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.

石棉引起的毒性仍然是一个重要的环境条件。尽管监管严格 控制措施以限制接触，每年有超过 130 万名工人接触危险水平的石棉 年，导致美国每年有超过 10 万人死亡。一个关键因素是 线粒体活性氧 (mtROS) 的产生是造成石棉暴露毒性严重程度的原因之一， 调节肺巨噬细胞的替代激活；然而，调节的分子机制 巨噬细胞 mtROS 的产生尚无明确定义。 NOX 酶之一 NOX4 可诱导 mtROS 各种刺激和多种细胞类型，但巨噬细胞表型的调节尚不清楚 由NOX4介导。我们的初步数据表明，石棉损伤受试者的肺巨噬细胞表达 与正常受试者相比，NOX4 基因水平较高。显着抑制或沉默 NOX4 废除 mtROS。更重要的是，NOX1/4 抑制剂 (GKT137831) 消除了 巨噬细胞。替代激活巨噬细胞的一项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动所必需的。 NOX1/4 抑制可减弱石棉引起的脂肪酸氧化。类似的观察结果在 NOX4-/- 小鼠。与野生型小鼠不同，NOX4-/- 小鼠的肺巨噬细胞表现出经典的激活， 它具有巨噬细胞的促纤维化激活作用。此外，NOX4-/- 小鼠免受石棉- 诱发毒性。我们的假设是 NOX4 介导的 mtROS 调节代谢重编程， 肺巨噬细胞的选择性激活和凋亡抵抗，促进石棉诱导的 毒性。我们将通过三个具体目标来检验这一假设。在目标 1 中，巨噬细胞 NOX4 在 巨噬细胞的可塑性和石棉引起的毒性的发病机制将在携带巨噬细胞的小鼠中进行测试 巨噬细胞中 NOX4 的缺失。目标 2 将测试 NOX4 衍生的 mtROS 在代谢中的作用 在暴露于石棉的巨噬细胞中使用遗传方法进行重编程和表型可塑性。目标 3 将测试 NOX4 对石棉损伤肺巨噬细胞代谢和表型的作用 受试者离体使用 GKT137831 和 RNAi 介导的 NOX4 沉默。这些研究可能揭示 NOX4 作为 通过调节线粒体代谢来减轻石棉引起的毒性的理想治疗靶点 巨噬细胞的可塑性。

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

Post-translational regulation of PGC-1α modulates fibrotic repair.

• DOI: 10.1096/fj.202100339r
• 发表时间: 2021-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Larson-Casey JL;Gu L;Davis D;Cai GQ;Ding Q;He C;Carter AB
• 通讯作者: Carter AB

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