Title: Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma.
Authors: Himes, Blanca E; Koziol-White, Cynthia; Johnson, Martin; Nikolos, Christina; Jester, William; Klanderman, Barbara; Litonjua, Augusto A; Tantisira, Kelan G; Truskowski, Kevin; MacDonald, Kevin; Panettieri Jr, Reynold A; Weiss, Scott T
Published In PLoS One, (2015)
Abstract: 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 TNFα-induced changes by asthma status and vitamin D treatment. Vitamin D inhibited TNFα-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.
PubMed ID: 26207385
MeSH Terms: Adolescent; Adult; Asthma/drug therapy; Asthma/genetics; Asthma/metabolism*; Chemokines/genetics; Chemokines/metabolism; Child; Cytokines/genetics; Cytokines/metabolism; Female; Gene Expression Regulation/drug effects; Humans; Male; Middle Aged; Muscle, Smooth/drug effects*; Muscle, Smooth/metabolism; Respiratory System/drug effects*; Respiratory System/metabolism; Transcriptome/drug effects*; Vitamin D/pharmacology*; Vitamin D/therapeutic use; Young Adult