Targeting Oxidative Stress in Chronic Beryllium 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）发病机制中的潜在作用。CBD是一种炎症性超敏性肺部疾病，发生在美国80多万接触铍的工人中，其特征是肺肉芽肿。铍调节慢性肺炎症和肉芽肿形成的分子机制尚不清楚。我们假设铍通过改变硫醇稳态诱导氧化应激，从而增强铍特异性T细胞产生过量的Th1细胞因子和增殖，这是CBD病理生理的两个关键特征。提出了三个具体目标来解决这一假设。特异性目的1将研究铍通过改变硫醇氧化还原状态刺激铍特异性CD4+ T细胞氧化应激的机制。特异性目的2将确定铍介导的氧化应激是否会改变组蛋白乙酰转移酶（HAT）和组蛋白去乙酰转移酶（HDAC）活性之间的平衡，从而调节CBD的炎症和类固醇敏感性。这一目标将测试铍暴露是否会产生氧化应激，从而损害HDAC活性，作为放大CBD炎症的机制。具体目标3将检查5氨基水杨酸对CBD受试者的潜在治疗效果。最后一个目的是评估一种针对铍介导的氧化应激和炎症的CBD患者的新疗法。这些实验阐明了解释细胞因子对铍过度反应的新机制，并明确了CBD中抗氧化失衡的作用和治疗CBD的机制方法。公共卫生相关性：CBD是一种肉芽肿性肺部疾病，发生在大量接触铍的美国工人中。提出的研究重点是新的发现，铍既是抗原和引发氧化应激，导致细胞硫醇状态的改变。该研究将利用一种新的治疗方法在CBD受试者中使用5氨基水杨酸来机械地靶向这些变化。

DESCRIPTION (provided by applicant): The overall goal of this application is to understand the role of oxidative stress as a potential target in the pathogenesis of chronic beryllium disease (CBD). CBD is an inflammatory hypersensitivity lung disease that occurs in over 800,000 beryllium-exposed workers in the US characterized by pulmonary granulomas. The molecular mechanisms by which beryllium regulates the chronic production of lung inflammation and granuloma formation are unknown. We hypothesize that beryllium induces oxidative stress by altering thiol homeostasis which enhances beryllium specific T cells to produce excessive Th1 cytokines and proliferate, two key features of CBD pathophysiology. Three specific aims are proposed to address the hypothesis. Specific aim 1 will examine the mechanisms by which beryllium stimulates oxidative stress in beryllium specific CD4+ T cells by altering thiol redox status. Specific aim 2 will determine whether beryllium-mediated oxidative stress alters the balance between histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) activities that modulates inflammation and steroid sensitivity in CBD. This aim will test whether beryllium exposure creates oxidative stress that impairs HDAC activity as a mechanism that amplifies inflammation in CBD. Specific aim 3 will examine the potential therapeutic effect of a 5 aminosalicylic acid in CBD subjects. This last aim will assess a novel new therapy in CBD patients that targets beryllium-mediated oxidative stress and inflammation. The proposed experiments elucidate novel mechanisms that explain the excessive cytokine response to beryllium and pinpoint the role of antioxidant imbalance in CBD and mechanistic approaches to treat CBD. PUBLIC HEALTH RELEVANCE: CBD is a granulomatous lung disease that occurs in a large population of US workers exposed to beryllium. The proposed study focuses on novel findings that beryllium is both an antigen and initiator of oxidative stress that results in alterations in cellular thiol status. The studies will mechanistically target these changes with a novel therapeutic approach using 5 aminosalicylic acid in CBD subjects.