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: 8429439
• 负责人: DAVID W KAMP
• 金额: $ 32.19万
• 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/8429439
• 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

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).

石棉引起石棉沉着病和恶性肿瘤的机制尚未完全阐明。程度 肺泡上皮细胞（AEC）损伤和修复的关键决定因素的纤维化潜力的有毒 如石棉。以前的研究，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战略。我们 已经表明来自线粒体电子传递链的铁衍生的活性氧（ROS） 介导石棉诱导的AEC DNA损伤和细胞凋亡的p53和p53调节（内在） 死亡之路我们最近的数据暗示了一种新机制的重要作用， 线粒体人8-氧代鸟嘌呤-DNA糖基化酶1（mt-hOgg 1）防止氧化剂诱导的内源性AEC 通过保存线粒体顺乌头酸酶（Aco 2）来进行凋亡。Bcl-2家族成员对于调节 然而，目前尚不清楚特异性Bcl-2蛋白如何调节石棉诱导的AEC凋亡， 这对于介导石棉肺是必不可少的。 我们的假设是，线粒体顺乌头酸酶的线粒体hOgg 1保存对于 减轻石棉诱导的AEC线粒体（mt）DNA损伤， 导致Bax/巴克内在AEC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)为了确定mt-hOgg 1保存Aco 2是否在衰减石棉中重要 （青石棉和利比闪石）诱导的AEC mtDNA损伤，导致内在凋亡。我们 还将利用Ogg 1-/-和Ogg 1过表达小鼠，从遗传学上评估Ogg 1 保存AEC Aco 2水平、细胞凋亡和石棉肺。 (2)评估小分子（例如Euk-134或Ogg 1裂解分子）是否保护Aco 2。我们将 还利用石棉肺的鼠模型来确定Euk-134是否减弱AEC线粒体ROS 产生，Aco 2和细胞凋亡的减少以及肺纤维化。 (3)为了确定不能产生AEC线粒体ROS的TFAMfl/fl小鼠是否受到保护， 对抗石棉诱导的AEC凋亡和纤维化。我们还将评估是否有 肺泡上皮细胞中Bax/巴克的条件性缺失可保护其免受石棉沉着病的侵害。 这些研究为石棉诱导AEC mtDNA的机制提供了新的思路 损伤和可导致肺纤维化的细胞凋亡。重要的是，石棉 范例可能提供有关其他肺部疾病的病理生理学事件的新信息， 确定可能被证明在预防肺纤维化和/或肺结核中有用的新的管理方法， 接触各种肺部毒素（如石棉、香烟烟雾、颗粒物等）后患癌症。