Metabolic Regulation of Pro-Fibrotic Macrophages in Pulmonary Fibrosis

肺纤维化中促纤维化巨噬细胞的代谢调节

基本信息

批准号：
10218253
负责人：
A BRENT CARTER
金额：
$ 33.28万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218253
关键词：
Alveolar Macrophages Animal Model Apoptosis B-Lymphocytes Cells Characteristics Chronic Disease Clinical Trials Data Defect Development Disease Progression Enrollment Enzymes Exhibits Fibrosis Gene Expression Generations Genes Genetic IL10 gene Inflammasome Inflammatory Injury Laboratories Link Liquid substance Lung Lung diseases Mediating Metabolic Metabolism Mitochondria Molecular Mus Myofibroblast NADPH Oxidase Oxidative Phosphorylation Pathogenesis Patients Peroxisome Proliferators Pharmacology Phase Phenotype Placebos Prevalence Pulmonary Fibrosis Reactive Oxygen Species Regulation Resistance Role Source Stimulus Testing Tissues Transforming Growth Factors Translating Work alveolar epithelium antifibrotic treatment cell type fatty acid oxidation fighting genetic approach idiopathic pulmonary fibrosis in vivo inhibitor/antagonist injury and repair insight lung injury macrophage metabolic phenotype metabolic profile mitochondrial metabolism mortality prevent recruit response therapeutic target

项目摘要

Idiopathic pulmonary fibrosis (IPF) is increasing in prevalence, and the recently approved anti-fibrotic therapies have limited efficacy. Alveolar macrophages have a critical role lung injury and repair. Macrophages in chronic disease typically exhibit apoptosis resistance, and their prolonged survival is generally associated with disease progression due to polarization to a pro-fibrotic phenotype. The generation of mitochondrial ROS (mtROS) in alveolar macrophages modulates pro-fibrotic polarization; however, the molecular mechanism(s) regulating macrophage mtROS in fibrosis is not clearly defined. One of the NOX enzymes, NOX4, generates mtROS with various stimuli and in several cell types, but the modulation of the macrophage phenotype has not been linked to NOX4. Our preliminary data show that alveolar macrophages from IPF subjects express high levels of the NOX4 gene compared to normal subjects, and there is more NOX4 localized in the mitochondria of IPF alveolar macrophages. NOX1/4 inhibition with GKT137831 or silencing NOX4 significantly abrogates mtROS. Moreover, GKT137831 down regulates pro-fibrotic polarization of macrophages and abrogates fatty acid oxidation and oxidative phosphorylation, which is characteristic metabolism for pro-fibrotic macrophages. In vivo, NOX4 modulates the polarization of alveolar macrophages to a pro-fibrotic phenotype. In addition, NOX4-/- mice, which are protected from pulmonary fibrosis, have significantly less alveolar macrophages in the BAL fluid suggesting either a defect in recruitment or an absence of apoptosis resistance. Our hypothesis is that NOX4 modulates macrophage mtROS and metabolism to polarize alveolar macrophages to a pro-fibrotic phenotype that is critical for fibrosis development. We will test this hypothesis with three specific aims. Aim 1 will determine if the Nox1/4 inhibitor (GKT137831) modulates alveolar macrophage metabolism and phenotype in IPF subjects enrolled in a Phase IIb clinical trial. In Aim 2, we will determine the effects of NOX4 in regulating mitochondrial metabolism and alveolar macrophage phenotype using pharmacologic (GKT137831) and genetic approaches. Aim 3 will determine macrophage-specific roles of NOX4 in regulating fibrotic responses to lung injury utilizing mice harboring a conditional deletion of NOX4 in macrophages. These studies may delineate NOX4 as a critical regulator of metabolism and macrophage plasticity suggesting it is an ideal therapeutic target to halt progression or reverse pulmonary fibrosis.

特发性肺纤维化（IPF）的患病率正在增加，最近批准的抗纤维化药物疗法的疗效有限。肺泡巨噬细胞对肺损伤和修复具有关键作用。巨噬细胞在慢性疾病中通常表现出细胞凋亡抵抗，并且它们的生存期延长通常与由于极化为促纤维化表型而导致疾病进展。线粒体ROS的产生肺泡巨噬细胞中的 (mtROS) 调节促纤维化极化；然而，分子机制在纤维化过程中调节巨噬细胞 mtROS 的机制尚不明确。 NOX 酶之一，NOX4，产生 mtROS 在多种细胞类型中受到各种刺激，但巨噬细胞表型的调节却没有与 NOX4 相关。我们的初步数据表明，IPF 受试者的肺泡巨噬细胞表达高与正常人相比，NOX4 基因水平较高，并且线粒体中定位有更多的 NOX4 IPF 肺泡巨噬细胞。使用 GKT137831 抑制 NOX1/4 或沉默 NOX4 可显着消除线粒体ROS。此外，GKT137831 下调巨噬细胞的促纤维化极化并消除脂肪酸氧化和氧化磷酸化，这是促纤维化巨噬细胞的特征代谢。在体内，NOX4 将肺泡巨噬细胞的极化调节为促纤维化表型。此外， NOX4-/- 小鼠免受肺纤维化的影响，其肺泡巨噬细胞明显减少。 BAL 液表明募集缺陷或缺乏细胞凋亡抵抗。我们的假设是 NOX4 调节巨噬细胞 mtROS 和代谢，使肺泡巨噬细胞极化为促纤维化对纤维化发展至关重要的表型。我们将通过三个具体目标来检验这一假设。目标1 将确定 Nox1/4 抑制剂 (GKT137831) 是否调节肺泡巨噬细胞代谢和表型参加 IIb 期临床试验的 IPF 受试者。在目标 2 中，我们将确定 NOX4 对使用药理学调节线粒体代谢和肺泡巨噬细胞表型 (GKT137831) 和遗传方法。目标 3 将确定 NOX4 在调节纤维化中的巨噬细胞特异性作用利用巨噬细胞中条件性删除 NOX4 的小鼠对肺损伤的反应。这些研究可能将 NOX4 描述为代谢和巨噬细胞可塑性的关键调节剂，表明它是一种理想的阻止进展或逆转肺纤维化的治疗目标。