Therapeutic Strategies for Environmental Lung Diseases

环境性肺病的治疗策略

基本信息

批准号：
7295871
负责人：
James Christopher Bonner
金额：
$ 22.28万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295871
关键词：
Address Affect Allergens Anti-Inflammatory Agents Anti-inflammatory Asthma Binding Bioavailable Bleomycin Blood Circulation Breathing Cell Surface Receptors Cell surface Cells Chemotaxis Child Chronic Chronic lung disease Cicatrix Clinical Treatment Clinical Trials Collagen Complication Connective Tissue Cells Data Deposition Development Diabetes Mellitus Diagnosis Disease Dose Environmental Exposure Exposure to Fibroblasts Fibrosis Figs - dietary Future Genetic Predisposition to Disease Gleevec Glucocorticoids Growth Growth Factor Health Human Imatinib Imatinib mesylate In Vitro Inflammatory Interleukin-13 Ligands Lung Lung diseases Mediating Mediator of activation protein Membrane Modeling Molecular Mus Myofibroblast Nature Oral Administration Outcome Ovalbumin PDGF receptor tyrosine kinase PDGFRB gene Pathogenesis Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Phosphorylation Platelet Inhibitors Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Play Prevention Process Production Protein Isoforms Protein Tyrosine Kinase Pulmonary Fibrosis Receptor Protein-Tyrosine Kinases Research Respiratory physiology Risk Role STAT6 Transcription Factor Signal Transduction Source System Testing Therapeutic Tissues Transition Elements Treatment Protocols Tyrosine Kinase Inhibitor United States Vanadium Work autocrine bis(maltolato)oxovanadium(IV)cell type concept cytokine design diabetes mellitus therapy fibrogenesis improved in vivo indium-bleomycin inhibitor/antagonist innovation interstitial intraperitoneal lung injury migration mouse model neutralizing antibody neutralizing monoclonal antibodies oxovanadium IV pre-clinical receptor receptor binding research study response response to injury small molecule toxicant transcription factor translational approach

项目摘要

DESCRIPTION (provided by applicant): There are currently no effective strategies for the treatment of chronic airway fibrosis in asthma or interstitial pulmonary fibrosis that result from environmental exposures to a wide variety of inhaled allergens and toxicants. It is generally accepted that current anti-inflammatory therapies fail to improve fibrotic outcomes in the lung. Therefore, the development of translational approaches that target fibrosis are urgently needed. Our work has shown that interleukin (IL)-13, a key mediator of asthma and fibrosis, stimulates the production of platelet-derived growth factor (PDGF). The binding of PDGF to cell-surface PDGF receptors results in the proliferation of fibroblasts, the principal cell type that secretes collagen to form fibrotic scar tissue. IL-13-induced PDGF production by lung cells is tightly regulated by STAT transcription factors; STAT-6 promotes IL-13-induced PDGF production while STAT-1 suppresses PDGF production. The primary objective of this project is to explore innovative strategies aimed at reducing IL-13-induced PDGF signaling and fibrosis. Our hypothesis is that inhibition of PDGF production, PDGF receptor binding, or PDGF receptor phosphorylation will reduce airway or interstitial fibrosis in established mouse models of chronic lung disease. In the first aim we will determine whether the oral administration of bis(maltolato)oxovanadium(IV) (BMOV), a bioavailable form of vanadium that is used for diabetes therapy, decreases PDGF levels and airway fibrosis in vivo in mouse models of asthma and interstitial pulmonary fibrosis. Because vanadium activates STAT-1 to reduce IL-13-induced PDGF production in lung cells in vitro, we will determine if BMOV reduces airway fibrosis in vivo using the ovalbumin mouse model of asthma and in a bleomycin mouse model of interstitial fibrosis. In the second aim we will determine whether administration of a monoclonal neutralizing antibody to selectively block PDGF binding to the PDGF receptor reduces fibrosis in mouse models of asthma and pulmonary fibrosis. In the final aim, we will determine whether blocking PDGF receptor tyrosine kinase activity reduces fibrosis in a mouse model of asthma. This aim will utilize the receptor tyrosine kinase inhibitor, imatinib mesylate, to block PDGFR phosphorylation. If any one of the three proposed strategies for blocking PDGF signaling result in amelioration of fibrosis, then this would provide a breakthrough for future application to clinical trials aimed at the treatment of airway fibrosis in asthma or interstitial pulmonary fibrosis. Asthma and pulmonary fibrosis are chronic lung diseases that result from environmental exposure and genetic susceptibility to a wide variety of inhaled allergens and toxicants. In the United States there are over 200,000 patients with pulmonary fibrosis, and of these over 40,000 expire annually. 20 million people in the United States have been diagnosed with asthma and nearly 9 million of them are children. Therefore, these chronic lung diseases clearly pose a major health problem. Airway fibrosis in asthma is part of a chronic remodeling process that contributes to the obstructive nature of this disease and reduces lung function. Moreover, there are currently no effective treatment strategies to reduce airway fibrosis in chronic asthma, nor are drugs available that significantly reduce interstitial pulmonary fibrosis. We will attempt to develop preclinical strategies aimed at reducing growth factor signaling, fibroblast proliferation, and collagen deposition in mouse models of chronic asthma and interstitial pulmonary fibrosis.

描述（由申请人提供）：目前还没有有效的策略来治疗哮喘中的慢性气道纤维化或间质性肺纤维化，这些纤维化是由于环境暴露于各种吸入性过敏原和毒物而引起的。人们普遍认为，当前的抗炎疗法无法改善肺部纤维化的结果。因此，迫切需要开发针对纤维化的转化方法。我们的工作表明，白介素 (IL)-13（哮喘和纤维化的关键介质）可刺激血小板衍生生长因子 (PDGF) 的产生。 PDGF 与细胞表面 PDGF 受体的结合导致成纤维细胞增殖，成纤维细胞是分泌胶原蛋白形成纤维化疤痕组织的主要细胞类型。 IL-13 诱导肺细胞产生 PDGF 受到 STAT 转录因子的严格调控； STAT-6 促进 IL-13 诱导的 PDGF 产生，而 STAT-1 抑制 PDGF 产生。该项目的主要目标是探索旨在减少 IL-13 诱导的 PDGF 信号传导和纤维化的创新策略。我们的假设是，抑制 PDGF 产生、PDGF 受体结合或 PDGF 受体磷酸化将减少已建立的慢性肺病小鼠模型中的气道或间质纤维化。在第一个目标中，我们将确定口服双（麦芽糖）氧钒（IV）（BMOV）（一种用于糖尿病治疗的生物可利用形式的钒）是否可以降低哮喘小鼠模型体内的 PDGF 水平和气道纤维化，以及肺间质纤维化。由于钒在体外激活 STAT-1 以减少肺细胞中 IL-13 诱导的 PDGF 产生，因此我们将使用卵清蛋白小鼠哮喘模型和博来霉素小鼠间质纤维化模型来确定 BMOV 是否可以减少体内气道纤维化。在第二个目标中，我们将确定施用单克隆中和抗体来选择性阻断 PDGF 与 PDGF 受体的结合是否可以减少哮喘和肺纤维化小鼠模型的纤维化。最终目标是确定阻断 PDGF 受体酪氨酸激酶活性是否可以减少哮喘小鼠模型的纤维化。这一目标将利用受体酪氨酸激酶抑制剂甲磺酸伊马替尼来阻断 PDGFR 磷酸化。如果三种提议的阻断PDGF信号传导策略中的任何一种能够改善纤维化，那么这将为未来应用于治疗哮喘气道纤维化或间质性肺纤维化的临床试验提供突破。哮喘和肺纤维化是慢性肺部疾病，由环境暴露和对多种吸入过敏原和毒物的遗传易感性引起。在美国，有超过 200,000 名肺纤维化患者，其中每年有超过 40,000 人死亡。美国有 2000 万人被诊断患有哮喘，其中近 900 万人是儿童。因此，这些慢性肺部疾病显然构成了重大的健康问题。哮喘中的气道纤维化是慢性重塑过程的一部分，导致这种疾病的阻塞性并降低肺功能。此外，目前尚无减少慢性哮喘气道纤维化的有效治疗策略，也没有可显着减少间质性肺纤维化的药物。我们将尝试开发临床前策略，旨在减少慢性哮喘和间质性肺纤维化小鼠模型中的生长因子信号传导、成纤维细胞增殖和胶原沉积。