The role of ECSODF in lung repair after silica-induces injury

描述(由申请人提供)： 矽肺在最初接触二氧化硅颗粒多年后发生，以慢性炎症、肺纤维化和最终呼吸损害为特征。目前还没有针对矽肺的有效治疗方法。因此，被诊断为矽肺的患者预后惨淡，许多患者仍在死于这种疾病。矽肺背后的生化机制尚不清楚，但氧化剂确实在疾病的发展中发挥了作用。抗氧化酶细胞外超氧化物歧化酶(EcSOD)是肺细胞外基质(ECM)中的主要抗氧化酶，对其他纤维性肺部疾病具有保护作用。以前的研究已经将EcSOD的丧失与肺损伤的恶化和有利于氧化的肺环境联系在一起。ECSOD的过度表达或用类似于SOD的药物治疗可以预防这种损伤。因此，有效治疗策略的一个组成部分可能是恢复肺内氧化剂/抗氧化剂的平衡。研究表明，骨髓间充质干细胞可参与氧化损伤后肺组织的修复。然而，人们对高度氧化的肺微环境对干细胞介导的组织修复的影响知之甚少。因此，研究人员假设，矽肺导致了有利于氧化的微环境，导致间充质干细胞修复肺损伤的效率降低。研究人员将采用小鼠矽肺模型，将从EcSOD缺失或过度表达的小鼠中纯化的MSCs移植到暴露于二氧化硅的动物身上。调节干细胞和受体小鼠的抗氧化剂水平的效果将取决于干细胞治疗的效果。这些研究完成后，将提供有关肺微环境对干细胞根除肺部疾病能力的影响的有价值的信息。这些研究还将开始探讨将具有增强抗氧化能力的纯化MSCs移植到矽肺疾病患者体内作为治疗的可行性。接触二氧化硅引起的肺部疾病(矽肺)是一个持续存在的公共卫生问题，没有有效的治疗方法。该项目研究在治疗矽肺时使用成体干细胞和增加抗氧化剂的水平。这些研究将有助于确定使用成人干细胞治疗矽肺患者的可行性。

DESCRIPTION (provided by applicant): Silicosis develops many years after initial exposure to silica particles and is characterized by chronic inflammation, lung fibrosis and ultimately respiratory impairment. There is no effective treatment for silicosis. As a result, patients diagnosed with silicosis are given a dismal prognosis and many patients are still dying of this disease. The biochemical mechanisms behind silicosis are poorly characterized, however oxidants do play a role in disease development. The antioxidant enzyme extracellular superoxide dismutase (ECSOD), the major antioxidant enzyme in the lung extracellular matrix (ECM), protects against other fibrotic lung diseases. Previous studies have correlated the loss of ECSOD with worsening lung injury and a pro-oxidant lung environment. ECSOD overexpression or treatment with SOD-mimetic drugs can prevent this injury. Thus, one component of an effective treatment strategy may be the restoration of the oxidant / antioxidant balance in the lung. Studies show that administration of mesenchymal stem cells (MSCs) can participate in the repair of lung tissue after oxidative injury. However, little is known about the effects of a highly oxidative lung microenvironment on stem cell-mediated tissue repair. Therefore, the investigators hypothesize that silicosis results in a pro-oxidant microenvironment that leads to the reduced efficacy of mesenchymal stem cells to repair lung damage. The investigators will employ a mouse silicosis model whereby MSCs purified from either ECSOD null mice or ECSOD overexpressing mice are administered to animals exposed to silica. The effects of modulating antioxidant levels of both the stem cells and the recipient mice will be determined on the efficacy of the stem cell treatment. When complete, these studies will provide valuable information on the influence of the lung microenvironment on the ability of stem cells to abrogate lung disease. These studies will also begin to address the feasibility of transplanting purified MSCs with augmented antioxidant capabilities into patients with silicotic lung disease as therapy. Lung disease due to silica exposure (silicosis) is a continuing public health problem that has no effective treatment. This project examines the use of adult stem cells along with increased levels of antioxidants in the treatment of silicosis. These studies will help determine the feasibility of using adult stem cells in the treatment of patients with silicosis.