Complement-Driven Platelet Activation in Pulmonary Vascular Remodeling and Pulmonary Hypertension

项目4(ESI)检查补体激活的血小板驱动内皮细胞的机制 活化与单核/巨噬细胞促炎症分化和募集，促进血管生成 肺动脉高压(PH)的重构。从我们的人类和动物研究中积累数据 实验室和其他人证明了血小板在PH的发生和发展中的作用，然而是什么驱动了PH 血小板活化和血小板如何在PH中调节血管重塑还没有被解决。项目4 利用几种新颖和创新的体内和体外方法，利用遗传学和药理学 方法在两种PH小鼠模型中检测补体介导的血小板活化的作用，以检测补体介导的血小板活化的作用。 总体假设是补体介导的血小板激活诱导内皮细胞激活并驱动 单核细胞对肺血管的募集和促炎活性 血管重塑和肺动脉高压。补体介导的血小板活化可能发生在 炎症状态是通过激活血小板的补体过敏毒素造成的。过敏性毒素是否激活 在PH中，血小板和驱动血小板活化是未知的，也是目标1的焦点。内皮功能障碍 在PH的发病机制中处于中心地位，来自PH患者和动物的内皮细胞显示 促进血小板-内皮细胞黏附的蛋白质表达增加。而血小板的作用机制 在止血和血栓形成中，内皮的募集和黏附被很好地描述，但它很少被描述 在炎症条件下被理解，在PH中没有被评估。目标2的目标是确定 补体介导的血小板活化对血小板内皮细胞黏附的作用机制 在实验性PH中，与内皮细胞的黏附促进了内皮细胞的激活。单核细胞和巨噬细胞 在血管周围/外膜间隙内的募集和聚集是肺间质纤维化的一贯特征 在人类和所有动物模型中与PH相关的血管重塑，然而驱动机制 人们对这些过程仍然知之甚少。目标3将研究补体的机制 活化的血小板支持血液携带的单核细胞向肺血管系统募集和激活 促进肺血管重塑和肺动脉高压。这些研究的总体目标是 是确定补体激活的血小板是否驱动内皮细胞和单核细胞的激活促进 肺血管重塑与肺高压，为未来针对血小板免疫的研究奠定基础 用目前可用的新疗法回应。

PROJECT 4 (ESI) examines the mechanisms by which complement activated platelets drive endothelial activation and monocyte/macrophage proinflammatory differentiation and recruitment, promoting vascular remodeling in pulmonary hypertension (PH). Accumulating data from both human and animal studies by our laboratory and others demonstrate a role for platelets in the initiation and progression of PH, however what drives platelet activation and how platelets mediate vascular remodeling in PH has not been addressed. Project 4 utilizes several novel and innovative in vivo and in vitro approaches employing genetic and pharmacologic methods to examine the role of complement mediated platelet activation in two murine models of PH to test the overall hypothesis that complement-mediated activation of platelets induces endothelial activation and drives the recruitment and proinflammatory activation of monocytes to the pulmonary vasculature promoting pulmonary vascular remodeling and pulmonary hypertension. Complement-mediated platelet activation may occur in inflammatory conditions via complement anaphylatoxin activation of platelets. Whether anaphylatoxins activate platelets and drive platelet activation in PH is unknown and is the focus of aim 1. Endothelial dysfunction is central to the pathogenesis of PH, and endothelial cells from patients and animals with PH demonstrate increased expression of proteins which promote platelet-endothelial adhesion. While the mechanisms for platelet recruitment and adherence to the endothelium is well described in hemostasis and thrombosis, it is poorly understood in inflammatory conditions and has not been evaluated in PH. The goal of aim 2 is to determine the mechanisms of complement mediated platelet activation to platelet endothelial adhesion and how platelet adhesion to the endothelium promotes endothelial activation in experimental PH. Monocyte and macrophage recruitment and accumulation within the perivascular/adventitial space is a consistent feature of pulmonary vascular remodeling associated with PH in both humans and all animal models, however the mechanisms driving these processes remain poorly understood. Aim 3 will investigate the mechanisms by which complement activated platelets support the recruitment and activation of blood borne monocytes to the pulmonary vasculature promoting pulmonary vascular remodeling and pulmonary hypertension. The overall objective of these studies is to determine whether complement activated platelets drive endothelial and monocyte activation promoting pulmonary vascular remodeling and PH, setting the stage for future studies targeting the platelet immune response with novel currently available therapies.