Department of Respiratory, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Korean J Intern Med. 2021 Mar;36(Suppl 1):S160-S169. doi: 10.3904/kjim.2019.098. Epub 2020 Jun 9.
BACKGROUND/AIMS: MicroRNAs (miRNAs) play critical regulatory roles in the pathogenesis of pulmonary fibrosis. The aim of this study was to explore whether miRNA antagomirs could serve as potential therapeutic agents in interstitial lung diseases.
A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (BLM). Using microarray analysis, up-regulated miRNAs were identified during the development of pulmonary fibrosis. miR-155 was chosen as the candidate miRNA. Fifteen mice were then randomized into the following three groups: BLM + antagomiR-155 group, treated with BLM plus intravenously injected with antagomiR-155; BLM group, treated with intratracheal BLM plus phosphate-buffered saline (PBS); and a control group, treated with PBS only. Lung tissues were collected for histopathological analysis, hydroxyproline measurement, and Western blotting. Enzyme-linked immunosorbent assays were used for the measurement of cytokines associated with pulmonary fibrosis.
Histological changes and hydroxyproline levels induced by BLM were significantly inhibited by antagomiR-155. The levels of interleukin 4 (IL-4) and transforming growth factor-β (TGF-β) expression were increased after BLM treatment. However, miR-155 silencing decreased the expression of IL-4, TGF-β, and interferon-γ. TGF-β-activated kinase 1/mitogen-activated protein kinase kinase kinase 7 (MAP3K7)-binding protein 2 (TAB2) of the mitogen-activated protein kinase (MAPK) signaling pathway, was activated by BLM and inhibited by in vivo silencing of miR-155 via antagomiR-155.
In vivo treatment with antagomiR-155 alleviated the pathological changes induced by BLM and may be a promising therapeutic strategy for pulmonary fibrosis.
背景/目的：微小 RNA（miRNA）在肺纤维化发病机制中发挥关键的调节作用。本研究旨在探讨 miRNA 拮抗剂是否可作为间质肺疾病的潜在治疗药物。
通过气管内注射博莱霉素（BLM）建立肺纤维化小鼠模型。采用微阵列分析鉴定肺纤维化发展过程中上调的 miRNA。选择 miR-155 作为候选 miRNA。随后将 15 只小鼠随机分为以下三组：BLM+antagomiR-155 组，给予 BLM 联合静脉注射 antagomiR-155；BLM 组，给予气管内 BLM 联合磷酸盐缓冲液（PBS）；对照组，仅给予 PBS。收集肺组织进行组织病理学分析、羟脯氨酸测定和 Western blot 分析。酶联免疫吸附试验用于测定与肺纤维化相关的细胞因子。
BLM 诱导的组织学改变和羟脯氨酸水平显著被 antagomiR-155 抑制。BLM 处理后白细胞介素 4（IL-4）和转化生长因子-β（TGF-β）的表达水平增加。然而，miR-155 沉默降低了 IL-4、TGF-β 和干扰素-γ的表达。博莱霉素激活丝裂原激活蛋白激酶（MAPK）信号通路中的 TGF-β 激活激酶 1/丝裂原激活蛋白激酶激酶激酶 7（MAP3K7）结合蛋白 2（TAB2），通过体内沉默 miR-155 并用 antagomiR-155 抑制，MAP3K7 结合蛋白 2 被抑制。
体内用 antagomiR-155 治疗可减轻 BLM 诱导的病理变化，可能是治疗肺纤维化的一种有前途的治疗策略。
