ROLE OF IFN GAMMA AND KGF IN HUMAN PULMONARY FIBROSIS

IFN GAMMA 和 KGF 在人肺纤维化中的作用

• 批准号: 6410577
• 负责人: Talmadge E King
• 金额: $ 20.88万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410577
• 关键词: berylliosis; clinical research; clinical trials; cytokine; disease /disorder etiology; disease /disorder prevention /control; drug screening /evaluation; fibroblast growth factor; human subject; human therapy evaluation; idiopathic pulmonary fibrosis; immunopathology; immunotherapy; inflammation; inhalation drug administration; interferon gamma; sarcoidosis; wound healing

The diffuse interstitial lung diseases (ILD) remain important clinical problems largely of unknown pathogenesis and often associated with a poor prognosis. Recent reports suggest the prevalence of ILD to be 25 to 30 individuals per 100,000 population, and there is evidence to suggest that the incidence is increasing. This proposal is the major clinical project in this SCOR program. It is a collaborative effort that complements the work planned in other projects in the SCOR. This project will study patients with ILD with two histopathological patterns: granulomatous inflammation (berylliosis or sarcoidosis) and usual interstitial pneumonitis [(UIP), idiopathic pulmonary fibrosis (IPF) or progressive systemic sclerosis, (PSS-PF)]. The major objectives are: (1) to improve our understanding of the immunopathogenesis of pulmonary fibrosis, with special emphasis on those factors that appear to prevent the development of fibrosis and (2) to investigate the role of the antifibrogenic cytokine, interferon gamma (IFNgamma), in modulating the inflammatory and fibrotic process in ILD. Patients with granulomatous inflammation tend to have a more benign clinical course usually without progression to irreversible pulmonary fibrosis; conversely, those with conditions characterized by UIP tend to progress to fibrosis and eventually succumb to their illness. Consequently, preventing the fibrotic response appears to offer the best hope for reducing the impact of this problem on the health of individuals afflicted with ILD. We hypothesize that the prevention of pulmonary fibrosis is the result of two processes: first, antifibrotic factors produced by (or acting upon) the cells central to the process (lymphocytes, macrophages, mast cells, and fibroblasts); and second, rapid re-epithelialization of the injured lung. Both are required to successfully modulate the inflammatory response and inhibit the fibroblastic response thereby limiting the degree of fibrosis. The study design involves: (l) cross sectional studies to identify (in lung tissue and bronchoalveolar lavage) the presence or absence of anti- or pro- fibrogenic factors in the alveolar micro environment responsible for modulating the mesenchymal cell response; and (2) longitudinal studies to determine the ability of inhaled recombinant IFNgamma to modulate the fibroproliferative response. We expect these studies to yield valuable information about the cellular mechanisms involved in the transition from inflammation to wound healing, repair and fibrosis in the human lung. In addition, the study will allow us to further identify and characterize biomarkers that may be useful in the assessment of disease stage and in predicting disease progression and prognosis. Finally, these studies will improve our understanding of how to prevent or inhibit pulmonary fibrosis and thereby determine how to intervene in the disease process to treat or reduce the morbidity and mortality of this devastating illness.

弥漫性间质性肺疾病（ILD）在临床上仍然很重要 问题很大程度上是未知的发病机制，并且通常与不良的健康状况有关 预后。最近的报告表明 ILD 的患病率为 25 至 30 每 100,000 人中就有一个人，并且有证据表明 发病率正在增加。本提案为重大临床项目 在这个 SCOR 计划中。这是一项协作努力，是对 SCOR 其他项目中计划的工作。本项目将研究 具有两种组织病理学模式的 ILD 患者：肉芽肿性 炎症（铍中毒或结节病）和常见的间质病 肺炎 [(UIP)、特发性肺纤维化 (IPF) 或进行性 系统性硬化症（PSS-PF）]。主要目标是：（1）提高 我们对肺纤维化免疫发病机制的理解 特别强调那些似乎阻碍发展的因素 纤维化的发生和（2）研究抗纤维化的作用 细胞因子，干扰素γ（IFNγ），在调节炎症和 ILD 中的纤维化过程。肉芽肿性炎症患者往往 具有更良性的临床病程，通常不会进展为 不可逆的肺纤维化；反之，有条件的 以 UIP 为特征的疾病倾向于进展为纤维化并最终死亡 对他们的疾病。因此，防止纤维化反应出现 为减少这一问题对世界的影响提供最好的希望 ILD 患者的健康。我们假设 预防肺纤维化是两个过程的结果：第一， 由中央细胞产生（或作用于）的抗纤维化因子 过程（淋巴细胞、巨噬细胞、肥大细胞和成纤维细胞）；和 第二，受损肺的快速上皮化。 两者都是必需的 成功调节炎症反应并抑制 成纤维细胞反应从而限制纤维化程度。研究 设计涉及：(l) 横断面研究以确定（在肺组织中 和支气管肺泡灌洗）是否存在抗或亲 肺泡微环境中的纤维形成因素 调节间充质细胞反应； (2) 纵向研究 确定吸入重组IFNγ调节的能力 纤维增殖反应。我们期望这些研究能够产生有价值的成果 有关从细胞转变所涉及的细胞机制的信息 炎症对人肺伤口愈合、修复和纤维化的影响。在 此外，这项研究将使我们能够进一步识别和表征 可能有助于评估疾病阶段和 预测疾病进展和预后。最后，这些研究将 提高我们对如何预防或抑制肺纤维化的理解 从而确定如何干预疾病过程来治疗或 降低这种毁灭性疾病的发病率和死亡率。