PAI-1 and aging-related susceptibility to lung fibrosis

PAI-1 和衰老相关的肺纤维化易感性

基本信息

批准号：
9336422
负责人：
RUI-MING LIU
金额：
$ 43.84万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336422
关键词：
Age Aging Alteplase Alveolar Animal Model Animals Antioxidants Apoptosis Bleomycin Cultured Cells Cysteine Data Development Elderly Enzymes Epithelial Cells Etiology Extracellular Matrix Proteins Fibrinolysis Fibroblasts Fibrosis Figs - dietary Glutathione Hamman-Rich syndrome Health Histocompatibility Testing Injury Knockout Mice Lead Light Lung Lung diseases MAPK phosphatase MAPK14 gene MAPK8 gene Mediating Modeling Modification Molecular Mus NADPH Oxidase Oxidation-Reduction Plasminogen Activator Inhibitor 1 Play Predisposition Proteins Pulmonary Fibrosis Reactive Oxygen Species Recurrence Resistance Risk Factors Rodent Role Small Interfering RNA Sulfhydryl Compounds TP53 gene Testing Therapeutic Therapeutic Agents Urokinase age related aged alveolar epithelium alveolar type II cell base effective therapy experience inhibitor/antagonist knock-down mouse model novel novel therapeutics response small hairpin RNA small molecule urokinase inhibitor

项目摘要

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an aging-related progressive fatal lung disorder with no known etiology and no effective treatment. Alveolar type II epithelial cell (AEC2) apoptosis and (myo)fibroblast apoptosis resistance are evident in IPF lungs and are believed to be a key in the initiation and progression of IPF. Interestingly, our studies show that old mice experience diminished fibroblast apoptosis but augmented AEC2 apoptosis and fibrotic response upon bleomycin challenge, compared to young mice, suggesting that dysregulation of AEC2 and fibroblast apoptosis may underlie the aging-related susceptibility to IPF. The mechanism underlying the dysregulation of fibroblast and AEC2 apoptosis during aging, however, is unknown. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators (tPA and uPA), plays an important role in the development of lung fibrosis. Importantly, our previous studies/preliminary data show that PAI-1 expression is increased with age in mouse lung fibroblasts and AEC2 and that inhibition of PAI-1 activity restored the sensitivity of lung fibroblasts from old mice to apoptosis. Our previous studies/preliminary data further show that inhibition of PAI-1 activity or knockdown of PAI-1 with PAI-1 siRNA induces p53, a master controller of apoptosis, and apoptosis in lung fibroblasts but suppresses p53 and apoptosis in AEC2. Based on these data, we hypothesize that aging-related increase in PAI-1 leads to dysregulation of AEC2 and fibroblast apoptosis, which underlies the increased susceptibility of the elderly to lung fibrosis. Redox imbalance is evident in aged animals and in IPF. How redox imbalance contributes to aging-related susceptibility to IPF, however, is unclear. Our previous studies/preliminary data show that the concentrations of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, decrease whereas the expression of NADPH oxidase 4 (Nox4), an important producer of reactive oxygen species (ROS), increases with age in rodent lungs. Our previous studies also showed that Nox4-derived ROS induced PAI-1 in fibroblasts through modifying/inhibiting MAPK phosphatase 1 (MKP-1) whereas GSH selectively inhibited TGF-β1-induced PAI-1 by blocking JNK/p38 activation. Importantly, our preliminary data show that MKP-1 thiol modification is increased whereas the activity of MKP-1 is decreased in the lung of old mice. Therefore, we further hypothesize that aging-related redox imbalance contributes to the dysregulation of AEC2 and fibroblast apoptosis through inducing PAI-1 by modifying/inhibiting MKPs (e.g. MKP-1). Four specific aims are proposed to test our hypotheses, using different animal models including novel PAI-1 conditional knockout mouse models recently generated in this lab. The therapeutic potential of a small molecule PAI-1 inhibitor for lung fibrosis will also be tested in aged mice. The results from these studies will nt only shed new light on the mechanism underlying aging-related susceptibility to IPF but may also lead to novel paradigm shifting concept as well as new therapeutics for the treatment of IPF.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种与衰老相关的进行性致命性肺部疾病，病因不明，并且没有有效的治疗方法，肺泡 II 型上皮细胞（AEC2）凋亡和（肌）成纤维细胞凋亡抵抗明显。 IPF 肺部被认为是 IPF 发生和进展的关键，我们的研究表明，老年小鼠的成纤维细胞凋亡减少，但 AEC2 细胞凋亡增加。与年轻小鼠相比，博来霉素攻击后的纤维化反应表明，AEC2 和成纤维细胞凋亡的失调可能是与衰老相关的 IPF 易感性的基础，然而，纤溶酶原激活剂抑制剂在衰老过程中成纤维细胞和 AEC2 凋亡失调的机制尚不清楚。 1 (PAI-1) 是组织型和尿激酶型纤溶酶原激活剂（tPA 和 uPA）的主要抑制剂，发挥着重要的是，我们之前的研究/初步数据表明，PAI-1 表达在小鼠肺成纤维细胞和 AEC2 中随着年龄的增长而增加，并且抑制 PAI-1 活性可以恢复老年小鼠肺成纤维细胞的敏感性。我们之前的研究/初步数据进一步表明，用 PAI-1 siRNA 抑制 PAI-1 活性或敲低 PAI-1 会诱导细胞凋亡的主控制器 p53，根据这些数据，我们发现与衰老相关的 PAI-1 增加会导致 AEC2 和成纤维细胞凋亡失调，这是老年人对肺纤维化的易感性增加的基础。然而，氧化还原失衡在老年动物和 IPF 中很明显，但我们之前的研究/初步数据表明，氧化还原失衡如何导致与衰老相关的 IPF 易感性。谷胱甘肽 (GSH) 是最丰富的细胞内游离硫醇和重要的抗氧化剂，其浓度会降低，而 NADPH 氧化酶 4 (Nox4) 的表达量会随着啮齿动物肺部年龄的增长而增加，NADPH 氧化酶 4 (Nox4) 是活性氧 (ROS) 的重要产生者。我们之前的研究还表明，Nox4 衍生的 ROS 通过修饰/抑制 MAPK 磷酸酶 1 (MKP-1) 诱导成纤维细胞中的 PAI-1，而 GSH通过阻断 JNK/p38 激活选择性抑制 TGF-β1 诱导的 PAI-1 重要的是，我们的初步数据表明，老年小鼠肺中 MKP-1 硫醇修饰增加，而 MKP-1 活性降低。此外，衰老相关的氧化还原失衡通过修饰/抑制 MKP（例如 MKP-1）诱导 PAI-1，导致 AEC2 失调和成纤维细胞凋亡。我们的目标是使用不同的动物模型来检验我们的假设，包括本实验室最近生成的新型 PAI-1 条件敲除小鼠模型。小分子 PAI-1 抑制剂对肺纤维化的治疗潜力也将在老年小鼠中进行测试。这些研究不仅将为与衰老相关的 IPF 易感性机制提供新的线索，而且还可能带来新的范式转变概念以及治疗 IPF 的新疗法。