Molecular Phenotypes Distinguish Patients with Relatively Stable from Progressive Idiopathic Pulmonary Fibrosis (IPF)

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis.Methodology and Principal FindingsTo begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value��0.05). The over expressed genes included surfactant protein A1, two members of the MAPK-EGR-1-HSP70 pathway that regulate cigarette-smoke induced inflammation, and Plunc (palate, lung and nasal epithelium associated), a gene not previously implicated in IPF. Interestingly, 26 of the up regulated genes are also increased in lung adenocarcinomas and have low or no expression in normal lung tissue. More importantly, we defined a SAGE molecular expression signature of 134 transcripts that sufficiently distinguished relatively stable from progressive IPF.ConclusionsThese findings indicate that molecular signatures from lung parenchyma at the time of diagnosis could prove helpful in predicting the likelihood of disease progression or possibly understanding the biological activity of IPF.

背景
特发性肺纤维化（Idiopathic Pulmonary Fibrosis, IPF）是一种进行性慢性间质性肺疾病，现有疗法对其无效，且常导致患者死亡。不过，不同患者的疾病进展速率存在显著差异。本研究假设，对比病情稳定与快速进展的IPF患者的基因表达谱，可助力发现疾病生物标志物，并加深对IPF发病机制的理解。

研究方法与主要结果
为验证该假设，本研究采用基因表达系列分析（Serial Analysis of Gene Expression, SAGE）技术，对12例IPF患者的诊断性外科肺活检组织进行肺表达谱分析：其中6例为病情相对稳定（或缓慢进展）患者，另6例为快速进展患者（进展判定依据为12个月内的一氧化碳弥散量（DLCO）与用力肺活量（FVC）变化）。
研究结果显示，本研究获得的IPF肺组织SAGE转录组谱与正常肺组织及其他慢性肺部疾病的转录组谱存在显著差异。为筛选疾病进展的候选标志物，本研究对比了病情稳定与进展期IPF患者的SAGE表达谱，在进展组中鉴定出102个至少上调5倍的转录本，以及89个至少下调5倍的转录本（P值<0.05）。上调基因包括表面活性蛋白A1、调控吸烟诱导炎症的MAPK-EGR-1-HSP70通路的两个成员，以及此前未被发现与IPF相关的腭肺鼻上皮相关基因（Plunc）。值得注意的是，其中26个上调基因在肺腺癌中同样呈高表达，且在正常肺组织中表达量极低或不表达。更为重要的是，本研究构建了包含134个转录本的SAGE分子表达特征谱，可有效区分病情稳定与快速进展的IPF患者。

结论
本研究结果表明，诊断时获取的肺实质分子特征谱，有望用于预测IPF患者的疾病进展风险，或加深对IPF生物学活性的理解。