RATIONALE Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a variable and unpredictable course. OBJECTIVES To determine whether BAL cell gene expression is predictive of survival in IPF. METHODS This retrospective study analyzed the BAL transcriptome of three independent IPF cohorts: Freiburg (Germany), Siena (Italy), and Leuven (Belgium) including 212 patients. BAL cells from 20 healthy volunteers, 26 patients with sarcoidosis stage III and IV, and 29 patients with chronic obstructive pulmonary disease were used as control subjects. Survival analysis was performed by Cox models and component-wise boosting. Presence of airway basal cells was tested by immunohistochemistry and flow cytometry. MEASUREMENTS AND MAIN RESULTS A total of 1,582 genes were predictive of mortality in the IPF derivation cohort in univariate analyses adjusted for age and sex at false discovery rate less than 0.05. A nine-gene signature, derived from the discovery cohort (Freiburg), performed well in both replication cohorts, Siena (P < 0.0032) and Leuven (P = 0.0033). nCounter expression analysis confirmed the array results (P < 0.0001). The genes associated with mortality in BAL cells were significantly enriched for genes expressed in airway basal cells. Further analyses by gene expression, flow cytometry, and immunohistochemistry showed an increase in airway basal cells in BAL and tissues of IPF compared with control subjects, but not in chronic obstructive pulmonary disease or sarcoidosis. CONCLUSIONS Our results identify and validate a BAL signature that predicts mortality in IPF and improves the accuracy of outcome prediction based on clinical parameters. The BAL signature associated with mortality unmasks a potential role for airway basal cells in IPF.

中文翻译：

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BAL细胞基因表达指示特发性肺纤维化的结局和气道基础细胞的参与。

理由：特发性肺纤维化（IPF）是一种致命疾病，病程可变且无法预测。目的确定BAL细胞基因表达是否可预测IPF生存。方法这项回顾性研究分析了包括212名患者在内的三个独立IPF队列的BAL转录组：弗莱堡（德国），锡耶纳（意大利）和鲁汶（比利时）。将来自20名健康志愿者，26例结节病的III和IV期患者以及29例慢性阻塞性肺疾病的BAL细胞用作对照组。生存分析通过Cox模型和逐组分增强进行。通过免疫组织化学和流式细胞术检测气道基底细胞的存在。测量和主要结果总计1 在对年龄和性别进行校正的单变量分析中，582个基因可预测IPF派生队列中的死亡率，假发现率小于0.05。来自发现队列（弗莱堡）的九基因签名在复制队列锡耶纳（P <0.0032）和鲁汶（P = 0.0033）中均表现良好。nCounter表达分析证实了阵列结果（P <0.0001）。BAL细胞中与死亡率相关的基因明显丰富了气道基底细胞中表达的基因。通过基因表达，流式细胞术和免疫组织化学的进一步分析显示，与对照组相比，BAL和IPF组织中的气道基底细胞增加，而在慢性阻塞性肺疾病或结节病中则没有。结论我们的结果鉴定并验证了BAL签名，该签名可预测IPF的死亡率并提高基于临床参数的结果预测的准确性。与死亡率相关的BAL信号揭示了IPF中气道基底细胞的潜在作用。