PROTECTIVE ROLE OF APOPTOSIS IN ASBESTOS PLEURAL INJURY

描述：胸膜间皮细胞， 石棉诱导的肿瘤间皮瘤，当暴露于 石棉 重要的机制可能包括氧自由基的产生，DNA 损伤和纤维内化。 因为细胞不能凋亡 可能允许DNA损伤的细胞存活，细胞凋亡的丧失可能是一个重要的因素。 是导致肿瘤形成的多步骤过程中的主要步骤。 因此，我们认为， 促进或抑制细胞凋亡的机制可能是一个动态过程 确定石棉的毒性作用是否最终导致 肿瘤形成 我们建议研究细胞凋亡在病理学中的作用， 间皮细胞和胸膜的石棉 起初布罗德斯医生 探讨石棉诱导细胞凋亡的主要机制 在兔和人胸膜间皮细胞和兔胸膜中。 通过 DNA损伤、氧化应激和应激相关信号的测量 （神经酰胺，jun激酶，MAP激酶）在体外和体内，她提出， 间皮细胞凋亡必不可少的途径 然后她会决定 某些信号的机制，即那些由 玻连蛋白受体，抑制石棉诱导的细胞凋亡。 使用 玻连蛋白包被的颗粒或抗整联蛋白抗体，以激活 整合素，她将确认玻连蛋白受体的作用， 抗凋亡，并确定整合素是否改变了平衡， 细胞凋亡途径如神经酰胺和JNK与增殖 如MAP激酶。 激活后家兔体内研究 或抑制玻连蛋白受体或在基因工程小鼠中 如果没有玻连蛋白或玻连蛋白受体， 这种抗凋亡的作用。 最后，她打算利用 石棉诱导的细胞凋亡的抑制剂（抗氧化剂β-胡萝卜素， PARP、玻连蛋白包被珠的抑制）以确定是否长期 细胞凋亡的抑制将导致DNA损伤的积累， 接触石棉的间皮细胞 我们将长期评估 石棉暴露细胞的DNA结构损伤的存在， 微核的存在和基因拷贝数的变化， 比较基因组杂交 通过这些研究，布罗德斯博士将 在基因工程小鼠中进行长期研究， 玻连蛋白，主要玻连蛋白受体的B5亚基，或p53， 证实这种细胞凋亡的抑制导致敏感性增加 石棉引起的异常包括间皮瘤 这些研究 应该提供有关石棉的作用机制的重要信息， 诱导间皮细胞凋亡和石棉诱导的 石棉诱导的病理学中的细胞凋亡。

DESCRIPTION: Pleural mesothelial cells, the progenitor of the asbestos-induced tumor mesothelioma, undergo apoptosis when exposed to asbestos. Important mechanisms may include oxygen radical generation, DNA damage and fiber internalization. Because an inability to undergo apoptosis may allow cells with DNA damage to survive, a loss of apoptosis may be a major step in the multistep process leading to neoplasia. Therefore, mechanisms promoting or inhibiting apoptosis may play a dynamic process determining whether the toxic effects of asbestos eventually result in neoplasia. We propose to investigate the role of apoptosis in the pathology of asbestos to the mesothelial cells and pleura. Initially, Dr. Broaddus aims to delineate the major mechanisms inducing asbestos-induced apoptosis in both rabbit and human pleural mesothelial cells and rabbit pleura. By measures of DNA damage, oxidant stress and stress-related signaling (ceramide, jun kinase, MAP kinase) in vitro and in vivo, she propose to show the pathways essential to mesothelial apoptosis. Then, she will determine the mechanisms by which certain signals, namely those initiated by vitronectin receptors, inhibit asbestos-induced apoptosis. Using vitronectin-coated particles or anti-integrin antibodies to activate the integrins, she will confirm the role of vitronectin receptors as anti-apoptotic, and identify whether the integrins are altering the balance of the apoptotic pathways such as ceramide and JNK with proliferative pathways such as MAP kinase. In in vivo studies in rabbits after activation or inhibition of vitronectin receptors or in genetically-engineered mice without vitronectin or vitronectin receptors, she will learn the importance of this anti-apoptotic effect in vivo. Finally, she intends to use inhibitors of asbestos-induced apoptosis (anti-oxidant B-carotene, inhibition of PARP, vitronectin-coated beads) to determine whether longterm inhibition of apoptosis will lead to accumulation of DNA damage in asbestos-exposed mesothelial cells. We will assess chronically asbestos-exposed cells for the presence of DNA structural damage by the presence of micronuclei and for changes in gene copy number using comparative genomic hybridization. From these studies, Dr. Broaddus will proceed to long term studies in genetically-engineered mice without vitronectin, the B5 subunit of a major vitronectin receptor, or p53 to confirm that this inhibition of apoptosis leads to an increased sensitivity to asbestos-induced abnormalities, including mesothelioma. These studies should provide important information about the mechanisms by which asbestos induces apoptosis in mesothelial cells and the role of asbestos-induced apoptosis in asbestos-induced pathology.