Department of Emergency, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, Henan, China.
Department of Emergency, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, Henan, China.
Biomed Pharmacother. 2018 Nov;107:703-711. doi: 10.1016/j.biopha.2018.08.040. Epub 2018 Aug 20.
Overwhelming lung inflammation is a key feature of acute lung injury (ALI). MicroRNAs (miRNAs) have been implicated in the regulation diverse cellular processes including the inflammatory response. However, little is known about their functions and molecular involvement in regulating the inflammatory process in ALI. Herein, we established a lipopolysaccharide (LPS)-induced ALI mouse model and used miRNA microarray analysis to investigate and compare the miRNA expression profiles in mouse lung tissues. We found that miR-92a was markedly upregulated in the lung tissues of ALI mice compared with that in normal lung tissues. This upregulation of miR-92a in LPS-induced ALI mice was further confirmed in lung tissues, splenocytes and bronchoalveolar lavage fluid (BALF) by quantitative real-time PCR. Inhibition of miR-92a by injection with antagomir-92a markedly reduced LPS-induced pathological changes associated with lung inflammation, and reduces lung wet/dry ratio (W/D ratio), and Evans blue dye extravasation (an indicator of lung epithelial permeability). Moreover, inhibition of miR-92a ameliorated the inflammatory response by reducing the repression of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 in lung tissues. In addition, we identified that miR-92a inhibited the phosphatase and tensin homolog on chromosome ten (PTEN) by binding to its 3'-UTR in RAW264.7 murine macrophage cells. Western blot analysis demonstrated that inhibition of miR-92a may ameliorate inflammatory response through blocking PTEN/AKT/NF-κB signaling pathway in ALI mice. Collectively, these results have revealed a significant role of miR-92a in the lung inflammatory response associated with ALI in mice, and suggest that miR-92a may have potential as a prognostic indicator and novel therapeutic target for the treatment of ALI in future.
弥漫性肺部炎症是急性肺损伤 (ALI) 的一个关键特征。微小 RNA (miRNA) 已被牵涉到调节多种细胞过程，包括炎症反应。然而，对于它们在调节 ALI 中的炎症过程中的功能和分子参与知之甚少。在此，我们建立了脂多糖 (LPS) 诱导的 ALI 小鼠模型，并使用 miRNA 微阵列分析来研究和比较小鼠肺组织中的 miRNA 表达谱。我们发现，与正常肺组织相比，miR-92a 在 ALI 小鼠的肺组织中明显上调。通过定量实时 PCR 进一步证实了 LPS 诱导的 ALI 小鼠中 miR-92a 的这种上调。用反义寡核苷酸-92a 抑制 miR-92a 可显著减轻 LPS 诱导的与肺炎症相关的病理变化，并降低肺湿/干重比 (W/D 比) 和 Evans 蓝染料渗出 (肺上皮通透性的指标)。此外，通过减少 TNF-α、IL-1β 和 IL-6 等促炎细胞因子在肺组织中的抑制作用，抑制 miR-92a 可改善炎症反应。此外，我们发现 miR-92a 通过结合其 3'UTR 抑制染色体 10 上的磷酸酶和张力蛋白同源物 (PTEN)，在 RAW264.7 鼠巨噬细胞中。Western blot 分析表明，抑制 miR-92a 可能通过阻断 ALI 小鼠中的 PTEN/AKT/NF-κB 信号通路来改善炎症反应。总之，这些结果表明 miR-92a 在与 ALI 相关的小鼠肺部炎症反应中具有重要作用，并表明 miR-92a 可能具有作为未来治疗 ALI 的预后指标和新型治疗靶标的潜力。
