PMID- 30659895 OWN - NLM STAT- MEDLINE DCOM- 20190416 LR - 20190416 IS - 1522-9629 (Electronic) IS - 1094-5539 (Linking) VI - 55 DP - 2019 Apr TI - Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis. PG - 17-24 LID - S1094-5539(18)30233-5 [pii] LID - 10.1016/j.pupt.2019.01.003 [doi] AB - BACKGROUND: Vitamin D (VitD) is a steroid hormone with cytoprotective and anti-inflammatory properties. Epidemiological studies have suggested a link between VitD deficiency and risk of development of chronic lung diseases. Its role in lung fibrosis is largely unknown. The aim of our study was to investigate the role of VitD in experimental and human lung fibrosis. METHODS: VitD (25-OH-D3, 2 mug/kg) was orally administered from day 3-day 13 following bleomycin-challenge, in 8-10 weeks-old C57/BL6 mice. Mouse Lung Fibroblasts (MLFs) were pre-treated with VitD (2 muM for 24 h) and then stimulated with TGFB1 (10 ng/ml). Serum samples from 93 patients with IPF and other forms of interstitial lung diseases (ILDs) were prospectively collected for VitD measurement. RESULTS: VitD administration prevented bleomycin-induced lung fibrosis, as assessed by reductions in hydroxyproline levels, mRNA levels of col1a1, col3a1 and a-SMA (1.4-, 3.1-, 2.25-, 2.5-fold, respectively) and Masson Trichrome staining compared to the untreated group and these changes were associated with restoration of the bleomycin-induced downregulation of vitamin D-receptor (Vdr) mRNA levels. Pre-treatment with VitD reduced the responsiveness of MLFs to pro-fibrotic stimuli, as indicated by significant decreases of col1a1, col3a1 and a-SMA (3.6-, 4.1- and 2.7-fold, respectively).These changes were associated with restoration of the TGFB1-induced downregulation of vitamin D-receptor (VDR) mRNA levels. VitD treatment deactivated TGFB1-induced Smad3 phosphorylation. Patients with IPF and other forms of ILDs displayed deficient VitD serum concentrations (mean VitD = 18.76 +/- 8.36 vs. 18.54 +/- 8.39 ng/ml, respectively, p = 0.9). VitD deficiency was correlated with baseline FVC%predicted (r = 0.47, p < 0.0001), DLCO%predicted (r = 0.6, p < 0.0001), GAP score (r = -0.4, p < 0.0001) and all-cause mortality in patients with IPF (HR: 3.7, p = 0.001). CONCLUSIONS: VitD could serve as a prognosticator and potential therapeutic target in patients with IPF. Further studies are sorely needed. CI - Copyright (c) 2019 Elsevier Ltd. All rights reserved. FAU - Tzilas, Vasilios AU - Tzilas V AD - 1st Academic Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest, "Sotiria", Athens, Greece. FAU - Bouros, Evangelos AU - Bouros E AD - 1st Academic Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest, "Sotiria", Athens, Greece. FAU - Barbayianni, Ilianna AU - Barbayianni I AD - Biomedical Sciences Research Center, "Alexander Fleming", Division of Immunology, Athens, Greece. FAU - Karampitsakos, Thodoris AU - Karampitsakos T AD - 1st Academic Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest, "Sotiria", Athens, Greece. FAU - Kourtidou, Sofia AU - Kourtidou S AD - 1st Academic Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest, "Sotiria", Athens, Greece. FAU - Ntassiou, Maria AU - Ntassiou M AD - 1st Academic Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest, "Sotiria", Athens, Greece. FAU - Ninou, Ioanna AU - Ninou I AD - Biomedical Sciences Research Center, "Alexander Fleming", Division of Immunology, Athens, Greece. FAU - Aidinis, Vassilis AU - Aidinis V AD - Biomedical Sciences Research Center, "Alexander Fleming", Division of Immunology, Athens, Greece. FAU - Bouros, Demosthenes AU - Bouros D AD - 1st Academic Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest, "Sotiria", Athens, Greece. FAU - Tzouvelekis, Argyris AU - Tzouvelekis A AD - 1st Academic Department of Respiratory Medicine, Medical School, National and Kapodistrian University of Athens, Hospital for Diseases of the Chest, "Sotiria", Athens, Greece; Biomedical Sciences Research Center, "Alexander Fleming", Division of Immunology, Athens, Greece. Electronic address: argyrios.tzouvelekis@fleming.gr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190116 PL - England TA - Pulm Pharmacol Ther JT - Pulmonary pharmacology & therapeutics JID - 9715279 RN - 0 (RNA, Messenger) RN - 0 (Receptors, Calcitriol) RN - 11056-06-7 (Bleomycin) RN - P6YZ13C99Q (Calcifediol) SB - IM MH - Administration, Oral MH - Aged MH - Aged, 80 and over MH - Animals MH - Bleomycin/toxicity MH - Calcifediol/*administration & dosage/pharmacology MH - Disease Models, Animal MH - Female MH - Fibroblasts/drug effects/pathology MH - Humans MH - Idiopathic Pulmonary Fibrosis/*drug therapy/physiopathology MH - Lung/*drug effects/physiopathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged MH - Prospective Studies MH - RNA, Messenger MH - Receptors, Calcitriol/genetics MH - Survival MH - Vitamin D Deficiency/*complications/drug therapy OTO - NOTNLM OT - Biomarker OT - Bleomycin-induced fibrosis OT - Fibroblasts OT - Idiopathic pulmonary fibrosis OT - Vitamin D EDAT- 2019/01/20 06:00 MHDA- 2019/04/17 06:00 CRDT- 2019/01/20 06:00 PHST- 2018/10/09 00:00 [received] PHST- 2019/01/13 00:00 [revised] PHST- 2019/01/14 00:00 [accepted] PHST- 2019/01/20 06:00 [pubmed] PHST- 2019/04/17 06:00 [medline] PHST- 2019/01/20 06:00 [entrez] AID - S1094-5539(18)30233-5 [pii] AID - 10.1016/j.pupt.2019.01.003 [doi] PST - ppublish SO - Pulm Pharmacol Ther. 2019 Apr;55:17-24. doi: 10.1016/j.pupt.2019.01.003. Epub 2019 Jan 16.