Sca-1 signaling, EPC, and the inflammatory response to septic infection

Sca-1 信号传导、EPC 和脓毒症感染的炎症反应

• 批准号: 10394812
• 负责人: PING ZHANG
• 金额: $ 35.1万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394812
• 关键词: Acute Lung Injury; Area; Biological; Blood Circulation; Blood Vessels; Blood capillaries; Bone Marrow; Cell Count; Cell Proliferation; Cells; Cyclin D1; Deterioration; Development; Disease; Drops; Edema; Endothelium; Escherichia coli; Exhibits; Genetic Transcription; Home; Homeostasis; Host Defense; Immune; Impairment; Infection; Inflammatory; Inflammatory Response; Injury; Investigation; KDR gene; Knowledge; Lung; MAPK3 gene; MAPK8 gene; Marrow; Mediating; Molecular; Organ; Organ failure; Pathway interactions; Patients; Phagocytes; Pilot Projects; Play; Proto-Oncogene Protein c-kit; Recruitment Activity; Regulation; Research; Role; SP1 gene; Sepsis; Septicemia; Signal Transduction; Surface; TLR4 gene; Testing; Time; Tissues; Transcription Factor AP-1; Up-Regulation; angiogenesis; body system; defense response; effective therapy; endothelial stem cell; experimental study; improved outcome; mortality; mouse model; neglect; novel therapeutic intervention; organ growth; organ injury; precursor cell; prevent; response; septic; stem cell proliferation; systemic inflammatory response; therapeutic target

Mobilization of phagocytes from bone marrow is critical for host defense against septic infection. However, the activity of these recruited immune cells also evokes systemic inflammation leading to widespread injury in microvasculature. Tissue edema resulted from the loss of capillary integrity in vital organ systems, particularly in the lung, is detrimental. The bone marrow houses endothelial progenitor cells (EPCs) which can participate in maintaining and/or restoring microvascular homeostasis. Recent investigations have revealed that the level of circulating EPCs increases in patients with sepsis. Drop of EPC number during sepsis commonly occurs with deterioration of the disease, development of organ failure, and increase in mortality. Conversely, a greater number of circulating EPCs is associated with improved outcomes in patients with sepsis and acute lung injury. At the present time, however, little information is available about molecular signaling mechanisms underlying the regulation of marrow EPC participation in host defense. Our pilot studies on murine models of septic infection with Escherichia coli revealed that the marrow pool of EPCs bearing the lin-c-kit+Sca-1+VEGFR2+ (VEGFR2+LKS) surface marker rapidly expanded following septic infection. AP1 signaling downstream of the TLR4-JNK pathway mediated upregulation of Sca-1 expression, which played an imperative role in EPC activation. Sca-1 signals with the TLR4-ERK1/2-cyclin D1 and TLR4-ERK1/2-SP1 pathways, respectively, to promote EPC proliferation and endothelial differentiation. EPCs in the expanded marrow VEGFR2+LKS cell pool exhibited a markedly enhanced angiogenic activity. Bone marrow-derived cells actively homed to the lung and integrated in the pulmonary microvasculature following septic infection. The current project will determine the biological role of marrow EPCs in host defense against septic infection with the focus on elucidating how marrow EPCs are activated for maintaining microvascular homeostasis. Our central hypothesis is that the marrow EPC response via Sca-1 signaling is essential for maintaining microvascular homeostasis during the inflammatory response to septic infection. Three specific aims are 1) to determine if the marrow EPC response plays a pivotal role in maintaining microvascular homeostasis in vital organ tissue, typically in the lung, during host defense against septic infection, 2) to characterize Sca-1 signaling in rapid expansion of VEGFR2+LKS cell pool in the bone marrow during the inflammatory response to septic infection, and 3) to delineate Sca-1 signaling in VEGFR2+LKS cell programming for enhancing angiogenesis during the inflammatory response to septic infection. Results obtained from this investigation will greatly advance our knowledge about the role of EPC response in host defense. It will also identify key targets for developing novel therapeutic interventions to prevent and treat vital organ injury caused by the inflammatory response to septic infection.

骨髓中的吞噬细胞动员对于宿主防御化粪池感染至关重要。然而， 这些招募的免疫细胞的活性还引起了全身性炎症，导致广泛损伤 微脉管系统。组织水肿是由于重要器官系统中毛细血管完整性的丧失而引起的，特别是 在肺中，有害。骨髓容纳内皮祖细胞（EPC），可以参与 维持和/或恢复微血管稳态。最近的调查显示了水平 败血症患者的循环EPC增加。败血症期间的EPC数量下降 随着疾病恶化，器官衰竭的发展和死亡率的增加。相反，更大 循环EPC的数量与败血症患者和急性肺损伤患者的预后改善有关。 然而，目前，几乎没有有关分子信号传导机制的信息 骨髓EPC参与宿主防御的规定。我们对化粪池鼠模型的试点研究 用大肠杆菌感染了EPC的骨髓池，带有LIN-C-KIT+SCA-1+VEGFR2+ （VEGFR2+LK）表面标记在化粪池感染后迅速扩张。 AP1在下游 TLR4-JNK途径介导了SCA-1表达的上调，在EPC中发挥了势在必行的作用 激活。带有TLR4-ERK1/2-Cyclin D1和TLR4-ERK1/2-SP1途径的SCA-1信号 促进EPC增殖和内皮分化。 EPC在扩展的骨髓VEGFR2+LKS细胞中 池表现出明显增强的血管生成活性。骨髓来源的细胞积极地归入肺 并整合在化粪池感染后的肺微脉管系统中。当前项目将确定 骨髓EPC在宿主防御性化粪池感染中的生物学作用，重点是阐明如何 骨髓EPC被激活以维持微血管稳态。我们的核心假设是 通过SCA-1信号传导骨髓EPC响应对于维持微血管稳态至关重要 对化粪池感染的炎症反应。三个具体目标是1）确定骨髓EPC是否反应 在维持重要器官组织中的微血管稳态方面起着关键作用，通常在肺部，期间 宿主防御性化粪池感染，2）在快速扩张VEGFR2+LKS中表征SCA-1信号传导 炎症反应对化粪池感染的炎症反应期间的骨髓中的细胞池，3）描绘SCA-1 VEGFR2+LKS细胞编程中的信号传导，以增强炎症反应期间的血管生成 化粪池感染。从本调查获得的结果将大大提高我们对 EPC在主机防御中的反应。它还将确定开发新型治疗干预措施的关键目标 预防和治疗因化粪池感染的炎症反应引起的重要器官损伤。