goal of our research is to identify novel treatment strategies for the endothelial injury of sepsis. The overall objective for this proposal is to identify the mechanisms by which endothelial progenitor cells (EPCs) modulate endothelial dysfunction in sepsis. EPCs are circulating, bone marrow-derived endothelial precursor cells which have been recently associated with sepsis. Specifically, EPCs from humans with sepsis demonstrate alterations in function compared to healthy controls and EPC proliferation is inversely related to organ dysfunction in human sepsis. Our data demonstrate that treatment with exogenous human cord blood derived EPCs improves survival, attenuates pulmonary vascular leak and improves organ injury in the murine cecal ligation and puncture (CLP) model of polymicrobial sepsis. A better understanding of the mechanisms by which EPCs exert their protective effects is crucial to the design of new therapeutic strategies. Endothelial cells (ECs) and EPCs are known to release exosomes and microparticles containing micro RNAs (miRNAs) that regulate endothelial function and barrier integrity. We have shown that treatment with EPCs alters circulating levels of EC relevant miRNAs in murine sepsis, including miR-126. Our findings provide strong evidence that miR-126 may play an important role in maintaining EPC/EC function and barrier integrity in sepsis. We propose two related hypotheses: 1) Endothelial progenitor cells regulate endothelial function and barrier integrity through release of specific miRNAs in sepsis and 2) Altered expression of miRNAs which regulate endothelial barrier integrity are associated with severity of illness and outcomes in human sepsis. Two specific aims address these hypotheses: Aim 1: Determine the mechanisms by which EPCs affect vascular barrier integrity in murine sepsis. Aim 2: Determine the expression patterns of miRNAs known to modulate endothelial function and barrier integrity in human sepsis. The proposed research will lay a critical foundation for the design of novel therapeutic strategies for sepsis.