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.

从骨髓中动员吞噬细胞对于宿主防御脓毒性感染是至关重要的。然而，在这方面， 这些募集的免疫细胞的活性也引起全身炎症， 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， 对肺部有害骨髓中含有内皮祖细胞（EPCs）， 维持和/或恢复微血管稳态。最近的调查显示， 败血症患者循环EPCs的数量增加。脓毒症时EPC数量下降是常见的 随着疾病的恶化、器官衰竭的发展和死亡率的增加。相反，更大的 循环EPCs数量与脓毒症和急性肺损伤患者预后改善相关。 然而，目前，关于潜在的分子信号传导机制的信息很少。 骨髓EPC参与宿主防御的调控。我们对脓毒症小鼠模型的初步研究 大肠杆菌感染显示，携带lin-c-kit + Sca-1 + VEGFR2+的EPCs的骨髓池 （VEGFR2 + LKS）表面标志物在脓毒性感染后迅速扩增。AP1信令下游 TLR4-JNK通路介导Sca-1表达上调，在EPC中起重要作用 activation. Sca-1分别通过TLR4-ERK1/2-cyclin D1和TLR4-ERK1/2-SP1途径进行信号传导， 促进EPC增殖和内皮分化。扩增的骨髓VEGFR2 + LKS细胞中的EPC 池显示出显著增强的血管生成活性。骨髓源性细胞主动归巢于肺 并在脓毒性感染后整合到肺微血管中。本项目将确定 骨髓EPCs在宿主防御脓毒症感染中的生物学作用，重点阐明如何 骨髓EPCs被激活以维持微血管稳态。我们的中心假设是， 通过Sca-1信号传导的骨髓EPC反应对于维持微血管稳态是必不可少的。 脓毒性感染的炎症反应。三个具体目标是：1）确定骨髓EPC反应是否 在维持重要器官组织（通常在肺中）的微血管稳态中起关键作用， 宿主对脓毒性感染的防御，2）表征VEGFR2 + LKS快速扩增中的Sca-1信号传导 脓毒性感染炎症反应期间骨髓中的细胞池，以及3）描绘Sca-1 VEGFR 2 + LKS细胞编程中的信号传导在炎症反应期间增强血管生成 脓毒性感染从这项调查中获得的结果将大大提高我们对 宿主防御中的EPC响应。它还将确定开发新的治疗干预措施的关键目标， 预防和治疗由脓毒性感染的炎症反应引起的重要器官损伤。