Department of Anesthesiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, Liaoning, China.
Department of Thoracic Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, Liaoning, China.
BMC Pulm Med. 2022 Apr 26;22(1):159. doi: 10.1186/s12890-022-01957-5.
Sevoflurane is considered as a lung-protective factor in acute lung injury (ALI), but the underlying molecular mechanism remains largely unknown. The present study identified for the first time that sevoflurane ameliorated lipopolysaccharide (LPS)-induced ALI through regulating a novel long non-coding RNA LINC00839, and uncovered its regulatory mechanism.
LPS-induced ALI models were established in mice or mouse pulmonary microvascular endothelial cells (MPVECs), and they were administered with sevoflurane. Real-Time quantitative PCR, western blot and bioinformatics analysis were performed to screen the aberrantly expressed long non-coding RNA and the downstream molecules in sevoflurane-treated ALI models, and their roles in the protection effect of sevoflurane were verified by functional recovery experiments.
Sevoflurane relieved LPS-induced lung injury, cell pyroptosis and inflammation in vitro and in vivo. LINC00839 was significantly suppressed by sevoflurane, and overexpression of LINC00839 abrogated the protective effects of sevoflurane on LPS-treated MPVECs. Mechanismly, LINC00839 positively regulated NOD-like receptor protein 3 (NLRP3) via sequestering miR-223. MiR-223 inhibitor reversed the inhibitory effects of LINC00839 knockdown on NLRP3-mediated pyroptosis in LPS-treated MPVECs. Furthermore, both miR-223 ablation and NLRP3 overexpression abrogated the protective effects of sevoflurane on LPS-treated MPVECs.
In general, our work illustrates that sevoflurane regulates the LINC00839/miR-223/NLRP3 axis to ameliorate LPS-induced ALI, which might provide a novel promising candidate for the prevention of ALI.
七氟醚被认为是急性肺损伤（ALI）的肺保护因子，但其中的潜在分子机制仍知之甚少。本研究首次发现，七氟醚通过调节一种新型长非编码 RNA LINC00839 来改善脂多糖（LPS）诱导的 ALI，并揭示了其调节机制。
在小鼠或小鼠肺微血管内皮细胞（MPVECs）中建立 LPS 诱导的 ALI 模型，并给予七氟醚处理。通过实时定量 PCR、western blot 和生物信息学分析筛选出七氟醚处理的 ALI 模型中异常表达的长非编码 RNA 和下游分子，并通过功能恢复实验验证它们在七氟醚保护作用中的作用。
七氟醚缓解了 LPS 诱导的肺损伤、细胞焦亡和炎症反应，无论是在体外还是体内。七氟醚显著抑制 LINC00839 的表达，而过表达 LINC00839 则削弱了七氟醚对 LPS 处理的 MPVECs 的保护作用。机制上，LINC00839 通过结合 miR-223 正向调节 NOD 样受体蛋白 3（NLRP3）。miR-223 抑制剂逆转了 LINC00839 敲低对 LPS 处理的 MPVECs 中 NLRP3 介导的焦亡的抑制作用。此外，miR-223 缺失和 NLRP3 过表达均削弱了七氟醚对 LPS 处理的 MPVECs 的保护作用。
总之，我们的工作表明，七氟醚通过调节 LINC00839/miR-223/NLRP3 轴来改善 LPS 诱导的 ALI，这可能为 ALI 的预防提供了一个有前途的新靶点。
