Fibrinolytic Proteases, meso-mesenchymal transition and pleural remodeling

纤溶蛋白酶、间质转化和胸膜重塑

• 批准号: 10084709
• 负责人: Torry Alle Tucker
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084709
• 关键词: Address; Asbestos; Attenuated; Bacterial Pneumonia; Biochemical; Bleomycin; Carbon Black; Cells; Cicatrix; Data; Deposition; Development; Empyema; Fibrin; Fibrinolysis; Fibrosis; Functional Imaging; Histology; Human; Imaging Techniques; Impairment; Injury; Intervention; Label; Lead; Link; Lung; Lung diseases; Manuscripts; Maps; Mediating; Medical; Mesenchymal; Mesothelial Cell; Modeling; Molecular; Mus; Myofibroblast; Nuclear; Outcome; Particulate; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmacotherapy; Phenotype; Phosphorylation; Physiological; Plasmin; Plasminogen; Plasminogen Activator Inhibitor 1; Pleura; Pleural; Pleural Mesothelial Cell; Process; Proteins; Quality of life; Radiation exposure; Reporting; Role; Signal Transduction; Smooth Muscle Actin Staining Method; Streptococcus; Surface; System; Techniques; Testing; Therapeutic Agents; Tissues; Transforming Growth Factors; Trauma; Urokinase; Urokinase Plasminogen Activator Receptor; Visceral pleura; X-Ray Computed Tomography; base; cell motility; defined contribution; glycogen synthase kinase 3 beta; improved outcome; inhibitor/antagonist; loss of function; mortality; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; prevent; pulmonary function; receptor; respiratory; response; urokinase inhibitor

Pleural injury often resolves with remodeling of the pleural surfaces, which in severe cases leads to pleural fibrosis (PF) and fibrothorax. These sequellae are associated with respiratory impairment, reduced quality of life and increased mortality. PF with lung restriction is often seen in medical practice but current treatment is unsatisfactory and effective pharmacotherapy is not available. PF is characterized by aberrant local fibrin deposition and proliferation of alpha-smooth muscle actin (α-SMA) expressing myofibroblasts. The expansion of myofibroblasts is largely due to mesenchymal transition (MT) of resident pleural mesothelial cells (PMC), termed MesoMT. These motile, matrix-producing cells are largely responsible for thickening of the pleura; pleural rind formation. MesoMT and PF are linked to fibrinolytic pathways, as proteases involved in fibrin degradation induce MesoMT. We recently reported that deficiency of plasminogen activator inhibitor (PAI)-1, the principal inhibitor of urokinase plasminogen activator (uPA) and tissue PA (tPA), increases plasmin activity and significantly worsens pleural injury. We also found that uPA and plasmin potently induce MesoMT. uPA- and plasmin-mediated MesoMT involves activation of glycogen synthase kinase (GSK)-3β, a new and promising target for the treatment of PF. Further, our preliminary studies show that GSK-3β inhibition with a novel inhibitor, 9ING41, significantly attenuates the progression of pleural injury and remodeling. Based on these observations and strong preliminary data, we strongly infer that uPA and plasmin and their activation of GSK-3β, substantively contribute to the progression of PF. In this project, we will test the central hypothesis that fibrinolysin-mediated changes and activation of GSK-3β are important steps that regulate PMC phenotype and pleural injury outcomes including PF. Our objective is to determine the mechanism by which fibrinolytic proteases, including uPA and plasmin, induce MesoMT and define their contribution to fibrosing pleural injury. We will also define the contribution of increased GSK-3β signaling to the progression of PF. Our specific aims are: 1) to define protease-receptor interactions by which the fibrinolytic system regulates MesoMT and pleural remodeling, 2) to determine the mechanism by which GSK-3β signaling is regulated in uPA and plasmin- induced MesoMT and 3) to determine the contribution of GSK-3β to the progression of pleural injury. We will use new models of fibrosing pleural injury and empyema, mice with mesothelial labelling for fate-mapping analyses, molecular, biochemical, histology and immunohistochemical techniques with which we have expertise, state of the art CT imaging and pulmonary function analyses to accomplish these aims. We will test whether new therapeutic agents including inhibitors of GSK-3β signaling effectively block the development of PF. These studies will address gaps in our understanding of the pathogenesis of PF and thereby advance the field. The proposal may also identify promising novel interventions that, if successful, could be further developed to ultimately improve outcomes of patients with fibrosing pleural injury.

胸膜损伤通常随着胸膜表面的重塑而消退，这在严重的情况下导致胸膜损伤。 纤维化（PF）和纤维胸。这些后遗症与呼吸功能障碍， 生命和死亡率上升。肺功能受限的肺纤维化在医学实践中常见，但目前的治疗方法是 目前还没有令人不满意和有效的药物治疗。PF的特征是异常的局部纤维蛋白 表达α-平滑肌肌动蛋白（α-SMA）的肌成纤维细胞的沉积和增殖。扩大 肌成纤维细胞的增殖主要是由于胸膜间皮细胞（PMC）的间质转化（MT）， 称为MesoMT。这些能动的、产生基质的细胞在很大程度上负责胸膜的增厚; 胸膜形成。MesoMT和PF与纤维蛋白溶解途径相关，作为参与纤维蛋白溶解的蛋白酶。 降解诱导MesoMT。我们最近报道了纤溶酶原激活物抑制剂（派）-1缺乏， 尿激酶纤溶酶原激活物（uPA）和组织PA（tPA）主要抑制剂，增加纤溶酶活性 并显著减轻胸膜损伤。我们还发现uPA和纤溶酶有效地诱导MesoMT。uPA- 纤溶酶介导的MesoMT涉及糖原合成酶激酶（GSK）-3β的激活，GSK-3 β是一种新的 此外，我们的初步研究表明，GSK-3β抑制与PF的治疗有关。 新型抑制剂9 ING 41显著减弱胸膜损伤和重塑的进展。基于 根据这些观察结果和强有力的初步数据，我们强烈推断uPA和纤溶酶及其激活的 GSK-3β在PF的发生、发展中起重要作用，本课题将对中心假设进行验证 纤溶酶介导的GSK-3β的变化和激活是调节PMC表型的重要步骤 和胸膜损伤的结果，包括PF。我们的目的是确定纤溶机制， 蛋白酶，包括uPA和纤溶酶，诱导MesoMT并确定它们对纤维化胸膜损伤的贡献。 我们还将确定GSK-3β信号传导增加对PF进展的贡献。 是：1）定义纤溶系统调节MesoMT和胸膜炎的蛋白酶-受体相互作用， 重塑，2）确定GSK-3β信号在uPA和纤溶酶- 诱导MesoMT; 3）确定GSK-3β对胸膜损伤进展的贡献。我们将 使用纤维化胸膜损伤和脓胸的新模型，用间皮瘤标记的小鼠进行命运绘图 分析，分子，生物化学，组织学和免疫组织化学技术，我们有 专业知识，最先进的CT成像和肺功能分析，以实现这些目标。我们将测试 包括GSK-3β信号传导抑制剂在内的新治疗药物是否能有效阻断 PF。这些研究将填补我们对PF发病机制理解的空白，从而促进对PF的研究。 领域该提案还可以确定有希望的新干预措施，如果成功，可以进一步 开发用于最终改善纤维化胸膜损伤患者的结局。

项目成果

KIF5A transports collagen vesicles of myofibroblasts during pleural fibrosis.

• DOI: 10.1038/s41598-017-04437-7
• 发表时间: 2017-07-04
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kamata H;Tsukasaki Y;Sakai T;Ikebe R;Wang J;Jeffers A;Boren J;Owens S;Suzuki T;Higashihara M;Idell S;Tucker TA;Ikebe M
• 通讯作者: Ikebe M

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL.

• DOI: 10.3390/cells11030563
• 发表时间: 2022-02-06
• 期刊: Cells
• 影响因子: 6
• 作者: Hao Q;Shetty S;Tucker TA;Idell S;Tang H
• 通讯作者: Tang H

Early IL-17A production helps establish Mycobacterium intracellulare infection in mice.

• DOI: 10.1371/journal.ppat.1010454
• 发表时间: 2022-04
• 期刊: PLoS pathogens
• 影响因子: 6.7

Myo5b Transports Fibronectin-Containing Vesicles and Facilitates FN1 Secretion from Human Pleural Mesothelial Cells.

• DOI: 10.3390/ijms23094823
• 发表时间: 2022-04-27
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Precision-guided, Personalized Intrapleural Fibrinolytic Therapy for Empyema and Complicated Parapneumonic Pleural Effusions: The Case for the Fibrinolytic Potential.

• DOI: 10.1097/cpm.0000000000000216
• 发表时间: 2017-07
• 期刊: Clinical pulmonary medicine
• 作者: Idell S;Florova G;Shetty S;Tucker T;Idell R;Koenig K;Azghani A;Rahman NM;Komissarov A
• 通讯作者: Komissarov A