School of Life Science, Beijing University of Chinese Medicine, Beijing, China; Shenzhen Research Institute, Beijing University of Chinese Medicine, Shenzhen, China.
School of Life Science, Beijing University of Chinese Medicine, Beijing, China.
Int Immunopharmacol. 2021 Dec;101(Pt B):108212. doi: 10.1016/j.intimp.2021.108212. Epub 2021 Oct 14.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrotic lung disease. However, there are insufficient drugs available for IPF treatment, and the currently used drugs are accompanied by many adverse reactions. Deficiency of vitamin D3 (VD3) in the development of IPF and the potential role of VD3 in the treatment of IPF have attracted increasing attention. In vivo experimental results showed that VD3 could increase the survival rate in bleomycin (BLM)-induced models, relieve lung inflammation, reduce hydroxyproline content, and inhibit collagen deposition and cell apoptosis. We further performed proteomics analysis and screened 251 target proteins that reflect VD3 intervention in BLM-induced animal models. These target proteins were involved in acute inflammation, oxidative stress, antioxidant activity and extracellular matrix binding. Combined with the comprehensive analysis of clinical samples, PSAT1 was screened out as a candidate target related to IPF disease and VD3 treatment. Through further computational analysis, the MAPK signaling pathway was considered to be the most probable candidate pathway for VD3 function targeting IPF. In in vivo experiments, VD3 inhibited BLM-induced expression of PSAT1 and phosphorylation of p38 and ERK1/2 in mouse lung tissue. The experiments of cell proliferation and western blot confirmed that VD3 inhibited the expression of PSAT1 and the activation of the mitogen-activated protein kinase (MAPK) pathway in human pulmonary fibroblasts (HPF). Furthermore, experiments with transfection plasmids overexpressing PSAT1 proved that VD3 could attenuate the proliferation and differentiation of HPF by suppressing the effect of PSAT1 on the MAPK signaling pathway. Finally, we confirmed that vitamin D receptor (VDR) could occupy the PSAT1 promoter to reveal the transcriptional regulation effect of VD3 on PSAT1. In conclusion, VD3 exerted a therapeutic effect on IPF by down-regulating the MAPK signaling pathway via targeting the expression of PSAT1.
特发性肺纤维化（IPF）是一种进行性和致命性的肺纤维化疾病。然而，用于 IPF 治疗的药物不足，且目前使用的药物伴有许多不良反应。维生素 D3（VD3）在 IPF 发病机制中的缺乏以及 VD3 在 IPF 治疗中的潜在作用引起了越来越多的关注。体内实验结果表明，VD3 可提高博来霉素（BLM）诱导模型中的存活率，缓解肺部炎症，降低羟脯氨酸含量，抑制胶原沉积和细胞凋亡。我们进一步进行了蛋白质组学分析，筛选出 251 个反映 VD3 干预 BLM 诱导动物模型的靶蛋白。这些靶蛋白参与急性炎症、氧化应激、抗氧化活性和细胞外基质结合。结合临床样本的综合分析，筛选出 PSAT1 作为与 IPF 疾病和 VD3 治疗相关的候选靶标。通过进一步的计算分析，认为 MAPK 信号通路是 VD3 针对 IPF 作用的最可能的候选通路。在体内实验中，VD3 抑制 BLM 诱导的小鼠肺组织中 PSAT1 的表达和 p38 和 ERK1/2 的磷酸化。细胞增殖和 western blot 实验证实，VD3 通过抑制 PSAT1 的表达和丝裂原活化蛋白激酶（MAPK）通路的激活，抑制人肺成纤维细胞（HPF）的表达。此外，用过表达 PSAT1 的转染质粒进行的实验证明，VD3 通过抑制 PSAT1 对 MAPK 信号通路的作用，可减弱 HPF 的增殖和分化。最后，我们证实维生素 D 受体（VDR）可占据 PSAT1 启动子，揭示 VD3 对 PSAT1 的转录调控作用。总之，VD3 通过靶向 PSAT1 的表达下调 MAPK 信号通路对 IPF 发挥治疗作用。
