Abstract：
Obliterative bronchiolitis (OB) is characterized by sub-epithelial inflammatory and fibrotic narrowing of the bronchioles, and it is the predominant factor limiting long-term survival after lung transplantation. To explore molecular mechanism of OB, we investigated the interaction of transcription factor (TF), microRNA, long noncoding RNA (lncRNA), and gene expression in the mice model of OB by integrated analysis of TF array, miRNA microarray, and lncRNA and mRNA microarray. After 28 days of orthotopic tracheal transplantation in mice, 42 TFs were significantly up-regulated in allogeneic graft compared to syngeneic graft; 62 miRNAs including miR-376-5p were up-regulated and 17 miRNAs including miR-338-3p were down-regulated over 2-fold; 137 mRNAs were down-regulated and 129 mRNAs were up-regulated over 2-fold; 234 lncRNAs were up-regulated and 212 lncRNAs were down-regulated over 2-fold in the allogeneic model compared to that in the syngeneic control group. We further analyzed potential interaction between TFs, miRNAs, lncRNAs and target genes by different algorithms. Four differentially expressed TFs (Myc/Max, FOXO1, FOXM1, and SMAD) were predicted to regulate 3 different miRNAs, 17 mRNAs, and 16 lncRNAs. These findings suggest that modulation of altered transcription factors such as Myc/Max and FOXO1, and miRNAs such as miR-376-5p and miR-338-3p may become a preventive or therapeutic targets in the chronic lung allograft dysfunction.
摘要：
闭塞性细支气管炎（OB）的特征是上皮下炎症和细支气管的纤维化狭窄，它是限制肺移植后长期存活的主要因素。探讨OB的分子机制,我们研究了转录因子（TF）的相互作用，microRNA,长链非编码RNA(lncRNA)，通过TF阵列的整合分析，在OB小鼠模型中基因表达，miRNA微阵列,以及lncRNA和mRNA微阵列。小鼠原位气管移植28天后，与同基因移植物相比，同种异体移植物中42个TFs显着上调；包括miR-376-5p在内的62个miRNA上调，包括miR-338-3p在内的17个miRNA下调超过2倍；137个mRNA下调，129个mRNA上调超过2倍；在同种异体模型中，与对照组相比，234个lncRNA上调，212个基因RNA下调超过2倍。我们进一步分析了TFs之间的潜在相互作用，miRNA,lncRNAs和靶基因通过不同的算法。四种差异表达的TFs(Myc/Max，预测FOXO1，FOXM1和SMAD）调节3种不同的miRNA，17个mRNA，和16个lncRNAs。这些发现表明，调节改变的转录因子如Myc/Max和FOXO1，以及miRNA如miR-376-5p和miR-338-3p可能成为慢性肺同种异体移植功能障碍的预防或治疗靶标。
