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

项目4（ESI）研究了补体激活血小板驱动内皮细胞的机制， 激活和单核细胞/巨噬细胞促炎分化和募集，促进血管 肺动脉高压（PH）的重塑。通过我们的研究积累了人类和动物研究的数据， 一个实验室和其他人证明了血小板在PH的启动和进展中的作用，但是是什么驱动了PH的发生和发展？ 血小板活化和血小板如何介导PH中的血管重塑尚未解决。项目4 利用了几种新颖的和创新的体内和体外方法，采用遗传和药理学 方法检测补体介导的血小板活化在两种PH小鼠模型中的作用， 补体介导的血小板活化诱导内皮细胞活化并驱动内皮细胞活化的总体假设 单核细胞向肺血管系统的募集和促炎性激活促进肺血管的形成。 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 通过补体过敏毒素激活血小板的炎性病症。过敏毒素是否激活 PH中的血小板和驱动血小板活化是未知的，并且是目标1的焦点。内皮功能失调的 PH发病机制的核心，来自PH患者和动物的内皮细胞显示 促进血小板-内皮粘附的蛋白质表达增加。虽然血小板的机制 在止血和血栓形成中，内皮细胞的募集和粘附得到了很好的描述， 目的2的目标是确定在炎症条件下的抗氧化能力，并且尚未在PH中进行评估。 补体介导的血小板活化对血小板内皮细胞粘附的作用机制及血小板对内皮细胞粘附的影响 粘附于内皮促进实验性PH中内皮活化。单核细胞和巨噬细胞 血管周围/外膜间隙内的募集和积聚是肺动脉高压的一致特征。 在人类和所有动物模型中，与PH相关的血管重塑，然而， 对这些过程仍然知之甚少。目的3将研究补体在体内的作用机制， 活化的血小板支持血液传播的单核细胞向肺脉管系统的募集和活化 促进肺血管重塑和肺动脉高压。这些研究的总体目标是 确定补体激活的血小板是否驱动内皮细胞和单核细胞活化促进 肺血管重塑和PH，为未来针对血小板免疫的研究奠定基础。 目前可用的新疗法的反应。

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.