TAK-242 treatment ameliorates liver ischemia/reperfusion injury by inhibiting TLR4 signaling pathway in a swine model of Maastricht-category-III cardiac death.
OBJECTIVE
This study aims to test the effects of TAK-242 on liver transplant viability in a model of swine Maastricht-category-III cardiac death.


METHODS
A swine DCD Maastricht-III model of cardiac death was established, and TAK-242 was administered prior to the induction of cardiac death. The protein and mRNA level of TLR4 signaling pathway molecules and cytokines that are important in mediating immune and inflammatory responses were assessed at different time points following the induction of cardiac death.


RESULTS
After induction of cardiac death, both the mRNA and protein levels of key molecules (TLR4, TRAF6, NF-ϰB, ICAM-1, MCP-1 and MPO), TNF-α and IL-6 increased significantly. Infusion of TAK-242 1h before induction of cardiac death blocked the increase of immune and inflammatory response molecules. However, the increase of TLR4 level was not affected by infusion of TAK-242. Histology study showed that infusion of TAK-242 protect liver tissue from damage during cardiac death.


CONCLUSIONS
These results indicates that TLR4 signaling pathway may contribute to ischemia/reperfusion injury in the liver grafts, and blocking TLR4 pathway with TAk-242 may reduce TLR4-mediated tissue damage.
Department of Organ transplantation, The First Hospital of China Medical University, Shenyang 110001, China.
Zigong
Z
Shao
Department of General Surgery, The First Hospital of Liaoning Medical University, Jinzhou 121000, China.
Baoping
B
Jiao
Department of Organ transplantation, The First Hospital of China Medical University, Shenyang 110001, China.
Tingting
T
Liu
Department of Organ transplantation, The First Hospital of China Medical University, Shenyang 110001, China. Electronic address: chengying75@sina.com.
Ying
Y
Cheng
Department of Organ transplantation, The First Hospital of China Medical University, Shenyang 110001, China.
Hao
H
Liu
Department of Organ transplantation, The First Hospital of China Medical University, Shenyang 110001, China.
Yongfeng
Y
Liu
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003643:Death; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D016031:Liver Transplantation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D034421:Sus scrofa; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D052096:Warm Ischemia
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D013449:Sulfonamides; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
Animal model; Ischemia/reperfusion injury; Liver transplantation; TLR