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.

（申请人摘要）在项目 5 中，我们建议定义 IPF/UIP 发病机制中成纤维细胞灶和肌成纤维细胞的存在，以测试 针对这种疾病的抗增殖疗法，并开发替代标记 预测结果。由于其抗增殖特性和 体外转化生长因子-β-1 (TGF-b1) 功能的拮抗作用， 以及 TGFb-1 驱动的肌成纤维细胞生成，我们建议研究 干扰素 γ (IFN)（皮下和吸入）在特发性中的疗效 肺纤维化/普通间质性肺炎（IPF/UIP）。在最近的 启动 III 期试验，我们将定义结果的替代指标；到 包括呼吸困难评分、生理测试、定量图像分析 高分辨率计算机断层扫描图像和纤维增生 生物标志物。最近，我们帮助组织了 NHLBI 研讨会 提出了对几种可用的新型治疗方法的系统评估 可以消除纤维增殖反应的药物。 肌成纤维细胞凋亡、增殖、克隆性和结构 成纤维细胞灶将与闭塞性细支气管炎组织进行比较 肺炎 (BOOP)，一种阳性结果超过 IPF/UIP 的疾病。 整个IPF[UIP肺的基因表达模式将通过微阵列进行分析 并与正常值和 BOOP 进行比较以确定差异和特征 模式。 IPF1UIP 和 Masson 体中成纤维细胞灶的显微解剖 将执行BOOP。以此为基础并利用激光捕获 将进行显微切割 BOOP 以确定诊断模式。这 目标是确定 IPF/UIP 和 BOOP 的基因表达模式，这 预测临床行为并且是该特定疾病的典型特征。我们将 还可以确定 IPFIUIP 组内哪些基因反映了不良与改善 成纤维细胞间的预后和差异基因表达模式 焦点 (IPF/IJIP) 和 Masson 体。