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.
Keywords: Obliterative bronchiolitis; molecular mechanism; orthotopic tracheal transplantation.