Project 1 Heavy Metal Induced Airway Remodeling and COPD

项目1 重金属诱导气道重塑与COPD

基本信息

批准号：
10560528
负责人：
Veena B. Antony
金额：
$ 18.27万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560528
关键词：
3-Dimensional Activities of Daily Living Address Affect Alabama Amidines Area Arginine Arginine deiminase Arsenic Atmosphere Biological Markers Cadmium Calcium Cell physiology Chronic Obstructive Pulmonary Disease Chronic lung disease Cities Citrulline Coke Communities Complex County Data Development Dimensions Disease susceptibility Environment Environmental Exposure Environmental Risk Factor Enzymes Exhalation Exposure to Fibroblasts Fractals Genetic Heavy Metals Human In Vitro Individual Industrialization Inhalation Intermediate Filament Proteins Lung Lung diseases Macrophage Manganese Measurement Mediating Metal exposure Mus Particulate Matter Pathogenesis Pathway interactions Patients Phenotype Phosphorylation Physical condensation Plasma Pollution Prevalence Proteins Pulmonary Emphysema Reporting Risk Factors Role Science Site Smoker Smoking Steel Structure of parenchyma of lung TLR4 gene Testing Toxic Environmental Substances Untranslated RNA Up-Regulation Validation Vimentin Work X-Ray Computed Tomography airway remodeling bronchiolar fibrosis cigarette smoke coal-fired power plant cohort comparison control demographics early detection biomarkers fine particles inhibitor mortality mouse model non-smoker novel novel therapeutic intervention pharmacologic prospective test smoking prevalence superfund site therapeutic target tool

项目摘要

The lung is a major portal for respirable environmental toxicants including heavy metals such as arsenic (As), cadmium (Cd), and manganese (Mn), all of which are recognized to cause chronic obstructive pulmonary disease (COPD). COPD is the third largest cause of mortality in the US. The prevalence of COPD is twice as high in the Affected Area in Birmingham, Alabama where the Superfund site is located when compared to the Control Area. Peptidyl arginine deiminase-2 enzyme (PAD2) in lung macrophages is activated by heavy metals in a calcium dependent manner and induces deimination (citrullination) of vimentin to citrullinated vimentin by the irreversible alteration of the arginine residue to the non-coded citrulline residue. Our hypothesis is that exposure to particulate matter containing heavy metals (As, Cd and Mn) leads to induction and activation of peptidyl arginine deiminase 2 in lung macrophages and deimination of vimentin. Activation of TLR4 in airway fibroblasts by deiminated(citrullinated) vimentin leads to a pro-invasive, pro-fibrogenic phenotype, with subsequent airway remodeling and COPD. We will examine this hypothesis in the following specific aims: Aim 1: We will use a novel, selective pharmacologic inhibitor of PAD2 (AFM30a) as well as a pan PAD inhibitor (BB-Cl-amidine) to evaluate if this leads to inhibition of citrullination of vimentin. We will also evaluate if citrullinated vimentin modulates airway fibroblast into an invasive, phenotype in 3D lung pulmospheres through upregulation of TLR4 in vitro. Aim 2: Determine whether heavy metal exposure leads to airway remodeling in a murine model of COPD and is associated with the activation of PAD2, the citrullination and secretion of vimentin and an invasive profibrotic phenotype of lung fibroblast. Pharmacologic or genetic inhibition of PAD2 will block the development of COPD. We will use TLR4-/- mice to evaluate if citrullinated vimentin directly causes airway remodeling and COPD as well as an invasive pro-fibrogenic phenotype of fibroblasts using 3D lung pulmospheres. Aim 3: Determine whether PAD2 and citrullinated vimentin, present in lung macrophages, BAL, plasma and EBC of a cohort of subjects from the Affected Area are biomarkers for COPD. Existing biospecimens have been tested in a discovery cohort of subjects and prospective testing will be conducted in a validation cohort of COPD subjects in parallel with airway fractal dimension (AFD) on CT scans, plasma and exhaled breath condensate (EBC) measurements. Early biomarkers of COPD in exhaled breath condensate may help us recognize disease susceptibility. Importantly, these studies may provide novel therapeutic strategies to block the effects of PAD2 in patients with chronic lung disease such as COPD.

肺部是可吸入环境毒物（包括砷等重金属）的主要门户 (As)、镉 (Cd) 和锰 (Mn)，所有这些元素都被认为会导致慢性阻塞性肺疾病疾病（慢性阻塞性肺病）。慢性阻塞性肺病是美国第三大死亡原因。 COPD 的患病率是与超级基金所在地阿拉巴马州伯明翰的受影响地区相比，这一数字同样高控制区。肺巨噬细胞中的肽基精氨酸脱亚胺酶 2 酶 (PAD2) 被重以钙依赖性方式结合金属并诱导波形蛋白脱亚胺化（瓜氨酸化）为瓜氨酸波形蛋白通过将精氨酸残基不可逆地改变为非编码的瓜氨酸残基。我们的假设是暴露于含有重金属（As、Cd 和 Mn）的颗粒物会导致诱导和激活肺巨噬细胞中的肽基精氨酸脱亚胺酶 2 和波形蛋白的脱亚胺化。气道中 TLR4 的激活去亚胺化（瓜氨酸化）波形蛋白对成纤维细胞产生促侵袭、促纤维化表型，随后的气道重塑和慢性阻塞性肺病。我们将在以下具体目标中检验这一假设：目标 1：我们将使用一种新型选择性 PAD2 药理学抑制剂 (AFM30a) 以及泛 PAD 抑制剂 (BB-Cl-脒)以评估这是否会导致波形蛋白瓜氨酸化的抑制。我们还将评估是否瓜氨酸波形蛋白通过以下方式将气道成纤维细胞调节为 3D 肺泡球中的侵袭性表型体外 TLR4 上调。目标 2：确定重金属暴露是否会导致患者气道重塑 COPD 小鼠模型，与 PAD2 的激活、波形蛋白的瓜氨酸化和分泌有关以及肺成纤维细胞的侵袭性促纤维化表型。 PAD2 的药物或基因抑制将阻断慢性阻塞性肺病的发展。我们将使用 TLR4-/- 小鼠来评估瓜氨酸波形蛋白是否直接导致气道使用 3D 肺进行重塑和 COPD 以及成纤维细胞的侵袭性促纤维化表型肺球。目标 3：确定 PAD2 和瓜氨酸波形蛋白是否存在于肺巨噬细胞、BAL、来自受影响地区的一组受试者的血浆和 EBC 是 COPD 的生物标志物。现有生物样本已在发现受试者队列中进行了测试，前瞻性测试将在验证队列中进行 COPD 受试者的 CT 扫描、血浆和呼出气与气道分形维数 (AFD) 平行冷凝水 (EBC) 测量。呼出气冷凝物中 COPD 的早期生物标志物可能对我们有帮助认识疾病易感性。重要的是，这些研究可能提供新的治疗策略阻断 PAD2 对慢性肺病（如 COPD）患者的影响。