Control of fibroblast function by prostaglandin E2 and plasminogen activation

前列腺素 E2 和纤溶酶原激活对成纤维细胞功能的控制

基本信息

批准号：
7910714
负责人：
MARC L PETERS-GOLDEN
金额：
$ 37.97万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-11 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7910714
关键词：
5&apos -Nucleotidase Alveolar Animal Model Arachidonic Acids Architecture Cell Adhesion Cell Line Cell surface Cells Cicatrix Collagen Cyclic AMP Cyclic AMP-Dependent Protein Kinases Deposition Development Dinoprostone Disease Effector Cell Extracellular Matrix Fibrinolysis Fibroblasts Fibrosis Figs - dietary Future GTP-Binding Proteins Hamman-Rich syndrome Histologic Human Injury Lung Lung diseases Mediating Mediator of activation protein Mesenchymal Modeling Mus Myofibroblast PTEN gene Pathogenesis Patients Peptide Hydrolases Phenotype Phosphoric Monoester Hydrolases Plasmin Plasminogen Plasminogen Activator Plasminogen Activator Inhibitor 1 Play Production Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Pulmonary Fibrosis Regulation Relative (related person)Research Role Signal Transduction System Testing Tissues Transforming Growth Factors Urokinase Urokinase Plasminogen Activator Receptor cell type fatty acid metabolism guanylate inhibitor/antagonist injured insight lipid mediator lung injury novel public health relevance receptor repaired response

项目摘要

DESCRIPTION (provided by applicant): Fibroblasts are the principal effector cells that mediate tissue remodeling in idiopathic pulmonary fibrosis (IPF) via their capacities for enhanced survival, proliferation, collagen deposition, and myofibroblast differentiation. Although research in the pathogenesis of pulmonary fibrosis has been dominated by studies investigating fibroblast activation signals, evidence indicates that this disorder is also characterized by a relative deficiency in counter-regulatory anti-fibrotic signals. Two such anti-fibrotic signals are the prostanoid prostaglandin E2 (PGE2) and plasminogen activator (PA) activity. Each of these has been shown to be deficient in patients with IPF, and deficiency of each has been established to be pathogenically important in animal models of pulmonary fibrosis. PGE2 is a lipid mediator derived from cyclooxygenase metabolism of the fatty acid arachidonic acid that acts via cell surface G protein-coupled E prostanoid receptors. The PA system is a proteolytic cascade that includes the protease urokinase-type PA (uPA) and its associated inhibitor (plasminogen activator inhibitor-1). Although PGE2 inhibits the activation of all relevant pro-fibrotic cellular phenotypes in lung fibroblasts via intracellular cyclic AMP (cAMP) signaling, the downstream mechanisms by which it does so are incompletely understood. The PA system is recognized to orchestrate fibrinolysis and to modulate cellular adhesion and cellular signaling, but little is known about its direct effects on fibroblasts or their relevant phenotypes. Finally, there is no information about cross-talk between PGE2 and the PA system in lung cells of any kind, including fibroblasts. This project seeks to understand the mechanisms by which both mediators modulate fibroblast function, to characterize the cross-talk between them, and to determine how fibrotic lung injury influences the responses of fibroblasts to each of them. The general hypothesis is that the PGE2 and PA systems up-regulate each other and interact to influence pulmonary fibroblast phenotypes in a manner which favors lung repair over fibrosis. This hypothesis will be tested in fibroblast cell lines and in primary cells isolated from normal and fibrotic murine and human lungs. Aim 1 will examine the roles of cAMP effectors protein kinase A and guanylate exchange protein activated by cAMP as well as the phosphatase PTEN in mediating PGE2 effects on fibroblast phenotypes. Aim 2 will determine the mechanisms by which PGE2 and PA activity influence the expression of each other, while the role of each in mediating the actions of the other will be explored in Aim 3. Aim 4 will compare the effects of PGE2 and PA activity on phenotypes of fibroblasts derived from normal vs. injured mouse lungs and from histologically normal vs. IPF human lungs. The proposed studies will provide novel insights into the regulation of fibroblast activation by these two mediators, and will inform future efforts to target these molecules therapeutically. PUBLIC HEALTH RELEVANCE: The development of a serious condition known as lung scarring (pulmonary fibrosis) is opposed by two substances produced by the body, prostaglandin E2 and urokinase plasminogen activator. This proposal will examine how these two substances act and interact to suppress scarring responses of the key lung cell type known as the fibroblast. These studies will enhance our understanding of how scarring responses are regulated, and may provide insight as to whether these substances could be administered to patients to treat this devastating condition.

描述（由申请人提供）：成纤维细胞是主要的效应细胞，通过增强存活、增殖、胶原沉积和肌成纤维细胞分化的能力来介导特发性肺纤维化（IPF）中的组织重塑。尽管肺纤维化发病机制的研究主要以成纤维细胞激活信号研究为主，但有证据表明，这种疾病的特征还在于反调节抗纤维化信号相对缺乏。两个这样的抗纤维化信号是前列腺素 E2 (PGE2) 和纤溶酶原激活剂 (PA) 活性。这些物质中的每一种都已被证明在 IPF 患者中存在缺陷，并且每种物质的缺乏都已被确定在肺纤维化动物模型中具有重要的致病作用。 PGE2 是一种脂质介质，源自脂肪酸花生四烯酸的环氧合酶代谢，通过细胞表面 G 蛋白偶联的 E 前列腺素受体发挥作用。 PA 系统是一个蛋白水解级联，包括蛋白酶尿激酶型 PA (uPA) 及其相关抑制剂（纤溶酶原激活剂抑制剂-1）。尽管 PGE2 通过细胞内环 AMP (cAMP) 信号传导抑制肺成纤维细胞中所有相关促纤维化细胞表型的激活，但其下游机制尚不完全清楚。 PA 系统被认为可以协调纤维蛋白溶解并调节细胞粘附和细胞信号传导，但对其对成纤维细胞或其相关表型的直接影响知之甚少。最后，没有关于任何类型的肺细胞（包括成纤维细胞）中 PGE2 和 PA 系统之间的串扰的信息。该项目旨在了解两种介质调节成纤维细胞功能的机制，表征它们之间的串扰，并确定纤维化肺损伤如何影响成纤维细胞对每种介质的反应。一般假设是 PGE2 和 PA 系统相互上调并相互作用，以有利于肺修复而不是纤维化的方式影响肺成纤维细胞表型。这一假设将在成纤维细胞系以及从正常和纤维化小鼠和人类肺部分离的原代细胞中进行测试。目标 1 将检查 cAMP 效应蛋白激酶 A 和由 cAMP 激活的鸟苷酸交换蛋白以及磷酸酶 PTEN 在介导 PGE2 对成纤维细胞表型的影响中的作用。目标 2 将确定 PGE2 和 PA 活性相互影响表达的机制，而各自在介导对方行为中的作用将在目标 3 中探讨。目标 4 将比较 PGE2 和 PA 活性对彼此表达的影响。正常与受损小鼠肺部以及组织学正常与 IPF 人类肺部来源的成纤维细胞的表型。拟议的研究将为这两种介质对成纤维细胞激活的调节提供新的见解，并将为未来以这些分子为治疗目标的努力提供信息。公共健康相关性：一种称为肺疤痕（肺纤维化）的严重疾病的发展受到身体产生的两种物质（前列腺素 E2 和尿激酶纤溶酶原激活剂）的阻碍。该提案将研究这两种物质如何作用和相互作用，以抑制关键肺细胞类型（称为成纤维细胞）的疤痕反应。这些研究将增强我们对疤痕反应如何调节的理解，并可能提供关于是否可以将这些物质给予患者来治疗这种破坏性病症的见解。