ECSOD in Asbestos-induced Pulmonary Fibrosis

ECSOD 在石棉引起的肺纤维化中的作用

• 批准号: 7284787
• 负责人: CHERYL L FATTMAN
• 金额: $ 10.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-07 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284787
• 关键词: Alveolar; Animal Model; Antioxidants; Apoptosis; Asbestos; Asbestos-related lung injury; Asbestosis; Binding; Biochemical; Biodistribution; Breathing; Cell Death; Characteristics; Chemicals; Chemotactic Factors; Chronic; Collagen; Collagen Type I; Data; Deposition; Development; Disease; Disease Progression; Doctor of Philosophy; Enzymes; Excision; Exposure to; Extracellular Matrix; Extracellular Space; Fiber; Fibrosis; Functional disorder; Future; Heparin Binding; Immunochemistry; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Laboratories; Lead; Lung; Lung diseases; Mediating; Mineral Fibers; Modification; Mus; Numbers; Oxidants; Pathogenesis; Personal Satisfaction; Play; Pneumoconiosis; Positioning Attribute; Process; Production; Protein Biochemistry; Protein Region; Proteolysis; Pulmonary Fibrosis; Reaction; Reactive Oxygen Species; Research Personnel; Role; Signal Transduction; Site; Staging; Stimulus; Superoxide Dismutase; Superoxides; Surface Properties; Testing; Tissues; Treatment Protocols; base; cell type; collagenase; design; extracellular; in vivo Model; insight; lung development; lung injury; neutrophil; novel; prevent; programs; research study; respiratory; response; size

DESCRIPTION (provided by applicant) Asbestosis is a debilitating disease caused by the inhalation of asbestos mineral fibers. Asbestosis is associated with chronic inflammatory reactions that can lead to the development of lung fibrosis years after the initial exposure. However, current treatment regimens are inadequate and new ones must be sought. It is well known that asbestos fibers generate reactive oxygen species in animal models of asbestosis, suggesting that oxidants play an important role in disease development. The enzyme extracellular supeoxide dismutase (ECSOD) is an antioxidant enzyme highly expressed in the lung and loss of ECSOD from the extracellular matrix (ECM) has been associated with pulmonary fibrosis in mice. ECSOD contains a heparin-binding domain that regulates its biodistribution in the ECM. This domain is sensitive to proteolysis, and removal of the heparin-binding domain may be an important mechanism regulating ECSOD levels in the ECM. ECSOD directly binds to type I collagen in alveolar septa, where it may protect collagen from superoxide-mediated fragmentation. Notably, collagen fragments are potent chemoattractants and activators of neutrophils. In addition, it has recently been shown that collagen fragments can induce apoptosis in a number of cell types. Therefore, any increase in superoxide production will accelerate both the inflammatory reactions and cellular destruction by initiating collagen degradation. The primary hypothesis to be tested in this proposal is that ECSOD protects against pulmonary fibrosis by preventing superoxide-mediated collagen degradation and apoptosis. To study this hypothesis, the applicant will pursue the following Specific Aims: 1) Investigate changes in ECSOD activity, biodistribution and sites of synthesis in mouse lungs at different stages of asbestos-induced lung injury, 2) Assess the structural effects of asbestos deposition on type I collagen, and 3) Determine the stimulus for and extent of programmed cell death in lungs of asbestos-treated mice.

描述（由申请人提供） 石棉肺是一种因吸入石棉矿物纤维而导致的衰弱性疾病。石棉沉着症与慢性炎症反应有关，可导致最初暴露后数年肺纤维化的发展。然而，目前的治疗方案是不够的，必须寻求新的治疗方案。众所周知，石棉纤维在石棉肺动物模型中产生活性氧，这表明氧化剂在疾病发展中起着重要作用。细胞外超氧化物歧化酶（ECSOD）是一种在肺中高度表达的抗氧化酶，细胞外基质（ECM）中ECSOD的丢失与小鼠肺纤维化有关。ECSOD含有肝素结合结构域，其调节ECSOD在ECM中的生物分布。该结构域对蛋白水解敏感，并且去除肝素结合结构域可能是调节ECM中ECSOD水平的重要机制。ECSOD直接与肺泡隔中的I型胶原结合，在那里它可以保护胶原免受超氧化物介导的断裂。值得注意的是，胶原蛋白片段是中性粒细胞的强效化学引诱剂和激活剂。 此外，最近已经显示胶原蛋白片段可以在许多细胞类型中诱导凋亡。因此，超氧化物产生的任何增加都将通过启动胶原降解加速炎症反应和细胞破坏。在这个提议中要测试的主要假设是ECSOD通过防止超氧化物介导的胶原降解和细胞凋亡来防止肺纤维化。为了研究这一假设，申请人将致力于以下具体目标：1）研究在石棉诱导的肺损伤的不同阶段小鼠肺中ECSOD活性、生物分布和合成位点的变化，2）评估石棉沉积对I型胶原的结构影响，以及3）确定石棉处理小鼠肺中程序性细胞死亡的刺激和程度。