Mechanisms of Asbestos-Induced Alveolar Epithelial Cell Injury

石棉引起的肺泡上皮细胞损伤的机制

• 批准号: 8445153
• 负责人: DAVID W KAMP
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445153
• 关键词: 8-Oxoguanine DNA Glycosylase; Aconitate Hydratase; Adverse effects; Air; Alveolar; Apoptosis; Asbestos; Asbestosis; Attenuated; BCL-2 Protein; BCL2 gene; Biological Preservation; Bronchogenic Carcinoma; Cell Death; Cessation of life; Chronic lung disease; DNA Damage; DNA Repair Enzymes; Data; Disease; Electron Transport; Epithelial Cells; Event; Exposure to; Family member; Fibrosis; Genetic Transcription; Hamman-Rich syndrome; Health; Human; Iron; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mesothelioma; Mitochondria; Mitochondrial DNA; Molecular; Mus; Noxae; Oxidants; Particulate Matter; Pathogenesis; Pathway interactions; Population; Production; Pulmonary Fibrosis; Reactive Oxygen Species; Role; Secondary to; Stream; Toxin; Veterans; alveolar epithelium; carcinogenesis; cell injury; cigarette smoking; injury and repair; insight; mitochondrial dysfunction; novel; prevent

DESCRIPTION (provided by applicant): Asbestos causes asbestosis (pulmonary fibrosis secondary to asbestos) and malignancies (bronchogenic carcinoma and mesothelioma) 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 (ETC) 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 specific p53-dependent transcriptional molecule, Noxa, as well as a novel mechanism by which mitochondrial human 8-oxoguanine-DNA glycosylase 1 (mt-hOgg1) prevents oxidant-induced intrinsic AEC apoptosis by preserving mitochondrial aconitase. Although Bcl-2 family members are crucial for regulating apoptosis, it is unclear how specific Bcl-2 proteins modulate asbestos-induced AEC apoptosis and whether downstream proapoptotic Bax/Bak activation is essential for mediating asbestosis. In this renewal, we investigate the molecular mechanisms underlying asbestos-induced AEC intrinsic apoptosis. Our HYPOTHESIS is that mitochondrial hOgg1 and aconitase are important for attenuating asbestos- induced AEC mtDNA damage resulting from mitochondrial ROS production that leads to p53 (Noxa) activation, Bax/Bak intrinsic AEC apoptosis and pulmonary fibrosis. Our SPECIFIC OBJECTIVES that will be examined over the next 4 years include: (1) To determine whether mitochondrial hOgg1 preservation of aconitase is important in attenuating asbestos- induced AEC mtDNA damage that results in p53 (Noxa) activation and intrinsic apoptosis. We will also assess whether Ogg1-/- mice are more susceptible to asbestosis. (2) To determine whether asbestos-induced ROS from AEC mitochondria activate p53 (Noxa)-dependent transcription that causes mitochondria (Bax/Bak)-regulated apoptosis. We will also determine whether mitochondrial ROS are crucial for mediating pulmonary fibrosis following asbestos exposure. (3) To determine whether asbestos-induced AEC p53 (Noxa) activation results in the loss of Mcl-1 leading to Bax/Bak-mediated apoptosis. We will determine whether mice with conditional loss of Bax/Bak at the alveolar epithelium are protected against asbestosis. There are several immediate and long-range benefits from these studies. First, they should provide insight into the mechanisms underlying asbestos-induced AEC DNA damage, p53 activation, mitochondrial dysfunction, and apoptosis as well as how these events cause pulmonary fibrosis. Second, these studies will characterize the role of mitochondrial hOgg1 preservation of aconitase in preventing asbestos-induced AEC mitochondrial dysfunction, p53 activation, and intrinsic apoptosis. Finally, and perhaps most importantly, our findings may provide new information about the pathophysiologic events of other chronic lung diseases that will identify novel management approaches. Strategies aimed at reducing mitochondrial ROS production and preserving mitochondrial DNA integrity may prove useful in preventing pulmonary fibrosis and/or lung cancer from exposure to various pulmonary toxins (e.g. asbestos, cigarette smoke, air-borne particulate matter etc).

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（继发于石棉的肺纤维化）和恶性肿瘤（支气管癌和间皮瘤）。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（ETC）介导石棉诱导的AEC DNA损伤和细胞凋亡的p53和p53调节（内在）死亡途径。我们最近的数据暗示了一个特定的p53依赖的转录分子，Noxa，以及一种新的机制，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防止氧化剂诱导的内在AEC凋亡的重要作用。虽然Bcl-2家族成员是至关重要的调节细胞凋亡，目前还不清楚具体的Bcl-2蛋白如何调节石棉诱导的AEC凋亡，以及下游促凋亡Bax/巴克激活是否是必不可少的介导石棉肺。在这次更新中，我们研究了石棉诱导AEC内在凋亡的分子机制。 我们的假设是，线粒体hOgg 1和顺乌头酸酶对于减轻石棉诱导的AEC mtDNA损伤是重要的，所述损伤由线粒体ROS产生导致p53（Noxa）活化、Bax/巴克内在AEC凋亡和肺纤维化。 我们将在未来4年内研究的特异性抑制剂包括：（1）确定线粒体hOgg 1对乌头酸酶的保护是否在减轻石棉诱导的AEC mtDNA损伤中重要，该损伤导致p53（Noxa）激活和内在凋亡。我们还将评估Ogg 1-/-小鼠是否更容易患石棉肺。(2)确定石棉诱导的AEC线粒体ROS是否激活p53（Noxa）依赖的转录，导致线粒体（Bax/巴克）调节的凋亡。我们还将确定线粒体活性氧是否是介导石棉暴露后肺纤维化的关键。(3)确定石棉诱导的AEC p53（Noxa）激活是否导致Mcl-1的丢失，从而导致Bax/Bak介导的凋亡。我们将确定肺泡上皮细胞Bax/巴克有条件缺失的小鼠是否能预防石棉肺。 这些研究有几个直接和长期的好处。首先，他们应该提供深入了解石棉诱导的AEC DNA损伤，p53激活，线粒体功能障碍和细胞凋亡以及这些事件如何导致肺纤维化的机制。其次，这些研究将表征线粒体hOgg 1保护乌头酸酶在预防石棉诱导的AEC线粒体功能障碍，p53激活和内在凋亡中的作用。最后，也许是最重要的，我们的研究结果可能提供有关其他慢性肺部疾病的病理生理学事件的新信息，这些信息将确定新的管理方法。旨在减少线粒体ROS产生和保持线粒体DNA完整性的策略可能证明可用于预防肺纤维化和/或肺癌暴露于各种肺毒素（例如石棉、香烟烟雾、空气传播的颗粒物等）。