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）： 石棉引起石棉（继发于石棉的肺纤维化）和恶性肿瘤（支气管癌和间皮瘤），这是通过未完全阐明的机制。肺泡上皮细胞（AEC）损伤和修复的程度是毒性剂（例如石棉）纤维化潜力的关键决定因素。先前的研究，包括来自我们小组的研究，已经确定了导致石棉不利影响以及保护性策略的一些重要因素。我们已经表明，线粒体电子传输链（ETC）的铁衍生的活性氧（ROS）介导石棉诱导的AEC DNA损伤和p53-和线粒体调控（内在）死亡途径的AEC DNA损伤和凋亡。我们最近的数据暗示了特定p53依赖性转录分子NOXA的重要作用，以及一种新颖的机制，通过这种机制，线粒体人类8-氧气8-氧气 - 氧气-DNA糖基化酶1（MT-HOGG1）可通过保留氧化剂诱导的固有的AEC凋亡，从而使氧化剂诱导的氧化剂通过保持线粒体质合酶。尽管BCL-2家族成员对于调节凋亡至关重要，但尚不清楚特定的Bcl-2蛋白如何调节石棉诱导的AEC凋亡以及下游促凋亡Bax/Bak激活是否对于介导石棉病是必不可少的。在这种续签中，我们研究了石棉诱导的AEC内在凋亡的分子机制。 我们的假设是，线粒体hogg1和a刺酶对于减轻石棉诱导的AEC mtDNA损伤很重要，该aec mtDNA损害是由线粒体ROS产生导致p53（noxa）激活，bax/bax/bak intinsic AEC凋亡和肺纤维纤维中的p53（noxa）激活。 我们将在接下来的4年中进行检查的我们的特定目标包括：（1）确定线粒体HOGG1保存a刺蛋白酶是否在减轻石棉诱导的AEC MTDNA损伤方面是否重要，从而导致p53（NOXA）激活和内在凋亡。我们还将评估OGG1 - / - 小鼠是否更容易受到石棉病的影响。 （2）确定石棉诱导的AEC线粒体诱导的ROS是否激活p53（NOXA）依赖性转录，导致线粒体（BAX/BAK）调节的细胞凋亡。我们还将确定线粒体ROS对于在石棉暴露后介导肺纤维化至关重要。 （3）确定石棉诱导的AEC P53（NOXA）激活是否导致MCL-1导致Bax/Bak介导的细胞凋亡。我们将确定在肺泡上皮处有条件损失的小鼠是否受到棉布病的保护。 从这些研究中有几种直接和远程的好处。首先，他们应该深入了解石棉诱导的AEC DNA损伤，p53激活，线粒体功能障碍和凋亡以及这些事件如何引起肺纤维化。其次，这些研究将表征线粒体HOGG1保存a刺酶在防止石棉诱导的AEC线粒体功能障碍，p53激活和内在细胞凋亡中的作用。最后，也许最重要的是，我们的发现可能会提供有关其他慢性肺部疾病的病理生理事件的新信息，这些事件将鉴定出新的管理方法。旨在减少线粒体ROS产生和保持线粒体DNA完整性的策略可能被证明可用于防止肺纤维化和/或肺癌暴露于各种肺毒素（例如石棉，香烟，气烟，空体颗粒物等）中有用。