A novel approach to protect fatty liver graft against I/R injury

Abstract

Backgrounds: Fatty liver accelerates the I/R injury after reperfusion that significantly affects the outcome of liver transplantation. In the study, we established a novel protein transduction system to prevent I/R injury of fatty livers. Methods and results: Modified human heme oxygenase-1 (HO-1) or enhanced green fluorescent protein (EGFP) recombinant protein containing a cell-penetrating domain (PTD) was generated. Their biological activities were investigated in a syngeneic liver transplantation model. PTD/HO-1 or PTD/EGFP was administered through portal vein after the graft harvesting and the grafts were preserved in cold UW solution. The targeted protein was found in the vessel wall of portal areas and adjuvant liver cells at 10 min after administration. Histomorphological analysis of the fatty liver grafts (microvesicle 40%) with 12 hrs cold preservation and 2 hrs reperfusion showed significantly less apoptotic cells (TUNEL positive), less endothelial cell activation (ICAM-1 positive), less neutrophil (myeloperoxidase positive) and macrophage (ED-1 positive) infiltration in PTD/HO-1-treated fatty liver grafts as compared to controls. In addition, electron microscopy shows a less intrahepatic bile duct damage after reperfusion in the graft treated with PTD-HO-1. Profiling the intragraft gene expression by real-time PCR showed less IL-1 and IL-6 proinflammatory gene expressions in PTD-HO-1-treated liver grafts as compared to controls. Conclusions: We demonstrated a novel method to protect fatty liver graft against I/R injury with great potential for clinical application.