Impact of Oxidative Stress-Regulated Angiogenesis in Pulmonary Fibrosis

描述（由申请人提供）：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）发病机制的标志，但这些病理改变的机制尚不清楚。未能理解和瞄准这些关键机制直接限制了治疗这种疾病的有效性。本研究的长期目标是开发一种有效的治疗肺纤维化的策略，这与国家心肺血液研究所的使命直接相关。本提案的总体目标是研究氧化应激调节的血管生成在博来霉素（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很强的正相关，但VEGF在肺纤维化中的作用尚不清楚。Aim 1旨在确立VEGF在肺纤维化发病机制中的作用，验证PI3K /Akt信号通路在blm诱导的肺纤维化中通过缺氧诱导因子(HIF)-11调控VEGF的假说。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尚未得到充分研究。初步数据显示，血管内皮细胞的血管新生在对BLM治疗的反应中显著增加。目的2旨在确定血管生成参与blm诱导的肺纤维化，并验证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，并确定其参与该过程的特定亚型。氧化应激的增加与肺损伤和纤维化有关，在动物模型中，氧化应激的抑制已显示出对肺纤维化的显著保护作用。Aim 3旨在评估锰超氧化物歧化酶（MnSOD）等抗氧化剂是否通过调节血管生成（PI3K/Akt->HIF-1->VEGF）途径介导肺纤维化。初步数据显示，锰（III）四akis（4-苯甲酸）卟啉（MnTBAP）， MnSOD的模拟物，显著阻断blm诱导的血管生成和纤维生成反应。我们假设mntpap可能通过调节血管生成途径有效抑制肺纤维化。提出的研究对于增加对参与肺纤维化发病机制的分子机制的理解将是重要的。该研究还将有助于确定关键分子靶点，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。

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.