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

从骨髓中动员吞噬细胞是宿主抵御败血症感染的关键。然而， 这些被招募的免疫细胞的活动也引起全身炎症，导致广泛的损伤。 微血管系统。组织水肿是由重要器官系统的毛细血管完整性丧失引起的，尤其是 在肺部，是有害的。骨髓中有内皮祖细胞，它可以参与 维持和/或恢复微血管动态平衡。最近的调查显示，这个水平 脓毒症患者循环内皮祖细胞数量增加。脓毒症时常出现EPC数下降 随着疾病的恶化，器官衰竭的发展，以及死亡率的增加。相反，一个更大的 循环内皮祖细胞的数量与脓毒症和急性肺损伤患者预后的改善有关。 然而，目前关于潜在的分子信号机制的信息很少。 骨髓EPC参与宿主防御的调控。我们对败血症小鼠模型的初步研究 感染大肠埃希氏菌后，EPC的骨髓池中含有Lin-c-kit+Sca-1+VEGFR2+ (VEGFR2+LKS)表面标志物在败血症感染后迅速扩张。AP1信令下行 TLR4-JNK通路介导的SCA-1表达上调在EPC中起重要作用 激活。分别带有TLR4-ERK1/2-Cyclin D1和TLR4-ERK1/2-SP1通路的SCA-1信号通路 促进内皮祖细胞增殖和内皮分化。扩增的骨髓VEGFR2+LKS细胞中的内皮祖细胞 POOL表现出明显增强的血管生成活性。骨髓源性细胞主动归巢于肺 并在败血症感染后整合到肺微血管中。当前项目将确定 骨髓内皮祖细胞在宿主抗败血症感染中的生物学作用及其机制 骨髓内皮祖细胞被激活以维持微血管动态平衡。我们的中心假设是 骨髓EPC通过SCA-1信号通路的反应是维持微血管内环境稳定的关键 对败血症感染的炎症反应。三个具体目标是1)确定骨髓内皮祖细胞应答 在维持重要器官组织(通常是肺组织)的微血管平衡方面起着关键作用。 宿主对败血症感染的防御，2)在VEGFR2+LKS快速扩张过程中SCA-1信号的特征 脓毒症感染炎症反应过程中骨髓中的细胞池，以及3)描绘SCA-1 在炎症反应中VEGFR2+LKS细胞编程促进血管生成的信号转导 败血症感染。从这次调查中获得的结果将极大地促进我们对 主机防御中的EPC响应。它还将确定开发新的治疗干预措施的关键目标 预防和治疗脓毒症感染引起的炎症反应引起的重要器官损伤。

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.