Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma
Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma
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DOI：
10.1371/journal.pone.0134057
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发表时间：
2015-07-24
期刊：
影响因子：
3.7
通讯作者：
Weiss, Scott T.
中科院分区：
文献类型：
--
作者：
Himes, Blanca E.;Koziol-White, Cynthia;Weiss, Scott T.
在全球范围内，哮喘是一种慢性炎症性呼吸道疾病，影响超过3亿人。一些哮喘患者通过常规治疗仍然控制不佳，并且经历更多危及生命的加重。维生素D作为一种辅助治疗，可以改善严重哮喘患者的疾病控制，因为维生素D增强糖皮质激素的反应性，减轻气道平滑肌（ASM）增生。我们试图通过使用RNA-Seq测量5名患有致命性哮喘的供体和10名非哮喘来源的供体在基线和维生素D治疗时的ASM转录表达，来表征致命性哮喘和非哮喘来源的ASM之间转录组对维生素D的反应性差异。基于Benjamini-Hochberg校正的p值< 0.05，基线时致命性哮喘与非哮喘来源的ASM中有838个基因差异表达，与基线条件相比，维生素D治疗分别诱导致命性哮喘和非哮喘来源的ASM中711和867个基因的差异表达。在所有组中高度代表的功能基因类别包括细胞外基质，以及对类固醇激素刺激和创伤的反应。维生素D差异表达的基因还包括细胞因子和趋化因子活性类别。对四种细胞因子（即CCL 2、CCL 13、CXCL 12、IL 8）进行后续qPCR和单个分析物ELISA实验，以测量哮喘状态和维生素D治疗引起的TNF α诱导的变化。维生素D抑制TNF α诱导的IL 8蛋白分泌水平在致死性哮喘和非哮喘源性ASM中的程度相当，即使IL 8在致死性哮喘源性ASM中具有显著更高的基线水平。我们的研究结果确定了维生素D特异性基因靶点，并提供了转录组学数据，以探索致命性哮喘和非哮喘来源供体的ASM差异。
Globally, asthma is a chronic inflammatory respiratory disease affecting over 300 million people. Some asthma patients remain poorly controlled by conventional therapies and experience more life-threatening exacerbations. Vitamin D, as an adjunct therapy, may improve disease control in severe asthma patients since vitamin D enhances glucocorticoid responsiveness and mitigates airway smooth muscle (ASM) hyperplasia. We sought to characterize differences in transcriptome responsiveness to vitamin D between fatal asthma-and non-asthma-derived ASM by using RNA-Seq to measure ASM transcript expression in five donors with fatal asthma and ten non-asthma-derived donors at baseline and with vitamin D treatment. Based on a Benjamini-Hochberg corrected p-value < 0.05, 838 genes were differentially expressed in fatal asthma vs. non-asthma-derived ASM at baseline, and vitamin D treatment compared to baseline conditions induced differential expression of 711 and 867 genes in fatal asthma-and non-asthma-derived ASM, respectively. Functional gene categories that were highly represented in all groups included extracellular matrix, and responses to steroid hormone stimuli and wounding. Genes differentially expressed by vitamin D also included cytokine and chemokine activity categories. Follow-up qPCR and individual analyte ELISA experiments were conducted for four cytokines (i.e. CCL2, CCL13, CXCL12, IL8) to measure TNF alpha-induced changes by asthma status and vitamin D treatment. Vitamin D inhibited TNF alpha-induced IL8 protein secretion levels to a comparable degree in fatal asthma-and non-asthma-derived ASM even though IL8 had significantly higher baseline levels in fatal asthma-derived ASM. Our findings identify vitamin D-specific gene targets and provide transcriptomic data to explore differences in the ASM of fatal asthma-and non-asthma-derived donors.