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: 8141684
• 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/8141684
• 关键词: 8-Oxoguanine DNA Glycosylase; Aconitate Hydratase; Adverse effects; Air; Alveolar; Apoptosis; Asbestos; Asbestosis; Attenuated; 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; Proteins; 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）： 石棉可引起石棉肺（继发于石棉的肺纤维化）和恶性肿瘤（支气管癌和间皮瘤），其机制尚未完全阐明。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。之前的研究，包括我们小组的研究，已经确定了导致石棉不利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 (ETC) 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 损伤和细胞凋亡。我们最新的数据表明特定的 p53 依赖性转录分子 Noxa 的重要作用，以及线粒体人 8-氧代鸟嘌呤-DNA 糖基化酶 1 (mt-hOgg1) 通过保留氧化剂诱导的内在 AEC 细胞凋亡的新机制。线粒体乌头酸酶。尽管 Bcl-2 家族成员对于调节细胞凋亡至关重要，但尚不清楚特定的 Bcl-2 蛋白如何调节石棉诱导的 AEC 细胞凋亡以及下游促细胞凋亡 Bax/Bak 激活是否对于介导石棉沉着症至关重要。在本次更新中，我们研究了石棉诱导 AEC 内在细胞凋亡的分子机制。 我们的假设是，线粒体 hOgg1 和乌头酸酶对于减轻石棉诱导的 AEC mtDNA 损伤非常重要，而线粒体 ROS 的产生会导致 p53 (Noxa) 激活、Bax/Bak 内在 AEC 细胞凋亡和肺纤维化。 我们将在未来 4 年进行的具体目标包括：（1）确定线粒体 hOgg1 乌头酸酶的保存​​对于减轻石棉诱导的 AEC mtDNA 损伤（导致 p53 (Noxa) 激活和内在细胞凋亡）是否重要。我们还将评估 Ogg1-/- 小鼠是否更容易患石棉沉着病。 (2) 确定石棉诱导的 AEC 线粒体 ROS 是否激活 p53 (Noxa) 依赖性转录，从而导致线粒体 (Bax/Bak) 调节的细胞凋亡。我们还将确定线粒体活性氧是否对于介导石棉暴露后的肺纤维化至关重要。 (3) 确定石棉诱导的 AEC p53 (Noxa) 激活是否会导致 Mcl-1 丢失，从而导致 Bax/Bak 介导的细胞凋亡。我们将确定肺泡上皮条件性缺失 Bax/Bak 的小鼠是否能够免受石棉沉着症的影响。 这些研究有几个直接和长期的好处。首先，他们应该深入了解石棉引起的 AEC DNA 损伤、p53 激活、线粒体功能障碍和细胞凋亡的机制，以及这些事件如何导致肺纤维化。其次，这些研究将表征线粒体 hOgg1 保存乌头酸酶在预防石棉诱导的 AEC 线粒体功能障碍、p53 激活和内在细胞凋亡中的作用。最后，也许最重要的是，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事件的新信息，从而确定新的治疗方法。旨在减少线粒体 ROS 产生和保持线粒体 DNA 完整性的策略可能有助于预防因接触各种肺部毒素（例如石棉、香烟烟雾、空气中的颗粒物等）而导致的肺纤维化和/或肺癌。