Long noncoding RNA maternally expressed gene 3 (lncRNA MEG3) was down-regulated in pulmonary fibrosis of rats induced by Nickel oxide nanoparticles (NiO NPs), while the downstream regulatory mechanisms of MEG3 remain unclear. This study aimed to investigate the relationship among MEG3, Hedgehog (Hh) signaling pathway and autophagy in pulmonary fibrosis caused by NiO NPs. The pulmonary fibrosis model in rats was constructed by intratracheal instillation of 0.015, 0.06, and 0.24 mg/kg NiO NPs twice a week for 9 weeks. Collagen deposition model was established by treating A549 cells with 25, 50, and 100 μg/mL NiO NPs for 24 h. Our results indicated that NiO NPs activated Hh pathway, down-regulated the expression of MEG3, and reduced autophagy activity in vivo and in vitro. Meanwhile, the autophagy process was promoted by Hh pathway inhibitor (CDG-0449), while the collagen formation in A549 cells was reduced by autophagy activator (Rapamycin). Furthermore, the overexpressed MEG3 inhibited the activation of Hh pathway, resulting in autophagy activity enhancement along with collagen formation reduction. In summary, lncRNA MEG3 can restrain pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy, which may serve as a potential therapeutic strategy for pulmonary fibrosis.

中文翻译：

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LncRNA MEG3通过调节hedgehog信号通路介导的自噬抑制NiO NPs诱导的肺纤维化

长链非编码RNA母源表达基因3（lncRNA MEG3）在氧化镍纳米颗粒（NiO NPs）诱导的大鼠肺纤维化中下调，而MEG3的下游调控机制尚不清楚。本研究旨在探讨 MEG3、Hedgehog (Hh) 信号通路与自噬在 NiO NPs 引起的肺纤维化中的关系。大鼠肺纤维化模型通过气管内滴注 0.015、0.06 和 0.24 mg/kg NiO NPs 每周两次，共 9 周。通过用 25、50 和 100 μg/mL NiO NPs 处理 A549 细胞 24 小时建立胶原沉积模型。我们的结果表明，NiO NPs 激活了 Hh 通路，下调了 MEG3 的表达，并降低了体内和体外的自噬活性。同时，自噬过程受到 Hh 通路抑制剂 (CDG-0449) 的促进，而 A549 细胞中的胶原形成被自噬激活剂 (雷帕霉素) 减少。此外，过表达的 MEG3 抑制了 Hh 通路的激活，导致自噬活性增强以及胶原形成减少。总之，lncRNA MEG3可以通过调节hedgehog信号通路介导的自噬来抑制NiO NPs诱导的肺纤维化，这可能是肺纤维化的潜在治疗策略。