Role of Surfactant Protein-C Mutation and Ozone Exposure in the Exacerbation of Pulmonary Fibrosis

项目概要/摘要： 肺纤维化（PF）是一种罕见的退行性疾病，其特征是进行性肺硬化， 诊断后3-5年内死亡。令人信服的临床证据表明上皮细胞的突变- 编码表面活性蛋白-C（SP-C）特异性基因与特别极端的肺表型有关。 人类PF的进展经常被炎性爆发打断，临床上称为“急性加重”， 会大大加速疾病的发展并缩短预期寿命。与此雅阁一致，单核细胞 动员和肺中单核细胞衍生的巨噬细胞的持续存在是PF的强预测因子 严重性。已经提出了几种环境因素促进和加速急性炎症 PF的恶化;然而，确切的机制尚未被询问。无处不在的空气污染 臭氧（O3）是导致肺部疾病的主要且不可避免的环境因素， 氧化应激和富含单核细胞/巨噬细胞的炎症。为了密切模拟人类PF的原因，我们 开发了一种新的小鼠模型，随着时间的推移，由于诱导异位 最常见的PF连锁SP-C突变（SP-CI 73 T）的表达。这种临床前模型提供了一种独特的 解释PF进展机制的平台，特别是急性加重（诱导）的作用 通过O3），浸润单核细胞，单核细胞衍生的巨噬细胞在促进PF。我们发表的工作表明， SP-C突变伴随着动态单核细胞/巨噬细胞炎症反应，由 上皮细胞初步证据证实，O3暴露放大了炎症细胞的流入， SP-C突变小鼠的炎症信号，恶化PF。 定义健康、急性炎症和完全纤维化肺对环境的反应的基本数据 exposure.我们的假设是，由SP-C突变驱动的O3诱导的PF急性加重增强了肺纤维化。 募集和激活炎性单核细胞，触发单核细胞衍生的巨噬细胞促纤维化 反应我们的具体目标是：1）定义O3诱导的肺部炎症后单核细胞动力学 2）研究单核细胞衍生的巨噬细胞和O3诱导的PF恶化的作用;和3）： 确定单核细胞亚群在PF表型中的作用。

Project Summary/Abstract: Pulmonary fibrosis (PF) is a rare degenerative disease characterized by progressive lung stiffening, resulting in death within 3-5 years of diagnosis. Compelling clinical evidence show that mutations of the epithelial cell- specific gene encoding surfactant protein-C (SP-C), are linked to a particularly extreme lung phenotype. Progression of PF in humans is often punctuated by inflammatory bursts, clinically termed “acute exacerbations”, that drastically accelerate the disease and reduce life expectancy. In accord with this notion, monocyte mobilization and the persistence of monocyte-derived macrophages in the lung are strong predictors of PF severity. Several environmental factors have been proposed to promote and accelerate acute inflammatory exacerbations of PF; however, the exact mechanisms have not been interrogated. The ubiquitous air pollutant ozone (O3) represents a major, and unavoidable, environmental contributor to pulmonary disease through oxidative stress and monocyte/macrophage rich inflammation. To closely mimic causes of human PF, we developed a novel mouse model that develops spontaneous lesions over time, as a result of inducible ectopic expression of the most common PF-linked SP-C mutation (SP-CI73T). This preclinical model provides a unique platform to decipher mechanisms of PF progression and specifically the roles of acute exacerbations (induced by O3), infiltrating monocytes, and monocyte-derived macrophages in promoting PF. Our published work showed that SP-C mutation is accompanied by a dynamic monocyte/macrophage inflammatory response, initiated by the epithelium. Preliminary evidence confirm that O3 exposure amplifies inflammatory cell influx and pro- inflammatory signaling in SP-C mutant mice, worsening PF. Assessment of the proposed paradigm will provide fundamental data to define the responses of the healthy, acutely inflamed, and fully fibrotic lung to environmental exposure. Our hypothesis is that O3-induced acute exacerbation of PF driven by SP-C mutation enhances the recruitment and activation of inflammatory monocytes, triggering a monocyte-derived macrophage pro-fibrotic response. Our Specific Aims are to: 1) Define monocyte dynamics following O3-induced pulmonary inflammation and PF. 2) Investigate the role of monocyte-derived macrophages and O3-induced exacerbation of PF; and 3) : Establish the role of monocyte subpopulations in the PF phenotype.