Therapeutic Strategies for Environmental Lung Diseases

描述（由申请人提供）：目前尚无治疗哮喘或间质性肺纤维化中慢性气道纤维化的有效策略，这些慢性气道纤维化是由环境暴露于各种吸入性过敏原和有毒物质所致。人们普遍认为，目前的抗炎治疗未能改善肺纤维化的结果。因此，迫切需要开发靶向纤维化的转化方法。我们的工作表明，白细胞介素（IL）-13，哮喘和纤维化的关键介质，刺激血小板衍生生长因子（PDGF）的生产。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以形成纤维化瘢痕组织的主要细胞类型。IL-13诱导的肺细胞PDGF生成受STAT转录因子的严格调控; STAT-6促进IL-13诱导的PDGF生成，而STAT-1抑制PDGF生成。该项目的主要目的是探索旨在减少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的产生，PDGF受体结合，或PDGF受体磷酸化将减少建立的慢性肺疾病小鼠模型的气道或间质纤维化。在第一个目标中，我们将确定口服给药双（麦芽）氧钒（IV）（BMOV），一种用于糖尿病治疗的钒的生物可利用形式，是否在哮喘和间质性肺纤维化的小鼠模型中降低体内PDGF水平和气道纤维化。由于钒激活STAT-1，减少IL-13诱导的PDGF在体外肺细胞中的产生，我们将确定是否BMOV减少体内使用卵清蛋白哮喘小鼠模型和博来霉素间质纤维化小鼠模型的气道纤维化。在第二个目标，我们将确定是否管理的单克隆中和抗体，选择性地阻止PDGF结合PDGF受体减少哮喘和肺纤维化小鼠模型中的纤维化。在最终的目标，我们将确定是否阻断PDGF受体酪氨酸激酶活性减少哮喘小鼠模型的纤维化。该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。如果所提出的阻断PDGF信号传导的三种策略中的任何一种导致纤维化的改善，那么这将为未来应用于旨在治疗哮喘或间质性肺纤维化中的气道纤维化的临床试验提供突破。哮喘和肺纤维化是由环境暴露和对各种吸入性过敏原和有毒物质的遗传易感性引起的慢性肺部疾病。在美国，有超过20万名肺纤维化患者，其中每年有超过4万人死亡。美国有2000万人被诊断患有哮喘，其中近900万是儿童。因此，这些慢性肺部疾病显然构成了一个重大的健康问题。哮喘中的气道纤维化是慢性重塑过程的一部分，其导致这种疾病的阻塞性并降低肺功能。此外，目前还没有有效的治疗策略来减少慢性哮喘的气道纤维化，也没有可显著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。

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.