Abstract
The aim of this study was to explore the protective effects of ulinastatin (urinary trypsin inhibitor, UTI) on liver ischemia-reperfusion injury (IRI) and graft survival. We employed mouse liver cold IRI and orthotopic liver transplantation (OLTx) models. UTI was added to lactated Ringer's (LR) solution for liver perfusion and preservation in vitro or combined with UTI injection intraperitoneally to the liver graft recipient. Our results indicated that UTI supplementation protected the liver from cold IRI in a dose-dependent manner and prolonged liver graft survival from extended cold preserved liver donors significantly. The underlying mechanism of UTI on liver IRI may be mediated by inhibition of proinflammatory cytokine release, increasing the expression of the antiapoptotic gene Bcl-2 and decreasing the expression of the proapoptosis genes of Caspase-3 and Bax, and further protects hepatocytes from apoptotic death and improves liver function.
Highlights
Liver transplantation has become one of the most effective methods for the treatment of end-stage liver disease
Rat anti-mouse IL-6, TNF-α, and Interferon-gamma IL (IFN-γ) antibodies were from BD Pharmingen (San Diego, CA, USA), rat anti-mouse IL-10 antibody was from Abcam (Cambridge, UK), B-cell lymphoma DC (Bcl)-2, caspase-3, and Bax, βactin were from Cell Signaling Technology, Inc., (Danvers, MA, USA), and the ApopTag Peroxidase In Situ Apoptosis Detection Kit was from the Millipore Corporation (Billerica, MA, USA)
The levels of ALT, AST, and lactate dehydrogenase (LDH) were detected to have significantly increased after 6 hours of cold preservation in the lactated Ringer (LR) control group
Summary
Liver transplantation has become one of the most effective methods for the treatment of end-stage liver disease. Hepatic ischemia-reperfusion injury (HIRI) remains a challenging issue for liver surgeons; the pathogenic mechanism of HIRI has not been elucidated completely. HIRI may be initiated by liver cell oxidative stress and may further induce primary graft nonfunction or function failure after liver transplantation. HIRI limits the applications of marginal donor livers. An effective therapeutic method for preventing HIRI is still lacking. It has been shown that UTI has certain protective effects against liver injury. The objectives of this study were to explore the protective effects of UTI against HIRI, the effects of UTI on liver cell oxidative stress, and the impact of UTI on graft survival, as well as the underlying mechanisms
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