TAK-242 treatment ameliorates liver ischemia/reperfusion injury by inhibiting TLR4 signaling pathway in a swine model of Maastricht-category-III cardiac death

Abstract

Objectives: 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.

Keywords: Animal model; Ischemia/reperfusion injury; Liver transplantation; TLR.