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: 8473917
• 负责人: Neelam Azad
• 金额: $ 23.75万
• 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/8473917
• 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(申请人提供)：血管生成和异常的细胞氧化还原状态是特发性肺纤维化(IPF)发病机制的特征，但这些病理变化背后的机制尚不清楚。未能了解和瞄准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。这项研究的长期目标是开发一种有效的治疗策略来对抗肺纤维化，这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与肺纤维化有很强的正相关关系，但对其在肺纤维化中的作用却知之甚少。目的1探讨血管内皮生长因子在肺纤维化发病机制中的作用，验证磷脂酰肌醇-3-激酶(PI3K)/Akt信号通路通过缺氧诱导因子(HIF)-11在博莱姆诱导的肺纤维化中调节血管内皮生长因子(VEGF)的假说。尽管已知促血管生成环境与进展性纤维化共存，但新生血管在纤维化进展中的作用尚未得到充分研究。初步数据显示，博莱姆治疗可显著增加血管内皮细胞的血管生成。目的探讨血管生成在博莱曼诱导的肺纤维化中的作用，并验证博莱曼诱导的肺纤维化过程中的血管生成部分依赖于Akt介导的血管生成介质血管内皮生长因子上调的假说。将使用基因敲除和药理学方法来阐明Akt的作用，并确定其特定的异构体(S)参与这一过程。氧化应激增加与肺损伤和纤维化有关，其抑制作用已被证明对动物模型中的肺纤维化具有显著的保护作用。目的3旨在评价抗氧化剂如锰超氧化物歧化酶(MnSOD)是否通过调节血管生成(PI3K/Akt-&GT；HIF-1-&GT；VEGF)通路而介导肺纤维化。初步数据表明，锰(III)四(4-苯甲酸)卟啉(MnTBAP)，一种锰超氧化物歧化酶的模拟物，显著阻断了博莱曼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地抑制肺纤维化。这项拟议的研究对于加深对肺纤维化发病机制的分子机制的理解具有重要意义。这项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记物，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。