Genetic effect of ischemia-reperfusion injury upon primary graft dysfunction and chronic lung allograft dysfunction in lung transplantation: evidence based on transcriptome data

Abstract

The unclear mechanism that ischemia-reperfusion injury (IRI) contributes to the development of primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) remains a major issue in lung transplantation. Differentially expressed PGD-related genes and CLAD-related genes during IRI (IRI-PGD common genes and IRI-CLAD common genes) were identified using GEO datasets (GSE127003, GSE8021, GSE9102) and GeneCards datasets. Enrichment analysis and four network analyses, namely, protein-protein interaction, microRNA (miRNA)-gene, transcription factor (TF)-gene, and drug-gene networks, were then performed. Moreover, GSE161520 was analyzed to identify the differentially expressed core miRNAs during IRI in rats. Finally, Pearson correlation analysis and ROC analysis were performed. Eight IRI-PGD common genes (IL6, TNF, IL1A, IL1B, CSF3, CXCL8, SERPINE1, and PADI4) and 10 IRI-CLAD common genes (IL1A, ICAM1, CCL20, CCL2, IL1B, TNF, PADI4, CXCL8, GZMB, and IL6) were identified. Enrichment analysis showed that both IRI-PGD and IRI-CLAD common genes were significantly enriched in "AGE-RAGE signaling pathway in diabetic complication" and "IL-17 signaling pathway". Among the core miRNAs, miR-1-3p and miR-335 were differentially expressed in IRI rats. Among core TFs, CEBPB expression had a significant negative correlation with P/F ratio (r = -0.33, P = 0.021). In the reperfused lung allografts, the strongest positive correlation was exhibited between PADI4 expression and neutrophil proportion (r = 0.76, P < 0.001), and the strongest negative correlation was between PADI4 expression and M2 macrophage proportion (r = -0.74, P < 0.001). In lung allografts of PGD recipients, IL6 expression correlated with activated dendritic cells proportion (r = 0.86, P < 0.01), and IL1B expression correlated with the neutrophils proportion(r = 0.84, P < 0.01). In whole blood of CLAD recipients, GZMB expression correlated with activated CD4+ memory T cells proportion (r = 0.76, P < 0.001).Our study provides the novel insights into the molecular mechanisms by which IRI contributes to PGD and CLAD and potential targets for therapeutic intervention.

Keywords: Bioinformatics analysis; Chronic lung allograft dysfunction; Ischemia-reperfusion injury; Lung transplantation; Primary graft dysfunction.