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Absence of toll‐like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model
Author(s) -
Shen XiuDa,
Ke Bibo,
Zhai Yuan,
Gao Feng,
Tsuchihashi SeiIchiro,
Lassman Charles R.,
Busuttil Ronald W.,
KupiecWeglinski Jerzy W.
Publication year - 2007
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1002/lt.21251
Subject(s) - medicine , tlr4 , liver transplantation , reperfusion injury , proinflammatory cytokine , viaspan , transplantation , receptor , inflammation , immunology , endocrinology , ischemia
This study analyzes how toll‐like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (IRI) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild‐type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4°C for 24 hours. Unlike WT OLTs, TLR4‐deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4 + T cell infiltration, interferon (IFN)‐γ‐inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM‐1), as well as tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐2, and IFN‐γ, yet increased IL‐4 and IL‐10 expression. The well‐functioning OLTs from TLR4 KO donors revealed attenuated activity of capase‐3, and enhanced heme oygenase‐1 (HO‐1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI‐dependent responses. Liver Transpl 13:1435–1443, 2007. © 2007 AASLD.