Lung Macrophage Metabolic Reprogramming in Asbestos-Induced Toxicity

石棉引起的毒性中的肺巨噬细胞代谢重编程

• 批准号: 10376784
• 负责人: A BRENT CARTER
• 金额: $ 33.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376784
• 关键词: Animal Model; Apoptosis; Asbestos; Attenuated; Cells; Cessation of life; Characteristics; Data; Development; Exposure to; Generations; Genes; Genetic; Human; Immune response; Injury; Liquid substance; Lung; Lung infections; Macrophage Activation; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mus; NADPH Oxidase; Nox enzyme; Nuclear; Pathogenesis; Peroxisome Proliferators; Pharmacology; Phenotype; Play; RNA Interference; Reactive Oxygen Species; Resistance; Role; Severities; Stimulus; Testing; Tissues; Toxic effect; United States; Wild Type Mouse; Work; cell type; curative treatments; exposed human population; fatty acid oxidation; fighting; genetic approach; inhibitor; injured; lung injury; macrophage; mitochondrial metabolism; mortality; novel; prevent; pulmonary function; response; therapeutic target

Asbestos-induced toxicity remains to be a significant environmental condition. Despite strict regulatory controls to limit exposure, more than 1.3 million workers are exposed to hazardous levels of asbestos every year, which results in more than 100,000 deaths annually in the United States. One critical factor that contributes to the severity of toxicity in asbestos exposure is the generation of mitochondrial ROS (mtROS), which modulates alternative activation of lung macrophages; however, the molecular mechanism(s) regulating macrophage mtROS generation is not clearly defined. One of the NOX enzymes, NOX4, induces mtROS with various stimuli and in several cell types, but the modulation of the macrophage phenotype is not known to be mediated by NOX4. Our preliminary data show that lung macrophages from asbestos-injured subjects express high levels of the NOX4 gene compared to normal subjects. Inhibition or silencing NOX4 significantly abrogates mtROS. More importantly, the NOX1/4 inhibitor (GKT137831) abolishes alternative activation of macrophages. One important characteristic of alternatively activated macrophages is metabolic reprogramming from glycolytic metabolism to fatty acid oxidation, which is necessary to support long-term cellular activities. NOX1/4 inhibition attenuates asbestos-induced fatty acid oxidation. Similar observations were recapitulated in NOX4-/- mice. Lung macrophages from NOX4-/- mice displayed classical activation unlike the wild type mice, which had pro-fibrotic activation of macrophages. Furthermore, NOX4-/- mice were protected from asbestos- induced toxicity. Our hypothesis is that NOX4-mediated mtROS modulates metabolic reprogramming, alternative activation, and apoptosis resistance of lung macrophages, which promotes asbestos-induced toxicity. We will test this hypothesis with three specific aims. In Aim 1, the role of macrophage NOX4 in macrophage plasticity and in the pathogenesis of asbestos-induced toxicity will be tested in mice harboring a deletion of NOX4 in macrophages. Aim 2 will test the role of NOX4-derived mtROS in metabolic reprogramming and phenotypic plasticity using genetic approaches in asbestos-exposed macrophages. Aim 3 will test the role of NOX4 on the metabolism and phenotype of lung macrophages from asbestos-injured subjects ex vivo with GKT137831 and RNAi-mediated NOX4 silencing. These studies may uncover NOX4 as an ideal therapeutic target to attenuate asbestos-induced toxicity by modulating mitochondrial metabolism and macrophage plasticity.

石棉诱导的毒性仍然是一种重要的环境条件。尽管严格的监管 控制限制暴露的控制，超过130万工人暴露于危险水平的石棉水平 一年，在美国，每年导致100,000多人死亡。一个关键因素 有助于石棉暴露的毒性严重程度是线粒体ROS（MTROS）的产生， 调节肺巨噬细胞的替代激活；但是，调节的分子机制 巨噬细胞MTROS的产生未明确定义。 NOX酶之一NOX4诱导Mtros 各种刺激和几种细胞类型中 由NOX4介导。我们的初步数据表明，来自石棉造成的受试者的肺巨噬细胞表达 与正常受试者相比，NOX4基因的高水平。抑制或沉默nox4显着 废除mtros。更重要的是，NOX1/4抑制剂（GKT137831）废除了替代激活 巨噬细胞。替代激活的巨噬细胞的一个重要特征是代谢重编程 从糖酵解代谢到脂肪酸氧化，这是支持长期细胞活性所必需的。 NOX1/4抑制减弱了石棉诱导的脂肪酸氧化。在 NOX4 - / - 鼠标。来自NOX4 - / - 小鼠的肺巨噬细胞显示经典激活，与野生型小鼠不同， 巨噬细胞的促纤维激活。此外，NOX4 - / - 小鼠免受石棉 - 诱导的毒性。我们的假设是NOX4介导的MTROS调节代谢重编程， 替代激活和肺巨噬细胞的凋亡抗性，促进石棉诱导的 毒性。我们将以三个特定的目标检验这一假设。在AIM 1中，巨噬细胞NOX4在 巨噬细胞的可塑性和石棉诱导的毒性的发病机理将在携带A的小鼠中测试 巨噬细胞中NOX4的删除。 AIM 2将测试NOX4衍生的MTRO在代谢中的作用 使用石棉暴露的巨噬细胞中的遗传方法重编程和表型可塑性。目标3 将测试NOX4在造成石棉的肺巨噬细胞代谢和表型中的作用 具有GKT137831和RNAi介导的NOX4沉默的受试者。这些研究可能会发现NOX4 通过调节线粒体代谢和 巨噬细胞塑性。

项目成果

SP-1 regulation of MMP-9 expression requires Ser586 in the PEST domain.

• DOI: 10.1042/bj20120053
• 发表时间: 2012-07-15
• 期刊: The Biochemical journal
• 作者: Murthy S;Ryan AJ;Carter AB
• 通讯作者: Carter AB

Nuclear factor kappa B-dependent gene transcription in cholecystokinin- and tumor necrosis factor-alpha-stimulated isolated acinar cells is regulated by p38 mitogen-activated protein kinase.

• DOI: 10.1016/j.amjsurg.2009.12.004
• 发表时间: 2010-08
• 期刊: AMERICAN JOURNAL OF SURGERY
• 影响因子: 3
• 作者: Williard, Deborah E.;Twait, Erik;Yuan, Zuobiao;Carter, A. Brent;Samuel, Isaac
• 通讯作者: Samuel, Isaac

Asbestos-induced MKP-3 expression augments TNF-alpha gene expression in human monocytes.

石棉诱导的 MKP-3 表达增强人单核细胞中 TNF-α 基因的表达。

• DOI: 10.1165/rcmb.2007-0356oc
• 发表时间: 2008
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Tephly,LindaA;Carter,ABrent
• 通讯作者: Carter,ABrent

NOX4-TIM23 interaction regulates NOX4 mitochondrial import and metabolic reprogramming.

• DOI: 10.1016/j.jbc.2023.104695
• 发表时间: 2023-05
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Pandey, Jyotsana;Larson-Casey, Jennifer L.;Patil, Mallikarjun H.;Joshi, Rutwij;Jiang, Chun-sun;Zhou, Yong;He, Chao;Carter, A. Brent
• 通讯作者: Carter, A. Brent

Targeting the isoprenoid pathway to abrogate progression of pulmonary fibrosis.

• DOI: 10.1016/j.freeradbiomed.2015.04.031
• 发表时间: 2015-09
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Osborn-Heaford HL;Murthy S;Gu L;Larson-Casey JL;Ryan AJ;Shi L;Glogauer M;Neighbors JD;Hohl R;Carter AB
• 通讯作者: Carter AB