Lung fibrosis: Treatment and myofibroblast control

肺纤维化：治疗和肌成纤维细胞控制

• 批准号: 6616357
• 负责人: Marvin I Schwarz
• 金额: $ 28.87万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616357
• 关键词: biomarker; cell differentiation; cell population study; diagnostic respiratory lavage; drug screening /evaluation; fibroblasts; gene expression; genetic susceptibility; histopathology; human subject; human therapy evaluation; idiopathic pulmonary fibrosis; immunotherapy; interferon gamma; interstitial lung diseases; microarray technology; muscle cells; patient oriented research; respiratory disorder chemotherapy

(Applicant's Abstract) In Project 5 we propose to define the role of the fibroblastic foci and myofibroblast presence in IPF/UIP pathogenesis, to test an antiproliferative therapy for this disorder, and develop surrogate markers which predict outcome. Because of its antiproliferative properties and antagonism of transforming growth factor-beta-1 (TGF-b1) functions in vitro, as well as TGFb-1 driven myofibroblast generation, we propose to study the efficacy of interferon gamma (IFN) (subcutaneous and inhaled) in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). In the recently initiated phase III trial, we will define surrogate markers of outcome; to include dyspnea scores, physiologic tests, quantitative image analysis of the high resolution computed tomographic images, and fibroproliferative biomarkers. Recently, we were instrumental in organizing an NHLBI workshop which proposed systematic evaluation of several available novel therapeutic agents that could abrogate the fibroproliferative response. Myofibroblast apoptosis, proliferation, clonality and structure of fibroblastic foci will be compared to bronchiolitis obliterans organizing pneumonia (BOOP), a disease whose positive outcome exceeds IPF/UIP. Gene expression patterns of whole IPF[UIP lung will be analyzed by microarray and compared to normals and BOOP to determine differences and characteristic patterns. Microdissection of fibroblastic foci in IPF1UIP and Masson's bodies of BOOP will be performed. Based on this and utilizing laser capture microdissection BOOP will be performed to determine diagnostic patterns. The goal is to determine gene expression patterns of IPF/UIP and BOOP, which predict clinical behavior and are typical for that particular disease. We will also determine within the IPFIUIP group which genes reflect a bad vs. improved prognosis and the differential gene expression pattern between Fibroblastic foci (IPF/IJIP) and Masson's bodies.

（申请人的摘要）在项目5中，我们建议定义 成纤维细胞灶和肌纤维细胞在IPF/UIP发病机理中的存在，以测试 对这种疾病的抗增生性疗法，并发展替代标记物 哪个预测结果。由于其抗增殖特性和 在体外转化生长因子-Beta-1（TGF-B1）功能的拮抗作用， 除TGFB-1驱动的肌纤维细胞产生外，我们还建议研究 干扰素伽玛（IFN）（皮下和吸入）在特发性的功效 肺纤维化/通常的间质性肺炎（IPF/UIP）。在最近 启动III期试验，我们将定义结果的替代标记。到 包括呼吸困难分数，生理测试，定量图像分析 高分辨率计算机断层图像和纤维增生性 生物标志物。最近，我们有助于组织NHLBI研讨会 提出了几种可用的新型治疗的系统评估 可以消除纤维增生反应的药物。 肌纤维细胞凋亡，增殖，克隆性和结构 将成纤维细胞灶与组织的细支气管炎进行比较 肺炎（BOOP），一种阳性结果超过IPF/UIP的疾病。 整个IPF的基因表达模式[UIP肺将通过微阵列分析 并与正常和嘘声相比，以确定差异和特征 模式。 IPF1UIP和Masson身体中成纤维细胞灶的微分解 将执行BOOP。基于此并利用激光捕获 将进行微分解的启动以确定诊断模式。这 目标是确定IPF/UIP和BOOP的基因表达模式， 预测临床行为，并且是该特定疾病的典型特征。我们将 还可以在IPFIUIP组中确定基因反映不良与改进的基因 预后和成纤维细胞之间的差异基因表达模式 FOCI（IPF/IJIP）和Masson的身体。