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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.

Purpose Chronic lung allograft dysfunction (CLAD) is the main limiting factor for long-term survival after lung transplantation (LT). However, there is a small number of LT patients which are long-term survivors with good allograft function (LTS). The aim of the present study was to compare the gene expression profile of CLAD and LTS patients and performing an enrichment analysis by using Reactome annotation database. Methods We analyzed whole-blood gene expression profiles of 60 double lung transplant recipients who were included in this multicenter cross-sectional study: 30 patients with CLAD and 30 patients with a stable allograft function 10 years after lung transplantation (LTS). Expression analysis were performed by microarray technology (ClariomTM D Arrays). Results We identified 458 differentially expressed genes (DEGs) between LTS and CLAD patients. Among them, 201 genes were up-regulated and 257 genes were down-regulated. Differentially expressed genes included MMP-8, LTF, TCN1 and OLFM4. Enrichment analysis showed involvement of neutrophil degranulation, class A/1 (Rhodopsin-like receptors), cell surface interaction at the vascular wall, antimicrobial peptides, interleukin-4 and 13 signaling, role of phospholipids in phagocytosis and activation of matrix metalloproteinases pathways. Conclusion It seems that neutrophil degranulation, matrix metalloproteinases and antimicrobial peptides gene expression pathways within others could be involve in differences between CLAD and LTS patients. Study financed by Instituto de Salud Carlos III (PI13/01076); the European Regional Development Fund (FEDER), FUCAP, Astellas, Novartis and Chiesi.

Chronic allograft dysfunction (CLAD) is the main limitation for Lung Transplantation (LT) survival. There is known 2 forms of CLAD: obliterative bronchiolitis syndrome (BOS) and restrictive allograft syndrome (RAS). The detection of the glycoprotein KL-6 in bronchoalveolar lavage (BAL) or serum in LT population may discriminate between both. The objective of the study was to analyse KL-6 levels in BAL and in serum from LT population in differents situations : stable (ST) , infection (LTI), BOS and RAS. Patients and methods - Forty four patients with bilateral LT and who survived more than 3 months were included. The population were divided in 4 groups : 14 ST patients, 10 LTI patients, 12 BOS patients and 8 patients with RAS. BAL and serum samples from the 44 patients were analysed with the Kit KL-6 ( Eidia Co.,Ltd.,Tokyo, Japan). U Mann Whitney were used to analysed differences between groups Results - KL-6 levels in serum were higher in RAS patients at a median of 1042 [IQR 504,9 to 1592]. Significant differences were shown between RAS vs ST, LTI and BOS patients with p-value of 0,0001, 0,0031 and 0,0055 respectively. KL-6 levels in BAL were higher in ST patients at a median of 262,3 [ IQR 117,9 to 661,8 ]. Significant differences were only shown between ST vs LTI patients (p=0,0088) and LTI vs BOS patients ( p=0,0168). Conclusion - KL-6 measured in serum from LT population with RAS are the highest values compared with the rest. KL-6 in serum seems to be better biomarker for RAS than in BAL.