Abstract
BackgroundIschemic-reperfusion (IR) injury still represents a major concern in clinical transplantation, especially in the era of extreme organ shortage and extended criteria donor organs. In the present study we aimed to investigate the hepatoprotective effects of remote ischemic conditioning (RIC) in a rat model of arterialized orthotopic liver transplantation (OLT).MethodsMale Lewis rats were used (n = 144 / 72 OLT cases; 240–340g) as donors and recipients. Livers were flushed and stored in 4°C HTK-solution for 8h before implantation. Recipients were randomly allocated into three experimental groups: RIC 1, RIC 2, Control. In RIC 1, RIC 2 groups, RIC was applied in the recipient before hepatectomy or after reperfusion (4x5-5min IR via clamping the infrarenal aorta), respectively. Animals were sacrificed at 1, 3, 24, 168h post-reperfusion (n = 6 recipient/group/time point). Hepatocellular injury, graft circulation, serum cytokines, tissue redox-stress and adenosine-triphosphate (ATP) levels have been assessed. Additional markers were analyzed, using Western blotting and reverse-transcription polymerase chain reaction.ResultsRIC 1 group showed significantly (p<0.05) improved portal venous and microcirculation flow as well as velocity. RIC has significantly reduced tissue injury according to the serum levels of transaminases and results of histopathological evaluation. Reduced TUNEL-staining (p<0.01 RIC 1–2 vs. Control) and elevated pBAD/BAD ratio was detected in the RIC groups (p<0.01 RIC 1 vs. Control). Supporting findings were obtained from measurements of serum IL-10 as well as tissue malondialdehyde and ATP levels. Hemoxygenase-1 (HO-1) mRNA-expression was significantly higher in RIC 1 compared to Control (p<0.05 RIC 1 vs. Control).ConclusionThese results suggest that RIC might confer potent protection against the detrimental effects of IR injury including tissue damage, apoptosis, graft circulation, inflammation, tissue energetic status in OLT. HO-1 overexpression might play an orchestrating role in RIC mediated organ protection. An earlier intervention (RIC 1 protocol) was more effective than remote conditioning after graft reperfusion.
Highlights
Due to the great improvements in surgical techniques, intensive therapy, organ preservation, and transplant immunology over the past decades, orthotopic liver transplantation (OLT) became the definitive treatment approach for end-stage liver diseases [1]
In the present study we aimed to investigate the hepatoprotective effects of remote ischemic conditioning (RIC) in a rat model of arterialized orthotopic liver transplantation (OLT)
Reduced transferase-mediated dUTP nick end labeling (TUNEL)-staining (p
Summary
Due to the great improvements in surgical techniques, intensive therapy, organ preservation, and transplant immunology over the past decades, orthotopic liver transplantation (OLT) became the definitive treatment approach for end-stage liver diseases [1]. Ischemic-reperfusion (IR) injury, still represents a major risk factor for post-transplant functional graft impairment, acute- and chronic rejection, or for post-transplant hepatocellular carcinoma recurrence [2, 3] These factors are even more important in clinical practice of the recent years, due to the extreme shortage of donor organs and the consequential need for alternative solutions (e.g. extended criteria donors, split liver transplantation, living donor liver transplantation, etc.) [3,4,5,6]. This study was designed to investigate the effects of two different remote ischemic conditioning protocols on graft injury in an arterialized rat liver transplantation model. In the present study we aimed to investigate the hepatoprotective effects of remote ischemic conditioning (RIC) in a rat model of arterialized orthotopic liver transplantation (OLT)
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