Characterization of Plasma-Derived Exosomes from Patient with Primary Graft Dysfunction after Lung Transplantation

Abstract

Purpose Recipient responses to primary graft dysfunction (PGD) after lung transplantation (LTx) have important implications for the fate of the allograft. Exosomes, small circulating vesicles, are considered critical mediators of intercellular information and play a role in injury-induced tissue repair processes in multiple physiological systems. Identifying the potential molecular components that contribute to patient-specific responses may lead to new strategies for LTx. Therefore, we seek to elucidate differences in plasma-derived exosomes gene expression in subjects who develop PGD after LTx. Methods Plasma-derived exosomes RNA expression was measured before and 72h after LTx in 6 consented age, sex, commodities, and primary diagnosis matched subjects (PGD n=3; Non-PGD n=3). RNA seq was normalized with the TMM normalization algorithm, and differential expression was performed by edgeR. Differential expressed genes with a p-value 1.5 were considered significant. Gene set enrichment analysis (GSEA) was applied by g: Profiler and genome.jp. PGD was defined as PGD3 at 48-72 hours after reperfusion. Results Compared to the baseline, the PGD group at 72h presented 251 genes with increased relative expression and 27 with decreased relative expression. The same comparison showed 86/16 genes with increased/decreased relative expression respectively in the non-PGD group (Table 1). GSEA in the PGD group identified 327 gene ontology (GO) terms associated with the upregulated gene set, some of these GO associations, such as morphogenesis of epithelium, epithelium development, TNF signaling pathway, MAPK signaling pathway, cytokine-cytokine receptor interaction, Th1 and Th2 cell differentiation, leukocyte transendothelial migration were exclusively found in the PGD group. In the non-PGD group, 237 GO terms were significantly associated with the upregulated gene set, such as HIF-1, tight junction, GO was not observed in the PGD. Conclusion We demonstrated that the RNA content from plasma-derived exosomes and preliminary investigation using GSEA associated with the differentially expressed genes in PGD patients is different from non-PGD patients. Our findings suggest a potential role of exosome-carried RNA in the pathogenesis of PGD. Future investigations are needed to confirm the findings.