Mitigation of asbestos induced alveolar epithelial cell injury

减轻石棉引起的肺泡上皮细胞损伤

• 批准号: 8295860
• 负责人: DAVID W KAMP
• 金额: $ 32.96万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 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/8295860
• 关键词: 8-Oxoguanine DNA Glycosylase; AGTR2 gene; Aconitate Hydratase; Adverse effects; Air; Alveolar; Amphiboles; Animal Model; Antioxidants; Apoptosis; Asbestos; Asbestosis; Attenuated; 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; Proteins; 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

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: Asbestos-related lung diseases (asbestosis, bronchogenic lung cancer and mesothelioma) continue to pose serious health concerns worldwide, yet the pathogenesis is incompletely understood. The proposed studies should provide insight into the molecular mechanisms underlying asbestos-induced alveolar epithelial cell (AEC) cell death (apoptosis), which is an important initial event leading to fibrosis and carcinogenesis following asbestos exposure as well as in other more common diseases, such as idiopathic pulmonary fibrosis and lung cancer for which more effective management strategies are clearly needed. Specifically, we investigate the role of mitochondrial DNA repair enzyme (hOgg1) and aconitase in preventing asbestos (crocidolite and Libby amphibole)-induced AEC apoptosis as well as the role of AEC mitochondria-derived ROS and down-stream Bax activation.

描述（由申请人提供）：石棉通过尚未完全阐明的机制引起石棉沉滞症和恶性肿瘤。肺泡上皮细胞（AEC）损伤和修复的程度是有毒物质（如石棉）致纤维化潜力的关键决定因素。以前的研究，包括我们小组的研究，已经确定了一些导致石棉不良影响的重要因素以及保护策略。我们已经表明，铁衍生的活性氧（ROS）从线粒体电子传递链介导石棉诱导的AEC DNA损伤和凋亡的p53和p53调节（内在）死亡途径。我们最近的数据暗示了一种新的机制，线粒体人8-氧代鸟嘌呤-DNA糖基化酶1（mt-hOgg 1）通过保护线粒体顺乌头酸酶（Aco 2）防止氧化剂诱导的内在AEC凋亡的重要作用。Bcl-2家族成员对调节细胞凋亡至关重要，但目前尚不清楚特定的Bcl-2蛋白如何调节石棉诱导的AEC凋亡，以及这是否是介导石棉沉着症所必需的。 我们的假设是，线粒体顺乌头酸酶的线粒体hOgg 1保护对于减轻石棉诱导的AEC线粒体（mt）DNA损伤是重要的，线粒体ROS的产生导致Bax/巴克内在AEC凋亡和肺纤维化。 我们将在未来5年内研究的具体目标包括：（1）确定Aco 2的mt-hOgg 1保存是否在减弱石棉（青石棉和利比角闪石）诱导的AEC mtDNA损伤中重要，该损伤导致内在凋亡。我们还将利用Ogg 1-/-和Ogg 1过表达小鼠的遗传学评估Ogg 1保存AEC Aco 2水平，细胞凋亡和石棉肺之间的关系。(2)评估小分子（例如Euk-134或Ogg 1裂解分子）是否保护Aco 2。我们还将利用石棉肺的小鼠模型来确定Euk-134是否减弱AEC线粒体ROS的产生、Aco 2和细胞凋亡的减少以及肺纤维化。(3)确定不能产生AEC线粒体ROS的TFAMfl/fl小鼠是否受到石棉诱导的AEC凋亡和纤维化的保护。我们还将评估肺泡上皮细胞Bax/巴克有条件缺失的小鼠是否受到石棉肺的保护。 这些研究将有助于深入了解石棉诱导的AEC线粒体DNA损伤和可导致肺纤维化的细胞凋亡的机制。重要的是，石棉范例可以提供有关其他肺部疾病的病理生理事件的新信息，这些信息将确定新的管理方法，这些方法可能被证明在预防暴露于各种肺毒素（例如石棉，香烟烟雾，颗粒物等）后的肺纤维化和/或肺癌中有用。 公共卫生关系：与石棉有关的肺部疾病（石棉沉着病、支气管肺癌和间皮瘤）继续在全世界造成严重的健康问题，但发病机制尚未完全了解。拟议的研究应提供深入了解石棉诱导的肺泡上皮细胞（AEC）细胞死亡（凋亡）的分子机制，这是一个重要的初始事件，导致纤维化和致癌石棉暴露后，以及在其他更常见的疾病，如特发性肺纤维化和肺癌，显然需要更有效的管理策略。具体而言，我们研究的作用，线粒体DNA修复酶（hOgg 1）和乌头酸酶在防止石棉（青石棉和利比闪石）诱导的AEC凋亡，以及AEC的活性氧和下游Bax激活的作用。