ROLE OF IFN GAMMA AND KGF IN HUMAN PULMONARY FIBROSIS

弥漫性间质性肺疾病(ILD)仍是临床上重要的疾病 主要是发病机制不明的问题，通常与不良相关 预后。最近的报告表明，ILD的患病率为25到30 每10万人，有证据表明 这种情况的发生率正在增加。这项建议是主要的临床项目 在这个SCOR项目中。这是一项协作努力，是对 在SCOR的其他项目中计划的工作。该项目将研究 有两种组织病理学类型的ILD患者：肉芽肿 炎症(铍病或结节病)和常见的间质 肺炎(UIP)、特发性肺纤维化(IPF)或进展性肺炎 系统性硬化症(PSS-PF)]。主要目标是：(一)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 和(2)研究抗纤维化的作用。 细胞因子，干扰素-γ(IFN-γ)，在调节炎症和 ILD的纤维化过程。肉芽肿性炎症患者倾向于 有更良性的临床病程，通常不会进展到 不可逆转的肺纤维化；相反，有条件的人 以UIP为特征的倾向于进展为纤维化并最终屈服 对他们的疾病。因此，预防纤维化反应就出现了。 为减少这一问题对经济的影响提供最好的希望 患有ILD的个人的健康状况。我们假设 预防肺纤维化是两个过程的结果：第一， 由(或作用于)中枢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)；以及 第二，损伤肺的快速再上皮化。两者都是必需的 为了成功地调节炎症反应并抑制 成纤维细胞的反应，从而限制纤维化的程度。这项研究 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)有无抗或亲- 肺泡微环境中的致纤维化因素 调节间充质细胞的反应；以及(2)纵向研究 测定吸入重组人干扰素-γ调节细胞周期的能力 纤维增生性反应。我们希望这些研究能产生有价值的成果 有关细胞机制的信息涉及从 炎症对人类肺部伤口愈合、修复和纤维化的影响。在……里面 此外，这项研究将使我们能够进一步识别和表征 生物标志物在疾病分期和临床诊断中的应用 预测疾病进展和预后。最后，这些研究将 提高对如何预防或抑制肺纤维化的认识 从而确定如何干预疾病过程以治疗或 减少这一毁灭性疾病的发病率和死亡率。

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.