A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis
A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2013-0310oc
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发表时间：
2015-02-01
影响因子：
6.4
通讯作者：
Kaminski, Naftali
中科院分区：
文献类型：
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作者：
Bauer, Yasmina;Tedrow, John;Kaminski, Naftali
博来霉素诱导的啮齿类动物肺纤维化模型通常用于研究肺纤维化的机制并测试潜在的治疗干预，尽管与人类特发性肺纤维化（IPF）存在公认的差异。因此，在本研究中，我们试图确定从肺组织研究联盟获得的100个IPF肺和108个对照肺以及在博莱霉素滴注后第3、7、14、21、28、42和56天收获的大鼠肺的基因表达谱之间的基因组共性。令人惊讶的是，在第7天观察到博来霉素处理的大鼠和IPF肺之间的最高基因表达相似性。在这一点上，最大的大鼠和人类的共性，我们确定了一套新的12疾病相关的翻译基因标记（C6，CTHRC1，CTSE，FHL2，GAL，GREM 1，LCN 2，MMP 7，NELL1，PCSK 1，PLA2G2A，和SLC 2A 5），能够将我们的队列和另外两个IPF/对照队列（GSE 10667和GSE 24206）中几乎所有IPF患者与对照受试者分开。此外，结合一氧化碳弥散量测量，翻译基因标志物集的4个成员有助于根据疾病严重程度对IPF患者进行分层。在博来霉素诱导的肺纤维化模型中，在转化生长因子β 1处理的原代人肺成纤维细胞和转化生长因子β 1处理的人上皮A549细胞中，吡非尼酮显著减弱了一种（CTHRC 1）翻译基因标志物的表达变化。我们的研究结果表明，一种专注于啮齿动物模型-人类疾病共性的策略可能会识别出可用于预测治疗干预的药理学影响的基因，从而促进这种毁灭性肺部疾病的新型治疗方法的开发。
The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat-human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-beta 1-treated primary human lung fibroblasts and transforming growth factor-beta 1-treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model-human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease.