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

项目摘要/摘要： 肺纤维化(PF)是一种罕见的退行性疾病，其特征是进行性肺僵硬，导致 确诊后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)的特定基因与一种特别极端的肺表型有关。 在人类中，PF的进展经常被炎性爆发所打断，临床上称之为“急性加重”， 这极大地加速了疾病的发展，缩短了预期寿命。根据这一概念，单核细胞 肺内单核细胞来源的巨噬细胞的动员和持久性是PF的强烈预测因素 严肃性。一些环境因素已被提出用来促进和加速急性炎症 PF的恶化；然而，确切的机制还没有被询问。无处不在的空气污染物 臭氧(O3)是导致肺部疾病的主要且不可避免的环境因素，通过 氧化应激和富含单核/巨噬细胞的炎症。为了更好地模仿人类肺泡炎的病因，我们 开发了一种新的小鼠模型，随着时间的推移，作为可诱导的异位的结果，会形成自发的损害 最常见的PF连锁SP-C突变(SP-CI73T)的表达。这种临床前模式提供了一种独特的 破译肺衰竭进展机制的平台，特别是急性加重(诱发)的作用 通过臭氧)、渗透的单核细胞和单核细胞来源的巨噬细胞促进PF。我们发表的研究成果显示 SP-C突变伴随着动态的单核/巨噬细胞炎症反应，由 上皮细胞。初步证据证实，臭氧暴露可放大炎性细胞内流并促进 SP-C突变小鼠的炎症信号，使PF恶化。对拟议范例的评估将提供 确定健康、急性炎症和完全纤维化的肺对环境的反应的基本数据 曝光。我们的假设是，由SP-C突变驱动的臭氧诱导的PF急性加重增强了 炎性单核细胞的募集和激活，触发单核细胞来源的巨噬细胞促纤维化 回应。我们的具体目标是：1)确定臭氧诱导的肺部炎症后的单核细胞动力学 和PF。2)研究单核细胞来源的巨噬细胞和臭氧诱导的PF加重的作用；以及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.