Integrated mRNA and miRNA expression profiling of long-term survivors with normal allograft function after lung transplantation

Background: Long-term survival with good allograft function (LTS) after lung transplantation (LT) is mainly limited by the development of chronic lung allograph dysfunction (CLAD). The objective of this study was to identify genes and miRNAs which might contribute to a better understanding of the molecular mechanisms influencing LTS after LT. Methods: The mRNA and miRNAs expression profiles were determined in blood samples from LTS (n=30) and CLAD patients (n=30) by microarray technology. Gene Ontology was used for enrichment analysis and the interactions between miRNAs and genes were studied by network analysis with the mixOmics R package. Results: The analysis of mRNA expression revealed that 458 genes were differentially expressed between LTS versus CLAD patients. Genes related to neutrophil-granulocyte activation and neutrophil degranulation were downregulated in LTS, suggesting a dysregulation of the innate immune system in CLAD patients. Regarding miRNAs expression analysis, 36 mature miRNAs were differentially expressed between both groups. Of these 36 elements, 30 miRNAs had experimentally validated target genes enriched in the set of 458 differentially expressed genes. Biological significance analysis showed that miRNA target genes differentially expressed between LTS and CLAD patients were related to neutrophil degranulation. Conclusion: Differences in both mRNA expression and upstream miRNA regulators have been found between LTS and CLAD patients. These results suggest that innate immune system may play a role in long-term survival after LT. Study financed by ISCIII (PI13/01076), FEDER, FUCAP, SEPAR (138/2016), Astellas, Novartis and Chiesi.