Vitamin D Modulates Expression of the Airway Smooth Muscle Transcriptome in Fatal Asthma

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.

Vitamin D and Bronchial Asthma: An Overview of Data From the Past 5 Years

“…Results highlight vitamin D-specific gene targets and provide novel transcriptomic data that can be used to further explore differences in ASM of patients with fatal asthma. 32 It is now well established that the inflammation in asthma involves several subsets of T-lymphocytes, not just Th2 cells. In naïve CD4 T-cells obtained from peripheral blood of young asthmatic subjects as well as healthy controls, it was found that stimulation of these cells under Th17 polarizing conditions led to the production of higher Th17 differentiation in asthmatic patients.…”

Resolving the etiology of atopic disorders by using genetic analysis of racial ancestry

“…248 Dissection of atopic disorders using these -omics approaches has been attempted at least to some extent. For example, transcriptome analyses have identified genes differentially expressed between asthmatic and control subjects 249 , between lesional and nonlesional skin in AD, 250 and between airway smooth muscles derived from patients with fatal asthma and healthy controls at baseline and after treatment with Vitamin D. 251 A recent study of transcriptome-wide responses to glucocorticoid treatment provides an interesting example of the use of transcriptomics to investigate the causes of population differences in allergic disease. 252 Proteomics has been used in several studies to identify biomarkers and peptide patterns associated with specific asthma endotypes.…”

The impact of vitamin D on asthmatic human airway smooth muscle

“…Analysis of the airway smooth muscle transcriptome in fatal and non-asthmatic derived ASM cells revealed that vitamin D induced differential expression of functional genes, such as those involved with the extracellular matrix and response to steroid hormone stimuli and wounding, as well as genes involved in cytokine and chemokine activity [65]. Using human fetal ASM cells as a model of the early post natal airways, it was found that calcitriol attenuated TNF-α enhancement of MMP-9 expression and activity as well as TNF-α and TGF-β induced collagen II expression and deposition [64].…”

“…Results highlight a potential role for vitamin D in the treatment of steroid-resistant asthma [68]. Treatment of ASM cells derived from fatal asthmatics with vitamin D inhibited TNF-α-induced IL-8 secretion from these cells when compared to non-asthmatic cells even though the fatal asthmatic ASM cells had significantly higher baseline levels of IL-8 [65]. …”