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）：石棉引起石棉沉滞和恶性肿瘤的机制尚未完全阐明。肺泡上皮细胞（AEC）损伤和修复的程度是石棉等有毒物质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，已经确定了导致石棉不良影响的一些重要因素以及保护策略。我们已经证明，来自线粒体电子传递链的铁源性活性氧（ROS）通过p53和线粒体调节的（内在）死亡途径介导石棉诱导的AEC DNA损伤和凋亡。我们最近的数据表明，线粒体人8-氧鸟嘌呤- dna糖基酶1 （mt-hOgg1）通过保存线粒体aconitase （Aco2）来防止氧化诱导的内在AEC凋亡的新机制具有重要作用。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细胞凋亡，以及这是否对介导石棉沉滞至关重要。我们的假设是，线粒体乌头酸酶的线粒体hOgg1保存对于减轻石棉诱导的AEC线粒体（mt）DNA损伤是重要的，这种损伤是由线粒体ROS产生导致Bax/Bak内在AEC凋亡和肺纤维化造成的。我们的具体目标将在未来5年内进行研究，包括：(1)确定mt-hOgg1保存Aco2在减轻石棉（crocidolite和Libby amphibole）诱导的AEC mtDNA损伤（导致内在凋亡）中是否重要。我们还将利用Ogg1-/-和Ogg1过表达小鼠来遗传评估Ogg1保存AEC Aco2水平、细胞凋亡和石棉沉滞之间的关系。(2)评估小分子（如Euk-134或Ogg1裂解分子）是否保护Aco2。我们还将利用石棉肺小鼠模型来确定Euk-134是否会减弱AEC线粒体ROS的产生、Aco2的减少和细胞凋亡以及肺纤维化。(3)确定TFAMfl/fl小鼠在AEC线粒体ROS生成能力不足的情况下，是否对石棉诱导的AEC凋亡和纤维化具有保护作用。我们还将评估肺泡上皮条件性丧失Bax/Bak的小鼠是否能预防石棉肺。这些研究将有助于深入了解石棉诱导的AEC mtDNA损伤和线粒体调控的细胞凋亡的机制，从而导致肺纤维化。重要的是，石棉模式可能提供关于其他肺部疾病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对预防暴露于各种肺部毒素（如石棉、香烟烟雾、颗粒物等）后的肺纤维化和/或肺癌有用。