title: Vitamin D attenuates cytokine-induced remodeling in human fetal airway smooth muscle cells.
abstract: Asthma in the pediatric population remains a significant contributor to morbidity and increasing healthcare costs. Vitamin D3 insufficiency and deficiency have been associated with development of asthma. Recent studies in models of adult airway diseases suggest that the bioactive Vitamin D3 metabolite, calcitriol (1,25-dihydroxyvitamin D3 ; 1,25(OH)2 D3 ), modulates responses to inflammation; however, this concept has not been explored in developing airways in the context of pediatric asthma. We used human fetal airway smooth muscle (ASM) cells as a model of the early postnatal airway to explore how calcitriol modulates remodeling induced by pro-inflammatory cytokines. Cells were pre-treated with calcitriol and then exposed to TNFα or TGFβ for up to 72 h. Matrix metalloproteinase (MMP) activity, production of extracellular matrix (ECM), and cell proliferation were assessed. Calcitriol attenuated TNFα enhancement of MMP-9 expression and activity. Additionally, calcitriol attenuated TNFα and TGFβ-induced collagen III expression and deposition, and separately, inhibited proliferation of fetal ASM cells induced by either inflammatory mediator. Analysis of signaling pathways suggested that calcitriol effects in fetal ASM involve ERK signaling, but not other major inflammatory pathways. Overall, our data demonstrate that calcitriol can blunt multiple effects of TNFα and TGFβ in developing airway, and point to a potentially novel approach to alleviating structural changes in inflammatory airway diseases of childhood.
authors.affiliation: Departments of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Britt
authors.forename: Arij
authors.initials: A
authors.lastname: Faksh
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Vogel
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Vivian
authors.initials: V
authors.lastname: Chu
authors.forename: Hitesh C
authors.initials: HC
authors.lastname: Pandya
authors.forename: Yassine
authors.initials: Y
authors.lastname: Amrani
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects*; D001249:Asthma / Q000378:metabolism*; D002117:Calcitriol / Q000172:deficiency*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D009130:Muscle, Smooth / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000378:metabolism*
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D002117:Calcitriol