title: 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.
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.affiliation: Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Koziol-White
authors.affiliation: Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Martin
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Nikolos
authors.affiliation: Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Jester
authors.affiliation: Partners Personalized Medicine, Boston, MA, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.affiliation: Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Truskowski
authors.affiliation: Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: MacDonald
authors.affiliation: Airways Biology Initiative, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.affiliation: Partners Personalized Medicine, Boston, MA, United States of America; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002648:Child; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects*; D014807:Vitamin D / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D018925:Chemokines; D016207:Cytokines; D014807:Vitamin D