维生素 D 可预防实验性肺纤维化，并可预测特发性肺纤维化患者的生存率。

Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis.

机构信息

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.

出版信息

Pulm Pharmacol Ther. 2019 Apr;55:17-24. doi: 10.1016/j.pupt.2019.01.003. Epub 2019 Jan 16.

DOI:10.1016/j.pupt.2019.01.003

PMID:30659895

Abstract

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 μg/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 μM 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.

摘要

背景

维生素 D（VitD）是一种具有细胞保护和抗炎特性的甾体激素。流行病学研究表明，VitD 缺乏与慢性肺部疾病的发展风险之间存在关联。其在肺纤维化中的作用在很大程度上尚不清楚。我们的研究旨在研究 VitD 在实验和人类肺纤维化中的作用。

方法

在博来霉素攻击后第 3-13 天，用 25-羟维生素 D3（25-OH-D3，2μg/kg）经口给予 8-10 周龄 C57/BL6 小鼠。用 VitD（2μM，24 小时）预处理小鼠肺成纤维细胞（MLFs），然后用 TGFB1（10ng/ml）刺激。前瞻性收集 93 例特发性肺纤维化（IPF）和其他类型间质性肺疾病（ILD）患者的血清样本，用于测定 VitD 水平。

结果

与未治疗组相比，VitD 给药可降低羟脯氨酸水平、col1a1、col3a1 和 a-SMA 的 mRNA 水平（分别为 1.4 倍、3.1 倍、2.25 倍和 2.5 倍）和 Masson 三色染色，从而预防博来霉素诱导的肺纤维化，这些变化与维生素 D 受体（Vdr）mRNA 水平的恢复有关。VitD 预处理可降低 MLFs 对促纤维化刺激的反应性，col1a1、col3a1 和 a-SMA 分别显著降低（分别为 3.6 倍、4.1 倍和 2.7 倍）。这些变化与 TGFB1 诱导的维生素 D 受体（VDR）mRNA 水平的下调恢复有关。VitD 治疗可使 TGFB1 诱导的 Smad3 磷酸化失活。IPF 和其他类型的 ILD 患者的 VitD 血清浓度不足（平均 VitD=18.76±8.36 与 18.54±8.39ng/ml，分别，p=0.9）。VitD 缺乏与基线 FVC%predicted（r=0.47，p<0.0001）、DLCO%predicted（r=0.6，p<0.0001）、GAP 评分（r=-0.4，p<0.0001）和 IPF 患者的全因死亡率相关（HR：3.7，p=0.001）。