Lane Jérôme, van Eeden Stephan F, Obeidat Ma'en, Sin Don D, Tebbutt Scott J, Timens Wim, Postma Dirkje S, Laviolette Michel, Paré Peter D, Bossé Yohan
Institut universitaire de cardiologie et de pneumologie de Québec, Quebec City, Canada.
University of British Columbia, Department of Medicine & Center for Heart Lung Innovation, St. Paul's Hospital, Vancouver, Canada.
PLoS One. 2015 Nov 4;10(11):e0142037. doi: 10.1371/journal.pone.0142037. eCollection 2015.
Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that alter the synthesis of cholesterol. Some studies have shown a significant association of statins with improved respiratory health outcomes of patients with asthma, chronic obstructive pulmonary disease and lung cancer. Here we hypothesize that statins impact gene expression in human lungs and may reveal the pleiotropic effects of statins that are taking place directly in lung tissues. Human lung tissues were obtained from patients who underwent lung resection or transplantation. Gene expression was measured on a custom Affymetrix array in a discovery cohort (n = 408) and two replication sets (n = 341 and 282). Gene expression was evaluated by linear regression between statin users and non-users, adjusting for age, gender, smoking status, and other covariables. The results of each cohort were combined in a meta-analysis and biological pathways were studied using Gene Set Enrichment Analysis. The discovery set included 141 statin users. The lung mRNA expression levels of eighteen and three genes were up-regulated and down-regulated in statin users (FDR < 0.05), respectively. Twelve of the up-regulated genes were replicated in the first replication set, but none in the second (p-value < 0.05). Combining the discovery and replication sets into a meta-analysis improved the significance of the 12 up-regulated genes, which includes genes encoding enzymes and membrane proteins involved in cholesterol biosynthesis. Canonical biological pathways altered by statins in the lung include cholesterol, steroid, and terpenoid backbone biosynthesis. No genes encoding inflammatory, proteases, pro-fibrotic or growth factors were altered by statins, suggesting that the direct effect of statin in the lung do not go beyond its antilipidemic action. Although more studies are needed with specific lung cell types and different classes and doses of statins, the improved health outcomes and survival observed in statin users with chronic lung diseases do not seem to be mediated through direct regulation of gene expression in the lung.
他汀类药物是3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，可改变胆固醇的合成。一些研究表明，他汀类药物与哮喘、慢性阻塞性肺疾病和肺癌患者呼吸健康状况的改善存在显著关联。在此，我们推测他汀类药物会影响人类肺部的基因表达，并可能揭示他汀类药物在肺组织中直接产生的多效性作用。人类肺组织取自接受肺切除或肺移植的患者。在一个发现队列（n = 408）和两个重复数据集（n = 341和282）中，使用定制的Affymetrix芯片测量基因表达。通过对他汀类药物使用者和非使用者进行线性回归评估基因表达，并对年龄、性别、吸烟状况和其他协变量进行调整。将每个队列的结果进行荟萃分析，并使用基因集富集分析研究生物途径。发现队列包括141名他汀类药物使用者。在他汀类药物使用者中，分别有18个和3个基因的肺mRNA表达水平上调和下调（错误发现率<0.05）。上调的18个基因中有12个在第一个重复数据集中得到验证，但在第二个重复数据集中均未得到验证（p值<0.05）。将发现队列和重复数据集合并进行荟萃分析，提高了12个上调基因的显著性，其中包括编码参与胆固醇生物合成的酶和膜蛋白的基因。他汀类药物在肺中改变的典型生物途径包括胆固醇、类固醇和萜类骨架生物合成。他汀类药物未改变编码炎症、蛋白酶、促纤维化或生长因子的基因，这表明他汀类药物在肺中的直接作用不超出其抗血脂作用。尽管需要对特定肺细胞类型以及不同类别和剂量的他汀类药物进行更多研究，但在患有慢性肺病的他汀类药物使用者中观察到的健康状况改善和生存率提高似乎并非通过对肺中基因表达的直接调节介导。
