Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Anshan Road No. 154, Heping District, Tianjin, 300052, People's Republic of China.
Department of Pediatric Surgery, Tianjin Children's Hospital, No. 238 LongYan Road, Tianjin, 300134, People's Republic of China.
Cell Stress Chaperones. 2019 Sep;24(5):883-889. doi: 10.1007/s12192-019-01026-7. Epub 2019 Aug 27.
The only effective clinical treatment for many end-stage lung diseases is lung transplantation. However, chronic rejection of transplanted lung affects the long-term efficacy of lung transplantation to a large extent, thereby limiting the clinical application of lung transplantation. Occlusive bronchiolitis (OB) is a major cause of chronic functional loss of the transplanted lung. However, the OB pathogenesis remains unclear. Therefore, studying the OB pathogenesis and finding effective intervention methods are highly important. This study analyzed changes in the expression profile of microRNAs and transcription factors in mice with OB after orthotopic tracheal transplantation. miR-27a-3p was upregulated in lung tissue 20 days after transplantation. Transcription factor microarray analysis revealed that Smad3 was significantly downregulated. A miRNA-mRNA interaction network was constructed, and specific regulatory effects of miR-27a-3p on Smad3 were found. Smad3 was strongly associated with tumorigenesis and organ fibrosis. Compared with the control group, miR-27a-3p inhibited the epithelial-mesenchymal transformation (EMT) of lung epithelial cells. In addition, miR-27a-3p inhibition promoted the invasion and migration of lung epithelial cells. Dual luciferase reporter gene assay showed that miR-27a-3p can regulate the promoter activity of Smad3. MiR-27a-3p also inhibited the expression of inflammatory cytokines. Western blot results showed that miR-27a-3p can upregulate the E-cadherin expression and downregulate the expression of vimentin, fibronectin, and α-SMA. By studying the OB pathogenesis, we found that inhibition or alteration of the occurrence of EMT may reduce the proportion of chronic rejection of lung transplantation. MiR-27a-3p may also be developed as a new drug for the OB therapy. This finding will provide many possibilities for OB treatment and improve the prognosis of patients with OB.
对于许多终末期肺部疾病，唯一有效的临床治疗方法是肺移植。然而，移植肺的慢性排斥反应在很大程度上影响了肺移植的长期疗效，从而限制了肺移植的临床应用。闭塞性细支气管炎（OB）是移植肺慢性功能丧失的主要原因。然而，OB 的发病机制尚不清楚。因此，研究 OB 的发病机制并找到有效的干预方法非常重要。本研究分析了同种异体气管移植后 OB 小鼠肺部 microRNA 和转录因子表达谱的变化。移植后 20 天，肺组织中 miR-27a-3p 表达上调。转录因子微阵列分析显示 Smad3 显著下调。构建了 miRNA-mRNA 相互作用网络，发现了 miR-27a-3p 对 Smad3 的特异性调控作用。Smad3 与肿瘤发生和器官纤维化密切相关。与对照组相比，miR-27a-3p 抑制了肺上皮细胞的上皮间质转化（EMT）。此外，miR-27a-3p 抑制了肺上皮细胞的侵袭和迁移。双荧光素酶报告基因检测显示，miR-27a-3p 可调节 Smad3 启动子活性。miR-27a-3p 还抑制了炎症细胞因子的表达。Western blot 结果表明，miR-27a-3p 可上调 E-钙黏蛋白的表达，下调波形蛋白、纤连蛋白和α-SMA 的表达。通过研究 OB 的发病机制，我们发现抑制或改变 EMT 的发生可能会降低肺移植慢性排斥的比例。miR-27a-3p 也可能被开发为治疗 OB 的新药。这一发现将为 OB 治疗提供许多可能性，并改善 OB 患者的预后。
