Background: MicroRNAs (miRNA) exert regulatory effects in biological mechanisms and had been recently targeted for therapeutic interventions. In Liver Transplantation (LT), graft function post reperfusion depends partially on the degree of ischemia reperfusion injury (IRI). We aimed to investigate changes in intrahepatic miRNA expression profiles in response to IRI.

Patients and Methods: Deceased donor grafts LT recipients were studied (n=41). Paired graft biopsy (n=82) were collected at pre implantation (Pre-I) and at 90 min post reperfusion (Post-R). Samples were grouped in Training (n=48) and Validation (n=34) sets. Total RNA was isolated, labeled, and hybridized in miRNA microarrays for the training set. Human miRNAs expression summaries were obtained using RMA algorithm. Post-R vs. Pre-I comparison were fit using two-sample t-test. A p-value ≤ 0.01 and controlled FDR ≤ 10% were considered significant. IPA tool was used for gene ontology and pathway analysis. Top significant miRNAs were assessed by qPCR in the validation set.

Results: Donor characteristics include: age of 47-yo, caucasian 79%, male 45%, with mean CIT of 6.8 hrs and mean WIT of 33 min. No significant differences were registered between study sets. In total, 32 miRNAs were significant and differentially expressed post-reperfusion. Of those, 15 were upregulated and 17 downregulated. Inflammation disease and response were top associated network functions incorporating 10 miRNAs. Of those, 7 miRNAs directly related to inflammatory disorders. Hepatic disorders were associated with 9 miRNAs: malignancies (miR-139, miR-885), steatosis (miR-451, miR-331), and fibrosis development (miR-27a, miR-27b, miR-29b-2*, miR-192), and apoptosis (miR-149*). Interestingly, the expression levels of 8 miRNAs resulted conditioned to external cellular stimuli such as amino acids (miR-486, miR-451, miR-378*, miR-378f, miR-29-2*, miR-192, miR-28), estrogens (miR-486, miR-223), and LPS and oxygen levels (miR-223). The top five miRNAs were successfully validated (validation set).

Conclusions: Inflammation and apoptosis were the most important identified molecular mechanisms associated with deregulation of miRNA profiles. Intervention or targeting those miRNAs and molecular processes may represent innovative therapies to minimize or avoid organ dysfunction post-LT.

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