Mitigation of asbestos induced alveolar epithelial cell injury

减轻石棉引起的肺泡上皮细胞损伤

基本信息

批准号：
8593294
负责人：
DAVID W KAMP
金额：
$ 32.52万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8593294
关键词：
8-Oxoguanine DNA Glycosylase AGTR2 gene Aconitate Hydratase Adverse effects Air Alveolar Amphiboles Animal Model Antioxidants Apoptosis Asbestos Asbestosis Attenuated BCL-2 Protein BCL2 gene Biological Preservation Bronchogenic Carcinoma Cell Death Cessation of life Cleaved cell Crocidolite Asbestos DNA Damage DNA Repair Enzymes Data Disease Electron Transport Epithelial Cells Event Exposure to Family member Fibrosis Functional disorder Hamman-Rich syndrome Health Human In Vitro Iron Lung Lung diseases Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mediating Mesothelioma Mitochondria Mitochondrial DNA Modeling Molecular Mus Outcome Oxidants Particulate Matter Pathogenesis Pathway interactions Patients Prevention Production Pulmonary Fibrosis Reactive Oxygen Species Regimen Resistance Role Stream Tobacco Toxic Environmental Substances Toxin alveolar epithelium carcinogenesis cell injury cigarette smoking in vivo injury and repair insight mitochondrial dysfunction novel overexpression prevent small molecule

项目摘要

Asbestos causes asbestosis and malignancies by mechanisms that are not fully elucidated. The extent of alveolar epithelial cell (AEC) injury and repair are critical determinants of the fibrogenic potential of toxic agents such as asbestos. Previous studies, including ones from our group, have identified some of the important factors contributing to the adverse effects of asbestos as well as strategies that are protective. We have shown that iron-derived reactive oxygen species (ROS) from the mitochondria electron transport chain mediate asbestos-induced AEC DNA damage and apoptosis by a p53- and mitochondria-regulated (intrinsic) death pathway. Our more recent data implicate an important role for a novel mechanism by which mitochondrial human 8-oxoguanine-DNA glycosylase 1 (mt-hOgg1) prevents oxidant-induced intrinsic AEC apoptosis by preserving mitochondrial aconitase (Aco2). Bcl-2 family members are crucial for regulating apoptosis yet it is unclear how specific Bcl-2 proteins modulate asbestos-induced AEC apoptosis and whether this is essential for mediating asbestosis. Our HYPOTHESIS is that mitochondrial hOgg1 preservation of mitochondrial aconitase is important for attenuating asbestos-induced AEC mitochondrial (mt)DNA damage resulting from mitochondrial ROS production that leads to Bax/Bak intrinsic AEC apoptosis and pulmonary fibrosis. Our SPECIFIC AIMS that will be examined over the next 5 years include: (1) To determine whether mt-hOgg1 preservation of Aco2 is important in attenuating asbestos (crocidolite and Libby amphibole)-induced AEC mtDNA damage that results in intrinsic apoptosis. We will also utilize Ogg1-/- and Ogg1 overexpressing mice to genetically assess the relationship between Ogg1 preservation of AEC Aco2 levels, apoptosis and asbestosis. (2) To assess whether a small molecule (e.g. Euk-134 or Ogg1 cleaved molecule) protects Aco2. We will also utilize a murine model of asbestosis to determine whether Euk-134 attenuates AEC mitochondrial ROS production, reductions in Aco2 and apoptosis as well as pulmonary fibrosis. (3) To determine whether TFAMfl/fl mice, incapable of AEC mitochondrial ROS production, are protected against asbestos-induced AEC apoptosis and fibrosis. We will also assess whether mice with conditional loss of Bax/Bak at the alveolar epithelium are protected against asbestosis. These studies should provide insight into the mechanisms underlying asbestos-induced AEC mtDNA damage and mitochondria-regulated apoptosis that can cause pulmonary fibrosis. Importantly, the asbestos paradigm may provide new information about the pathophysiologic events of other lung diseases that will identify novel management approaches that may prove useful in preventing pulmonary fibrosis and/or lung cancer following exposure to various pulmonary toxins (e.g. asbestos, cigarette smoke, particulate matter etc).

石棉导致石棉肺和恶性肿瘤的机制尚未完全阐明。程度肺泡上皮细胞（AEC）损伤和修复是有毒物质纤维化潜力的关键决定因素剂，如石棉。之前的研究，包括我们小组的研究，已经确定了一些造成石棉不利影响的重要因素以及保护策略。我们研究表明，线粒体电子传递链中的铁源性活性氧（ROS）通过 p53 和线粒体调节（内在）介导石棉诱导的 AEC DNA 损伤和细胞凋亡死亡途径。我们最新的数据表明一种新机制的重要作用，通过该机制线粒体人 8-氧鸟嘌呤-DNA 糖基化酶 1 (mt-hOgg1) 可防止氧化剂诱导的内在 AEC 通过保留线粒体乌头酸酶 (Aco2) 来凋亡。 Bcl-2家族成员对于调节至关重要但尚不清楚特定的 Bcl-2 蛋白如何调节石棉诱导的 AEC 细胞凋亡以及是否这对于调节石棉沉着症至关重要。我们的假设是线粒体 hOgg1 保存线粒体乌头酸酶对于减轻由线粒体 ROS 引起的石棉诱导的 AEC 线粒体 (mt)DNA 损伤导致 Bax/Bak 内在 AEC 细胞凋亡和肺纤维化的产生。我们将在未来 5 年内审查的具体目标包括： (1) 确定 mt-hOgg1 对 Aco2 的保存对于减少石棉是否重要（青石棉和利比角闪石）诱导的 AEC mtDNA 损伤，导致内在细胞凋亡。我们还将利用 Ogg1-/- 和 Ogg1 过表达小鼠来从基因角度评估 Ogg1 之间的关系 AEC Aco2 水平、细胞凋亡和石棉肺的保存。 (2) 评估小分子（例如 Euk-134 或 Ogg1 裂解分子）是否保护 Aco2。我们将还利用石棉沉滞症小鼠模型来确定 Euk-134 是否减弱 AEC 线粒体 ROS 产生、Aco2 减少和细胞凋亡以及肺纤维化。 (3) 确定无法产生 AEC 线粒体 ROS 的 TFAMfl/fl 小鼠是否受到保护对抗石棉诱导的 AEC 细胞凋亡和纤维化。我们还将评估小鼠是否患有肺泡上皮有条件地丧失 Bax/Bak 可预防石棉肺。这些研究应该可以深入了解石棉诱导 AEC mtDNA 的潜在机制损伤和线粒体调节的细胞凋亡可导致肺纤维化。重要的是，石棉范式可能提供有关其他肺部疾病的病理生理事件的新信息，这些信息将确定可能有助于预防肺纤维化和/或肺纤维化的新管理方法接触各种肺部毒素（例如石棉、香烟烟雾、颗粒物等）后罹患癌症。