Impact of Oxidative Stress-Regulated Angiogenesis in Pulmonary Fibrosis

氧化应激调节血管生成对肺纤维化的影响

• 批准号: 8324502
• 负责人: Neelam Azad
• 金额: $ 24.95万
• 依托单位: HAMPTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324502
• 关键词: 1-Phosphatidylinositol 3-Kinase; Angiogenesis Inhibitors; Animal Model; Antioxidants; Biological Markers; Bleomycin; Cell Proliferation; Cell Survival; Characteristics; Collagen; Combined Modality Therapy; Data; Development; Disease; Environment; Enzymes; Exposure to; Failure; Fibroblasts; Fibrosis; Goals; Hamman-Rich syndrome; Hypoxia Inducible Factor; Link; Lung; Manganese Superoxide Dismutase; Mediating; Mediator of activation protein; Mission; Mitochondria; Modality; Molecular; Molecular Target; National Heart, Lung, and Blood Institute; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Phosphorylation; Play; Prevention strategy; Process; Production; Protein Isoforms; Pulmonary Fibrosis; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stimulus; Testing; Therapeutic; Tumor Angiogenesis; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; angiogenesis; cell type; design; hypoxia inducible factor 1; indium-bleomycin; kinase inhibitor; knockout gene; lung injury; mimetics; neovascularization; novel; porphyrin a; response; tetrakis(4-benzoic acid)porphyrin; therapeutic effectiveness

DESCRIPTION (provided by applicant): Angiogenesis and aberrant cellular redox state are the hallmarks of the pathogenesis of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying these pathologic alterations are poorly understood. Failure to understand and target such critical mechanisms directly limits the effectiveness of the therapeutic efforts against this disease. The long-term goal of this study is to develop an effective therapeutic strategy against pulmonary fibrosis and is directly relevant to the mission of National Heart, Lung and Blood Institute. The overall objective of this proposal is to investigate the contribution of oxidative stress-regulated angiogenesis in the pathogenesis of bleomycin (BLM)-induced pulmonary fibrosis. In spite of a strong positive correlation between the angiogenic mediator vascular endothelial growth factor (VEGF) and pulmonary fibrosis, the role of VEGF in pulmonary fibrosis is poorly understood. Aim 1 is designed to establish the role of VEGF in the pathogenesis of pulmonary fibrosis and test the hypothesis that phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway regulates VEGF via hypoxia inducible factor (HIF)-11 in BLM-induced pulmonary fibrosis. Although pro-angiogenic environment is known to co-exist with progressive fibrosis, the contribution of neovascularization to the progression of fibrosis is understudied. The preliminary data demonstrates a significant increase in angiogenesis in vascular endothelial cells in response to BLM treatment. Aim 2 is designed to establish the involvement of angiogenesis in BLM-induced pulmonary fibrosis and test the hypothesis that angiogenesis during BLM-induced pulmonary fibrosis is dependent, in part, upon Akt mediated upregulation of the angiogenic mediator VEGF. Gene knockout and pharmacological approaches will be used to elucidate the role of Akt and identify its specific isoform(s) involved in the process. Increased oxidative stress have been implicated in lung injury and fibrosis and its inhibition has shown to offer significant protection against pulmonary fibrosis in animal models. Aim 3 is designed to evaluate if antioxidants such as manganese superoxide dismutase (MnSOD) mediate lung fibrosis by regulating the angiogenic (PI3K/Akt->HIF-1->VEGF) pathway. The preliminary data shows that Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP), an MnSOD mimetic, significantly blocked BLM-induced angiogenic and fibrogenic response. We hypothesize that MnTBAP might be effective in suppressing pulmonary fibrosis by modulating the angiogenic pathway. The proposed study will be important for the increased understanding of the molecular mechanisms involved in the pathogenesis of pulmonary fibrosis. The study will also aid in identifying key molecular targets, which may serve as novel biomarkers and provide alternative avenues for the development of potential therapeutic and preventive strategies for this fatal disease.

描述（由申请方提供）：血管生成和异常细胞氧化还原状态是特发性肺纤维化（IPF）发病机制的标志，但对这些病理学改变的机制知之甚少。未能理解和靶向这些关键机制直接限制了针对这种疾病的治疗努力的有效性。本研究的长期目标是开发有效的肺纤维化治疗策略，与国家心肺血液研究所的使命直接相关。本研究的总体目标是探讨氧化应激调节的血管生成在博莱霉素（BLM）诱导的肺纤维化发病机制中的作用。尽管血管生成介质血管内皮生长因子（VEGF）与肺纤维化之间存在强正相关性，但对VEGF在肺纤维化中的作用了解甚少。目的1探讨VEGF在肺纤维化发病机制中的作用，并验证磷脂酰肌醇-3-激酶（PI 3 K）/Akt信号通路通过缺氧诱导因子（HIF）-11调节VEGF在BLM诱导的肺纤维化中的作用。虽然已知促血管生成环境与进行性纤维化共存，但新血管形成对纤维化进展的贡献研究不足。初步数据表明，在血管内皮细胞中的血管生成的显着增加，以响应BLM治疗。目的2旨在建立BLM诱导的肺纤维化中血管生成的参与，并测试BLM诱导的肺纤维化过程中血管生成部分依赖于Akt介导的血管生成介质VEGF的上调的假设。基因敲除和药理学方法将用于阐明Akt的作用，并鉴定其参与该过程的特异性亚型。增加的氧化应激与肺损伤和纤维化有关，其抑制已显示在动物模型中提供针对肺纤维化的显著保护。目的3探讨锰超氧化物歧化酶（MnSOD）等抗氧化剂是否通过调节血管生成途径（PI 3 K/Akt->HIF-1->VEGF）介导肺纤维化。初步数据显示，锰（III）四（4-苯甲酸）卟啉（MnTBAP），MnSOD模拟物，显着阻断博莱霉素诱导的血管生成和纤维化反应。我们推测MnTBAP可能通过调节血管生成途径有效抑制肺纤维化。这项研究对于进一步了解肺纤维化发病机制的分子机制具有重要意义。该研究还将有助于确定关键的分子靶点，这些靶点可能作为新的生物标志物，并为开发这种致命疾病的潜在治疗和预防策略提供替代途径。