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: 6302454
• 负责人: Talmadge E King
• 金额: $ 24.9万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302454
• 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.

弥漫性间质肺疾病（ILD）仍然很重要 主要是未知的发病机理的问题，通常与较差有关 预后。最近的报告表明，ILD的流行率为25至30 个人每100,000人口，有证据表明 发病率正在增加。该建议是主要的临床项目 在此SCOR程序中。这是一项协作努力，可以补充 在SCOR的其他项目中计划的工作。这个项目将研究 具有两种组织病理学模式的ILD患者：肉芽肿 炎症（贝利利病或结节病）和通常的间隙 肺炎[（UIP），特发性肺纤维化（IPF）或进行性 全身性硬化，（PSS-PF）]。主要目标是：（1）改进 我们对肺纤维化的免疫发病发生的理解， 特别强调似乎阻止发展的因素 纤维化和（2）研究抗纤维化的作用 细胞因子，干扰素伽马（Ifngamma）调节炎症和 ILD中的纤维化过程。肉芽肿性炎症的患者往往 通常没有进步的临床课程更良性 不可逆的肺纤维化；相反，有条件的人 UIP的特征倾向于发展为纤维化，并最终屈服 患病。因此，防止纤维化反应出现 为了减少此问题对此的影响提供最大的希望 患有ILD的个人的健康。我们假设 预防肺纤维化是两个过程的结果：首先 由（或作用于）中心的细胞产生的抗纤维化因子 过程（淋巴细胞，巨噬细胞，肥大细胞和成纤维细胞）；和 其次，受伤的肺的快速重新上皮化。 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，从而限制了纤维化程度。研究 设计涉及：（l）横截面研究以识别（在肺组织中 和支气管肺泡灌洗）存在或不存在抗或前 肺泡微环境中的纤维化因子负责 调节间充质细胞反应； （2）纵向研究 确定吸入重组IFNGAMMA调制的能力 纤维增生反应。我们希望这些研究能产生有价值的 有关从 人体肺部炎症会因伤口愈合，修复和纤维化。在 此外，该研究将使我们能够进一步识别和表征 可能在评估疾病阶段和中有用的生物标志物 预测疾病的进展和预后。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以治疗或 降低这种毁灭性疾病的发病率和死亡率。