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）：成纤维细胞是主要效应细胞，可通过其能力提高生存率，增殖，胶原蛋白沉积和肌纤维细胞差异，从而介导特发性肺纤维化（IPF）的组织重塑。尽管研究成纤维细胞激活信号的研究主导了肺纤维化发病机理的研究，但证据表明，这种疾病的特征在于反调节性抗纤维化信号的相对缺乏。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。这些中的每一种都被证明在IPF患者中缺乏，并且已经确定了每种患者在肺纤维化动物模型中在病原上很重要。 PGE2是一种脂质介质，它源自脂肪酸花生四烯酸的环氧合酶代谢，该脂肪酸蛛网膜含量通过细胞表面G蛋白偶联E前列腺素受体作用。 PA系统是一种蛋白水解级联反应，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抑制了通过细胞内循环AMP（CAMP）信号传导肺成纤维细胞中所有相关促纤维细胞表型的激活，但其下游机制的激活是不完全理解的。 PA系统被认为是协调纤维蛋白溶解并调节细胞粘附和细胞信号传导的，但对其对成纤维细胞或相关表型的直接影响知之甚少。最后，在任何形式的肺细胞中，包括成纤维细胞的肺细胞中没有有关PGE2和PA系统之间的串扰的信息。该项目试图了解两个介体调节成纤维细胞功能的机制，以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它们的反应。一般的假设是，PGE2和PA系统相互上调并相互作用以影响肺成纤维细胞表型，其方式有利于肺修复而不是纤维化。该假设将在成纤维细胞系以及从正常和纤维化鼠和人类肺部分离的原代细胞中进行检验。 AIM 1将检查cAMP效应物蛋白激酶A的作用和被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。 AIM 2将确定PGE2和PA活性影响彼此表达的机制，而AIM 3将探讨彼此的表达。AIM 4将比较PGE2和PA活性对从正常VS.受伤的小鼠肺和组织学正常的ipf ips ips ips的纤维细胞表型的影响。拟议的研究将为这两个介体对成纤维细胞激活的调节提供新的见解，并将为未来的努力提供治疗靶向这些分子的努力。公共卫生相关性：一种称为肺疤痕（肺纤维化）的严重疾病的发展与人体产生的两种物质，前列腺素E2和尿激酶纤溶酶原激活剂相反。该建议将研究这两种物质如何作用和相互作用以抑制称为成纤维细胞的关键肺细胞类型的疤痕反应。这些研究将增强我们对疤痕反应的调节方式的理解，并可能会提供有关是否可以将这些物质施用给患者治疗这种毁灭性疾病的见解。