Department of Internal Medicine, Jiangxi Chest Hospital, Nanchang 330006, China.
Department of Thoracic Surgery, Jiangxi Chest Hospital, Nanchang 330006, China.
Life Sci. 2021 Mar 15;269:119085. doi: 10.1016/j.lfs.2021.119085. Epub 2021 Jan 20.
Pulmonary fibrosis (PF), which is characterized by excessive matrix formation, may ultimately lead to irreversible lung damage and thus death. Fibroblast activation has been regarded as a central event during PF pathogenesis. In our previous study, we confirmed that the miR-627/high-mobility group box protein 1 (HMGB1)/Nuclear factor kappa beta (NF-κB) axis modulates transforming growth factor beta 1 (TGFβ1)-induced pulmonary fibrosis. In the present study, we investigated the upstream factors leading to miR-627 dysregulation in the process of pulmonary fibroblast activation and PF. The lncRNA MIR155 host gene (MIR155HG) was found to be abnormally upregulated in pulmonary fibrosis tissues and TGFβ1-stimulated normal human primary lung fibroblasts (NHLFs). By directly binding to miR-627, MIR155HG inhibited miR-627 expression. MIR155HG overexpression enhanced TGFβ1-induced increases in HMGB1 protein expression and p65 phosphorylation, NHLF proliferation, and extracellular matrix (ECM) deposition. In contrast, miR-627 overexpression attenuated the TGFβ1-induced changes in NHLFs and significantly reversed the effects of MIR155HG overexpression. Under TGFβ1 stimulation, miR-627 inhibition promoted, whereas JSH-23 treatment inhibited NF-κB activation; in NHLFs, NF-κB overexpression upregulated, whereas JSH-23 treatment downregulated MIR155HG expression. In tissue samples, HMGB1 protein levels and p65 phosphorylation were increased; MIR155HG was negatively correlated with miR-627 and positively correlated with HMGB1. In conclusion, we validated that the MIR155HG/miR-627/HMGB1/NF-κB axis formed a regulatory loop that modulates TGFβ1-induced NHLF activation. Considering the critical role of NHLF activation in PF pathogenesis, the NF-κB/MIR155HG/miR-627/HMGB1 regulatory loop could exert a vital effect on PF pathogenesis. Further in vivo and clinical investigations are required to confirm this model.
肺纤维化（PF）的特征是基质过度形成，最终可能导致不可逆转的肺损伤和死亡。成纤维细胞激活被认为是 PF 发病机制中的一个中心事件。在我们之前的研究中，我们证实了 miR-627/高迁移率族蛋白 1（HMGB1）/核因子 kappa beta（NF-κB）轴调节转化生长因子β 1（TGFβ1）诱导的肺纤维化。在本研究中，我们研究了导致肺成纤维细胞激活和 PF 过程中 miR-627 失调的上游因素。发现长链非编码 RNA MIR155 宿主基因（MIR155HG）在肺纤维化组织和 TGFβ1 刺激的正常人肺成纤维细胞（NHLFs）中异常上调。MIR155HG 通过直接结合 miR-627，抑制 miR-627 的表达。MIR155HG 过表达增强了 TGFβ1 诱导的 HMGB1 蛋白表达和 p65 磷酸化、NHLF 增殖和细胞外基质（ECM）沉积。相反，miR-627 过表达减弱了 TGFβ1 诱导的 NHLFs 的变化，并显著逆转了 MIR155HG 过表达的作用。在 TGFβ1 刺激下，miR-627 抑制促进，而 JSH-23 处理抑制 NF-κB 激活；在 NHLFs 中，NF-κB 过表达上调，而 JSH-23 处理下调 MIR155HG 的表达。在组织样本中，HMGB1 蛋白水平和 p65 磷酸化增加；MIR155HG 与 miR-627 呈负相关，与 HMGB1 呈正相关。总之，我们验证了 MIR155HG/miR-627/HMGB1/NF-κB 轴形成了一个调节环，调节 TGFβ1 诱导的 NHLF 激活。考虑到 NHLF 激活在 PF 发病机制中的关键作用，NF-κB/MIR155HG/miR-627/HMGB1 调节环可能对 PF 发病机制产生重要影响。需要进一步的体内和临床研究来证实这一模型。
