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

ECSODF 在二氧化硅诱导损伤后肺修复中的作用

• 批准号: 8126387
• 负责人: CHERYL L FATTMAN
• 金额: $ 38.51万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126387
• 关键词: Address; Adult; Alveolar Cell; Alveolus; Animals; Antioxidants; Apoptosis; Area; Asbestos; Biochemical; Biodistribution; Biological Models; Bleomycin; Bone Marrow; Cell Culture Techniques; Cell Survival; Cells; Chronic; Deposition; Development; Diagnosis; Disease; Doctor of Philosophy; Engraftment; Environment; Enzymes; Equilibrium; Excision; Exposure to; Extracellular Matrix; Extracellular Space; Fibroblasts; Fibrosis; Genes; Goals; Heparin Binding; Impairment; In Vitro; Inflammatory; Injury; Knockout Mice; Knowledge; Lead; Longevity; Lung; Lung Inflammation; Lung diseases; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Modality; Modeling; Mus; Myofibroblast; Natural regeneration; Nodule; Outcome; Oxidants; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Protein Region; Public Health; Pulmonary Fibrosis; Radiation; Reaction; Reactive Oxygen Species; Research Personnel; Role; Silicon Dioxide; Silicosis; Site; Stem cells; Structure; Structure of parenchyma of lung; Superoxide Dismutase; Testing; Therapeutic; Tissues; Translating; Transplantation; Work; Wound Healing; adult stem cell; alveolar destruction; design; effective therapy; extracellular; improved; in vivo; induced pluripotent stem cell; injured; intravenous administration; lung development; lung injury; migration; mimetics; outcome forecast; overexpression; particle; prevent; programs; repaired; respiratory; response; restoration; tissue regeneration; treatment strategy

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.

描述（由申请人提供）： 矽肺在初次暴露于二氧化硅颗粒多年后发展，其特征在于慢性炎症、肺纤维化和最终的呼吸障碍。目前还没有有效的治疗硅肺的方法。因此，被诊断患有硅肺的患者预后很差，许多患者仍然死于这种疾病。矽肺背后的生物化学机制的特点是少，但氧化剂确实在疾病的发展中发挥作用。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，可预防其他纤维化肺病。先前的研究已经将ECSOD的丧失与肺损伤的恶化和促氧化的肺环境相关联。ECSOD过表达或用SOD模拟药物治疗可以防止这种损伤。因此，有效治疗策略的一个组成部分可能是恢复肺中的氧化剂/抗氧化剂平衡。研究表明，间充质干细胞（MSCs）的管理可以参与氧化损伤后肺组织的修复。然而，关于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，研究人员假设硅肺导致促氧化微环境，导致间充质干细胞修复肺损伤的功效降低。研究人员将采用小鼠硅肺模型，其中将从ECSOD缺失小鼠或ECSOD过表达小鼠纯化的MSC给予暴露于二氧化硅的动物。调节干细胞和受体小鼠的抗氧化剂水平的效果将根据干细胞治疗的功效来确定。当完成时，这些研究将提供有关肺微环境对干细胞消除肺部疾病的能力的影响的有价值的信息。这些研究也将开始，以解决的可行性移植纯化的骨髓间充质干细胞与增强抗氧化能力的患者与矽肺肺病作为治疗。由于二氧化硅暴露（矽肺）引起的肺部疾病是一个持续的公共卫生问题，没有有效的治疗方法。本项目探讨了成人干细胞沿着增加抗氧化剂水平在矽肺治疗中的应用。这些研究将有助于确定使用成体干细胞治疗矽肺患者的可行性。