SYNTHESIS & ROLE OF METALLOTHIONEIN IN THE LUNG

合成

• 批准号: 3250227
• 负责人: BETH A HART
• 金额: $ 14.65万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-07-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3250227
• 关键词: air pollution; alveolar macrophages; atomic absorption spectrometry; autoradiography; cadmium; cytotoxicity; density gradient ultracentrifugation; environmental toxicology; free radicals; gel electrophoresis; glucocorticoids; hyperplasia; hypertrophy; lung; metal poisoning; metallothionein; pollution related respiratory disorder; polymerization; radioimmunoassay; radiotracer; scanning electron microscopy; scintillation counter; statistics /biometry

Cadmium is a known environmental and industrial pollutant and a contaminant of cigarette smoke. Prior inhalation to Cd results in pulmonary adaptation which helps protect the lung against an acute inhaled dose. Metallothionein (MT), a metal and sulfur rich protein, is synthesized by the lung in response to Cd inhalation. Type II alveolar cells appear to be a primary site for MT synthesis. The role of MT and type II alveolar cells in pulmonary adaptation/tolerance to Cd will be investigated. The dose and time dependent nature of Cd adaptation/tolerance will be determined and correlated with pulmonary MT levels. Ultrastructural morphometry and quantitative autoradiography will assess type II cell hyperplasia and/or hypertrophy during Cd adaptation. Calculations of the type II cell contribution to total lung MT will be made using morphometric data and biochemical analyses of MT content of lung homogenates and isolated type II cells. Sub-cellular localization of MT in isolated type II cells and in situ in lung will be performed using immunohistochemical techniques to establish whether translocation of MT from the cytoplasm to the nucleus occurs during the Cd adaptive process. The role of glucocorticosteroids in the pulmonary response to Cd will be investigated by: (a) correlating plasma corticosterone levels during repeated or acute Cd exposures with the inflammatory cell response; (b) testing whether adrenalectomy exacerbates the toxic effects of Cd and/or reduces the ability of the lung to adapt to Cd; and (c) determining whether dexamethasone administration induces MT synthesis in the lung and/or reduces Cd-induced lung injury. The hypothesis that MT acts as a scavenger of free radicals in the lung will be tested by determining whether Cd-adapted animals, which have elevated levels of pulmonary MT, are more resistant to lung injury induced by oxygen or bleomycin. Animals made tolerant to oxygen will be tested for induction of pulmonary MT and cross tolerance to Cd. Experiments will be performed to differentiate the protective effect of metallothionein in Cd-adapted animals from that provided by glutathione, glutathione shuttle enzymes, and/or superoxide dismutase. The results of the proposed research will increase our understanding of the effects of cadmium inhalation and the roles that metallothionein and the type II cell play in pulmonary defense.

镉是一种已知的环境和工业污染物，是污染物 香烟烟。 对CD的事先吸入会导致肺部适应 这有助于保护肺部免受急性吸入剂量。 金属蛋白（MT）是一种金属和富含硫的蛋白，由 响应CD吸入的肺。 II型肺泡细胞似乎是 MT合成的主要部位。 MT和II型肺泡细胞的作用 在肺适应性/耐受性中，将研究CD。 剂量和 CD适应/公差的时间依赖性将被确定，并且 与肺MT水平相关。 超微结构形态测定法和 定量自显影术将评估II型细胞增生和/或 CD适应过程中的肥大。 II型细胞的计算 对总肺MT的贡献将使用形态计量数据和 肺匀浆和II型的MT含量的生化分析 细胞。 MT在孤立的II型细胞中的细胞亚细胞定位和 肺的原位将使用免疫组织化学技术进行 确定MT是否从细胞质转移到核 发生在CD自适应过程中。 糖皮质激素在 肺对CD的反应将通过：（a）相关 重复或急性CD暴露期间血浆皮质酮水平与 炎症细胞反应； （b）测试肾上腺切除术是否恶化 CD的毒性作用和/或降低了肺适应的能力 光盘; （c）确定地塞米松给药是否诱导MT 肺中的合成和/或减少CD诱导的肺损伤。 这 假设MT充当肺中自由基的清道夫将是 通过确定是否升高的CD适应动物进行测试 肺MT的水平对氧气诱导的肺损伤具有更大的抵抗力 或博来霉素。 对氧气耐受的动物将被测试以诱导 肺MT和对CD的交叉耐受性。 实验将进行 区分金属硫蛋白在CD适应中的保护作用 谷胱甘肽，谷胱甘肽穿梭酶提供的动物， 和/或超氧化物歧化酶。 拟议研究的结果将 提高我们对镉吸入的影响和 金属硫硫蛋白和II型细胞在肺防御中发挥作用的作用。