Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis.
Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis.
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DOI：
10.1136/thoraxjnl-2012-202943
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发表时间：
2013-12
期刊：
影响因子：
10
通讯作者：
Schwartz DA
中科院分区：
文献类型：
--
作者：
Yang IV;Coldren CD;Leach SM;Seibold MA;Murphy E;Lin J;Rosen R;Neidermyer AJ;McKean DF;Groshong SD;Cool C;Cosgrove GP;Lynch DA;Brown KK;Schwarz MI;Fingerlin TE;Schwartz DA
特发性肺纤维化（IPF）是一种无法治愈的肺部疾病，中位生存期仅为3-5年，使用临床，放射学和病理学标准的组合进行诊断。在组织学上，IPF的特征是普通型间质性肺炎（UIP），这是一种纤维化间质性肺炎，具有纤维化和重塑肺的异质性胸膜下区域模式。我们假设肺组织的基因表达谱可以识别疾病的分子亚型，从而对具有临床意义的IPF/UIP亚型进行分类。我们收集了119名IPF/UIP患者和50名非疾病对照的肺组织转录谱。使用协方差分析（ANCOVA）模型结合每个患者的临床诊断以及年龄、性别和吸烟状况来鉴定个体转录物的差异表达。在111例IPF/UIP和39例非疾病对照的独立队列中进行验证。我们的分析基于与先前与纤维化相关的基因（基质金属蛋白酶、骨桥蛋白、角蛋白）、纤毛基因和功能未知的基因的表达相关的强分子特征，鉴定了IPF/UIP的两种亚型。我们证明，纤毛基因的表达升高与更广泛的显微镜下蜂窝状结构以及气道粘蛋白基因MUC 5 B和金属蛋白酶MMP 7的更高表达有关，金属蛋白酶MMP 7是最近与伤口修复期间减弱纤毛细胞分化有关的基因。纤毛基因的表达似乎可以识别IPF/UIP的两种独特的分子表型。不同的分子特征可能与IPF/UIP患者的治疗反应有关。
Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disease with a median survival of only 3–5 years that is diagnosed using a combination of clinical, radiographic and pathologic criteria. Histologically, IPF is characterised by usual interstitial pneumonia (UIP), a fibrosing interstitial pneumonia with a pattern of heterogeneous, subpleural regions of fibrotic and remodelled lung. We hypothesised that gene expression profiles of lung tissue may identify molecular subtypes of disease that could classify subtypes of IPF/UIP that have clinical implications. We collected transcriptional profiles on lung tissue from 119 patients with IPF/UIP and 50 non-diseased controls. Differential expression of individual transcripts was identified using an analysis of covariance (ANCOVA) model incorporating the clinical diagnosis of each patient as well as age, gender and smoking status. Validation was performed in an independent cohort of 111 IPF/UIP and 39 non-diseased controls. Our analysis identified two subtypes of IPF/UIP based on a strong molecular signature associated with expression of genes previously associated with fibrosis (matrix metalloproteinases, osteopontin, keratins), cilium genes and genes with unknown function. We demonstrate that elevated expression of cilium genes is associated with more extensive microscopic honeycombing and higher expression of both the airway mucin gene MUC5B and the metalloproteinase MMP7, a gene recently implicated in attenuating ciliated cell differentiation during wound repair. Expression of cilium genes appears to identify two unique molecular phenotypes of IPF/UIP. The different molecular profiles may be relevant to therapeutic responsiveness in patients with IPF/UIP.
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DOI：
10.1165/rcmb.2012-0083oc
发表时间：
2013-03-01
影响因子：
6.4
作者：
Gharib, Sina A.;Altemeier, William A.;Chen, Peter
通讯作者：
Chen, Peter
DOI：
10.1152/ajplung.00070.2010
发表时间：
2010-08-01
影响因子：
4.9
作者：
Ramos, Carlos;Becerril, Carina;Selman, Moises
通讯作者：
Selman, Moises
影响因子：
6
作者：
Cigna, Natacha;Moshai, Elika Farrokhi;Mailleux, Arnaud A.
通讯作者：
Mailleux, Arnaud A.
DOI：
10.1164/rccm.200504-644oc
发表时间：
2006-01-15
影响因子：
24.7
作者：
Selman, M;Pardo, A;Zlotnik, A
通讯作者：
Zlotnik, A
影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
通讯作者：
Staudt, LM