Role of Oxidatve Stress in Chronic Beryllium Disease

氧化应激在慢性铍病中的作用

• 批准号: 6787705
• 负责人: Brian J Day
• 金额: $ 25.2万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-04 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787705
• 关键词: T lymphocyte; antigen presenting cell; antioxidants; berylliosis; beryllium; biomarker; cell proliferation; chronic disease /disorder; clinical research; cytokine; glutathione; high performance liquid chromatography; human subject; leukocyte activation /transformation; lipopolysaccharides; metalloporphyrins; oxidative stress; patient oriented research; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The overall goal of this application is to understand the role of oxidative stress in chronic beryllium disease (CBD). CBD is an inflammatory hypersensitivity lung disease that continues to occur in 10% of the estimated 800,000 beryllium-exposed workers in the United Sates and is characterized by the presence of non-caseating granulomas with accumulation of macrophages and beryllium specific CD4+ T lymphocytes. Upon beryllium stimulation in vitro, these T cells proliferate and produce Th1 cytokines (i.e. TNF-alpha, INF-gamma, and IL-2) at unusually high levels. The precise molecular mechanism(s) by which beryllium regulates the production of these high levels of cytokines is unknown. It is hypothesized that oxidative stress enhances the APC's ability to present beryllium antigen to T cells, which may, in part, explain both the excessive cytokine response and associated lung granuloma formation. Exciting preliminary studies indicate that the redox status of the antigen presenting cell (APC) affects the T cell's response and may help explain why only a portion of the people exposed to beryllium actually develop CBD. The presence of APCs expressing class II molecules is required for CD4+ T cells from CBD patients to proliferate in the presence of beryllium in vitro. This project will use a modification of the clinical beryllium lymphocyte proliferation test (BeLPT) to examine the effect of redox balance on beryllium antigen presentation. This system will enable the testing of the hypothesis that oxidative stress affects the APC's ability to present beryllium antigen to T cells and the role of oxidative stress in modulating T cell activation. The hypothesis is addressed by the AIMS: (1) examine the effect of beryllium on APC and T cell antioxidant status and stimulation response; (2) examine the effect of altered APC glutathione status on beryllium antigen presentation; (3) examine the effect of altered oxidant status on beryllium antigen presentation by APC and T cell activation. Primary endpoints measured are (1) glutathione and enzymes involved in its synthesis and utilization; (2) markers of lipid, protein and DNA oxidation; and (3) T cell proliferation and Th1 cytokine release and accessory molecule expression. It is proposed that beryllium, itself; initiates oxidative stress in the APC and also serve as the antigen. Inherent differences in either resting APC antioxidant status or APC oxidant response to beryllium are predicted to be critical factors in determining whether people exposed to beryllium go on to develop CBD. These studies have the potential to further define the etiology of CBD, risk factors, and suggest novel approaches to prevent and treat this disease.

描述（由申请人提供）：本申请的总体目标是了解氧化应激在慢性铍病（CBD）中的作用。 CBD 是一种炎症性超敏性肺部疾病，在美国估计有 800,000 名接触铍的工人中，有 10% 的人持续患有 CBD，其特征是存在非干酪性肉芽肿，并伴有巨噬细胞和铍特异性 CD4+ T 淋巴细胞积聚。在体外铍刺激下，这些 T 细胞增殖并产生异常高水平的 Th1 细胞因子（即 TNF-α、INF-γ 和 IL-2）。铍调节这些高水平细胞因子产生的精确分子机制尚不清楚。据推测，氧化应激增强了 APC 向 T 细胞呈递铍抗原的能力，这可能部分解释了过度的细胞因子反应和相关的肺肉芽肿形成。令人兴奋的初步研究表明，抗原呈递细胞 (APC) 的氧化还原状态会影响 T 细胞的反应，并可能有助于解释为什么只有一部分接触铍的人实际上会产生 CBD。 CBD 患者的 CD4+ T 细胞在铍存在的情况下体外增殖需要表达 II 类分子的 APC 的存在。该项目将使用临床铍淋巴细胞增殖试验（BeLPT）的改进来检查氧化还原平衡对铍抗原呈递的影响。该系统将能够测试氧化应激影响 APC 向 T 细胞呈递铍抗原的能力以及氧化应激在调节 T 细胞激活中的作用这一假设。该假设由 AIMS 提出：（1）检查铍对 APC 和 T 细胞抗氧化状态和刺激反应的影响； (2) 检查改变的 APC 谷胱甘肽状态对铍抗原呈递的影响； (3) 检查氧化状态改变对 APC 和 T 细胞活化呈递铍抗原的影响。测量的主要终点是（1）谷胱甘肽和参与其合成和利用的酶； (2)脂质、蛋白质和DNA氧化标记物； (3) T细胞增殖和Th1细胞因子释放及辅助分子表达。建议铍本身；启动 APC 中的氧化应激，同时也充当抗原。静息 APC 抗氧化状态或 APC 对铍的氧化反应的固有差异预计将是决定接触铍的人是否继续发展 CBD 的关键因素。这些研究有可能进一步明确 CBD 的病因、危险因素，并提出预防和治疗这种疾病的新方法。