title: Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.
abstract: Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid droplet-associated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex.
authors: Telethon Kids Institute, the University of Western Australia, Perth, Western Australia, Australia; Rachel.Foong@telethonkids.org.au.
authors: Rachel E
authors: 0000-0002-1201-6785
authors: RE
authors: Foong
authors: Telethon Kids Institute, the University of Western Australia, Perth, Western Australia, Australia;
authors: Anthony
authors: A
authors: Bosco
authors: Telethon Kids Institute, the University of Western Australia, Perth, Western Australia, Australia;
authors: Niamh M
authors: NM
authors: Troy
authors: Telethon Kids Institute, the University of Western Australia, Perth, Western Australia, Australia;
authors: Shelley
authors: S
authors: Gorman
authors: Telethon Kids Institute, the University of Western Australia, Perth, Western Australia, Australia;
authors: Prue H
authors: PH
authors: Hart
authors: Telethon Kids Institute, the University of Western Australia, Perth, Western Australia, Australia; School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia; Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Western Australia, Australia; Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Western Australia, Australia; and.
authors: Anthony
authors: A
authors: Kicic
authors: School of Medicine, Faculty of Health Science, University of Tasmania, Hobart, Tasmania, Australia.
authors: Graeme R
authors: GR
authors: Zosky
mesh_terms: D056151:Airway Remodeling; D000403:Airway Resistance / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008807:Mice, Inbred BALB C; D008868:Microtubule Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D039981:Pyroglyphidae / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases; D014808:Vitamin D Deficiency / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008868:Microtubule Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: RNA-Seq; airway hyperresponsiveness; airway remodeling; house dust mite; mouse model