Targeting Oxidative Stress in Chronic Beryllium Disease

描述(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)发病机制中的潜在靶点作用。CBD是一种炎症性过敏性肺部疾病，发生在美国超过80万名接触铍的工人中，其特征是肺肉芽肿。铍调节慢性肺部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来诱导氧化应激，这种稳态增强了铍特异性T细胞产生过多的Th1细胞因子和增殖，这是CBD病理生理学的两个关键特征。针对这一假设，本文提出了三个具体目标。具体目标1将研究铍通过改变硫醇氧化还原状态来刺激铍特异的CD4+T细胞的氧化应激的机制。具体目标2将确定铍介导的氧化应激是否改变组蛋白乙酰转移酶(HAT)和组蛋白去乙酰基转移酶(HDAC)活性之间的平衡，从而调节CBD的炎症和类固醇敏感性。这一目标将测试暴露于铍是否会造成氧化应激，从而削弱HDAC活性，作为放大CBD炎症的机制。具体目标3将检测5-氨基水杨酸在CBD患者中的潜在治疗效果。这最后一个目标将评估针对铍介导的氧化应激和炎症的CBD患者的新疗法。拟议的实验阐明了解释细胞因子对铍的过度反应的新机制，并明确了抗氧化剂失衡在CBD中的作用以及治疗CBD的机制方法。与公共卫生相关：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。这项拟议的研究集中在新的发现上，即铍既是氧化应激的抗原，也是氧化应激的起始者，氧化应激导致细胞硫醇状态的改变。这些研究将机械地针对这些变化，在CBD受试者中使用5氨基水杨酸的一种新的治疗方法。

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.