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The inhibition of aldose reductase attenuates hepatic ischemia-reperfusion injury through reducing inflammatory response.

Abstract：

OBJECTIVE:We aim to investigate the role of aldose reductase (AR) in hepatic ischemia-reperfusion injury (IRI) of normal and fatty livers and to explore the underlying mechanisms. BACKGROUND:Hepatic IRI is a typical inflammatory response during liver surgery. It contributes to liver graft failure or nonfunction after transplantation. Increasing evidence implicates that AR plays a key role in a number of inflammatory diseases. However, the role of AR in hepatic IRI is still unknown. METHODS:Intragraft AR expression profile and the association with liver graft injury were investigated in both human and rat liver transplantation using normal or fatty graft. The direct role of AR in hepatic IRI was studied in the AR knockout mice IRI model with or without fatty liver. They were further validated by the simulated IRI in vitro model using fatty LO2 cells with or without AR inhibitor zopolrestat and primary peritoneal macrophages isolated from AR knockout and wild-type mice. Gene expression of inflammatory cytokines/chemokines, the infiltration of macrophages/neutrophils, and NF-κB pathway activation were compared among different groups. RESULTS:AR was overexpressed in liver graft after human and rat liver transplantation and correlated with consequent liver injuries. The knockout of AR significantly attenuated hepatic sinusoidal damage and apoptosis in both normal and fatty livers after IRI. The expression of proinflammatory cytokines/chemokines and neutrophil chemoattractants, infiltration of macrophage and neutrophil, and activation of inflammation-associated NF-κB and JNK pathway were downregulated in AR knockout mice. Furthermore, the inhibition of AR effectively suppressed macrophage migration and decreased lipopolysaccharide (LPS)-induced production of proinflammatory cytokines/chemokines in isolated macrophages. CONCLUSIONS:The deficiency of AR attenuated hepatic IRI in both normal and fatty livers by reducing liver inflammatory responses.

journal_name

Ann Surg

journal_title

Annals of surgery

authors

Li CX,Ng KT,Shao Y,Liu XB,Ling CC,Ma YY,Geng W,Qi X,Cheng Q,Chung SK,Lo CM,Man K

doi

10.1097/SLA.0000000000000429

subject

Has Abstract

pub_date

2014-08-01 00:00:00

pages

317-28

issue

eissn

0003-4932

issn

1528-1140

journal_volume

260

pub_type

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The inhibition of aldose reductase attenuates hepatic ischemia-reperfusion injury through reducing inflammatory response.