Gene Set Analysis of Lung Samples Provides Insight into Pathogenesis of Progressive, Fibrotic Pulmonary Sarcoidosis
Gene Set Analysis of Lung Samples Provides Insight into Pathogenesis of Progressive, Fibrotic Pulmonary Sarcoidosis
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DOI：
10.1164/rccm.200912-1855oc
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发表时间：
2010-06-15
影响因子：
24.7
通讯作者：
Ho, Ling-Pei
中科院分区：
文献类型：
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作者：
Lockstone, Helen E.;Sanderson, Sharon;Ho, Ling-Pei
理论基础：大约60%到70%的肺结节病患者的疾病可以自发消退；其余的患者则遵循慢性病程，并伴有不同程度的纤维化。目的：确定自限性结节病患者与进展性纤维性疾病患者肺组织基因表达谱的差异，并分析这些差异表达基因的生物学相关性。方法：我们检测了活动性但自限性(n=8)与活动性进行性(+/-)肺病患者(n=7)经纤维支气管镜活检组织中26,626个基因的微阵列表达。0.01，贝叶斯缓和t检验)。基因集浓缩分析显示，在进展性纤维化组上调的基因中，与宿主免疫激活、增殖和防御相关的基因集(由基因本体论定义)过度表达(前43个基因集为FDR Q<；0.0001)，并且进行性纤维性结节病和过敏性肺炎(HP)之间的基因表达谱显著丰富和相似，(Q<；0.001)，而不是特发性肺纤维化。结论：进行性/纤维性肺结节病患者肺内存在与宿主防御相关的免疫活性，其过程更类似于幽门螺杆菌而非特发性肺纤维化。研究还表明，经纤维支气管镜肺活检标本可以为基因表达谱提供高质量的RNA，支持其作为肺结节病预后分类的潜在用途。
Rationale: Approximately 60 to 70% of patients with pulmonary sarcoidosis have disease that resolves spontaneously; the rest follow a chronic course with varying levels of fibrosis. It is unclear why some patients progress and if treatment affects outcome.Objectives: To determine differential gene expression profile in lungs of patients with self-limiting sarcoidosis compared to those with progressive-fibrotic disease, and to analyze the biological relevance of these differentially expressed genes.Methods: We examined microarray expression of 26,626 genes in transbronchial biopsies of granulomatous areas in lungs of patients with active but self-limiting (n = 8) versus those with active, progressive (+/- fibrotic) pulmonary disease (n = 7).Measurements and Main Results: Three hundred thirty-four genes were differentially expressed between the two groups (P < 0.01, Bayesian moderated t test). Gene Set Enrichment Analysis showed over-representation of gene-sets (defined by Gene Ontology) related to host immune activation, proliferation, and defense, among genes up-regulated in the progressive-fibrotic group (FDR q < 0.0001 for the top 43 gene sets), and a marked enrichment of, and similarity in gene expression profiles between, progressive-fibrotic sarcoidosis and hypersensitivity pneumonitis (HP), (q < 0.001), but not idiopathic pulmonary fibrosis (IPF).Conclusions: The findings suggest that patients with progressive/fibrotic pulmonary sarcoidosis have intense immune activity related to host defense in their lungs, with processes more similar to HP than IPF. The study also demonstrates that transbronchial lung biopsy samples can provide good-quality RNA for gene expression profiling, supporting its potential use as a prognostic classifier for pulmonary sarcoidosis.