Establishing and Validating a Biomolecular Signature of Ischemia/Reperfusion Injury in a Porcine Pancreas Allotransplantation Model.

Abstract

Background: Despite considerable advancement in surgical and immunological management in pancreas transplantation, graft pancreatitis remains a feared complication after pancreas transplantation. Identification of molecular mechanisms of underlying ischemia/reperfusion injury (IRI) in pancreas transplantation could, therefore, pave the path for targeted therapy to improve surgical outcomes. The aim of the study was to identify and validate the genes differentially expressed in the early period (24 h) of graft reperfusion in pancreas transplantation.

Methods: A porcine pancreas allotransplant model (n = 4) was used to identify and validate the genes aberrantly expressed in 60 min postreperfusion tissue samples (phase 1). Trends of expression of selected genes from phase 1 and corresponding protein product levels in serum were validated at defined time points for >24 h in a technically replicated external cohort (n = 3; phase 2).

Results: A total of 104 genes were found to be upregulated at 60 min after pancreas graft reperfusion. The most consistently overexpressed genes were IL6, THBS1, and MIR-21 (micro-RNA) mapped to protein kinase and intracellular signaling molecular pathways. Levels of expression of these genes correlated significantly with serum interleukin-6 (R = 0.60-0.81; P < 0.01) and tumor necrosis factor-alpha levels (R = 0.34-41; P > 0.05) at corresponding time points.

Conclusions: The results provide new insights into biomolecular pathways (THBS1-IL6-MIR-21 crosstalk and hydroxymethylglutarate coenzyme A reductase-linked nuclear factor kappa B activation) linked to pancreatic IRI in porcine transplantation model. Identification and validation of some novel molecular pathway interactions in human pancreas transplantation could pave the path for potential targeted therapy in alleviating graft injury in the early phases of pancreatic IRI.