Open Access

TAK242 suppresses the TLR4 signaling pathway and ameliorates DCD liver IRI in rats

  • Authors:
    • Xiang Zhong
    • Qi Xiao
    • Zhongzhong Liu
    • Wei Wang
    • Chin‑Hui Lai
    • Wang Yang
    • Pengpeng Yue
    • Qifa Ye
    • Jiansheng Xiao
  • View Affiliations

  • Published online on: June 27, 2019     https://doi.org/10.3892/mmr.2019.10439
  • Pages: 2101-2110
  • Copyright: © Zhong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ischemia‑reperfusion injury (IRI) is a notable cause of tissue damage during surgical procedures and a major risk factor in graft dysfunction in liver transplantation. Livers obtained from donors after circulatory death (DCD) are prone to IRI and toll‑like receptor 4 (TLR4) serves a prominent role in the inflammatory response associated with DCD liver IRI. The present study was designed to investigate whether TAK242, a specific TLR4 inhibitor, improves hepatic IRI following a DCD graft and to investigate its underlying protective mechanisms. Male Sprague‑Dawley rats were randomized into 4 groups: Control, TAK242, DCD and DCD+TAK242 groups. Rats were pretreated with TAK242 or its vehicle for 30 min, then the livers were harvested without warm ischemia (control group and TAK242 group) or with warm ischemia in situ for 30 min. The livers were stored in cold University of Wisconsin solution for 24 h and subsequently perfused for 60 min with an isolated perfused rat liver system. Rat liver injury was evaluated thereafter. When compared with the DCD group, DCD livers with TAK242 pretreatment displayed significantly improved hepatic tissue injury and less tissue necrosis (P<0.05). Compared with DCD livers, mechanistic experiments revealed that TAK242 pretreatment alleviated mitochondrial dysfunction, reduced reactive oxygen species and malondialdehyde levels and inhibited apoptosis. Additionally, TAK242 significantly inhibited the IRI‑associated inflammatory response, indicated by the decreased expression of TLR4, interleukin (IL)‑1β, IL‑6 and cyclooxygenase 2 at the mRNA and protein levels (P<0.05). TAK242 ameliorates DCD liver IRI via suppressing the TLR4 signaling pathway in rats. The results of the present study have revealed that TAK242 pretreatment harbors a potential benefit for liver transplantation.

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September 2019
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Copy and paste a formatted citation
APA
Zhong, X., Xiao, Q., Liu, Z., Wang, W., Lai, C., Yang, W. ... Xiao, J. (2019). TAK242 suppresses the TLR4 signaling pathway and ameliorates DCD liver IRI in rats. Molecular Medicine Reports, 20, 2101-2110. https://doi.org/10.3892/mmr.2019.10439
MLA
Zhong, X., Xiao, Q., Liu, Z., Wang, W., Lai, C., Yang, W., Yue, P., Ye, Q., Xiao, J."TAK242 suppresses the TLR4 signaling pathway and ameliorates DCD liver IRI in rats". Molecular Medicine Reports 20.3 (2019): 2101-2110.
Chicago
Zhong, X., Xiao, Q., Liu, Z., Wang, W., Lai, C., Yang, W., Yue, P., Ye, Q., Xiao, J."TAK242 suppresses the TLR4 signaling pathway and ameliorates DCD liver IRI in rats". Molecular Medicine Reports 20, no. 3 (2019): 2101-2110. https://doi.org/10.3892/mmr.2019.10439