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Hypothermic Oxygenated Machine Perfusion Alleviates Donation After Circulatory Death Liver Injury Through Regulating P-selectin-dependent and -independent Pathways in Mice

Zeng, Xianpeng, MD1; Li, Minli, MD1; Fan, Xiaoli, MD1; Xue, Shuai, MD1; Liang, Wenjin, MD1; Fang, Zehong, MD1; Zeng, Cheng, MD1; Fan, Lin, MD1; Xiong, Yan, MD1; Wang, Yanfeng, MD1; Ye, Qifa, MD, PhD1,2

doi: 10.1097/TP.0000000000002621
Original Basic Science—Liver
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Background. Hypothermic oxygenated machine perfusion (HOPE) has been shown to improve the quality of liver donation after circulatory death (DCD) compared to cold storage (CS). However, the mechanism by which HOPE works is unclear. In this study, a mouse liver HOPE system was developed to characterize the role of P-selectin in the protective effect of HOPE on DCD livers.

Methods. A warm ischemia model of the liver and an isolated perfused liver system were established to determine a suitable flow rate for HOPE. Perfusate and tissue samples from wild-type and P-selectin knockout (KO) mice were used to determine liver function, apoptosis and necrosis rates, deoxyribonucleic acid injury and oxidative stress levels, leukocyte and endothelial cell activation, and inflammatory reactions.

Results. A mouse liver HOPE system was successfully established. HOPE at flow rates between 0.1 and 0.5 mL/min · g were shown to have a protective effect on the DCD liver. P-selectin KO improved the quality of the DCD liver in the CS group, and reduction of P-selectin expression in the wild-type HOPE group had similar protective effects. Moreover, there was a reduction in the degree of oxidative stress and deoxyribonucleic acid injury in the P-selectin KO HOPE group compared with the P-selectin KO CS group.

Conclusions. We established a mouse HOPE system and determined its suitable flow. We also proved that P-selectin deficiency alleviated DCD liver injury. HOPE protected the DCD liver through regulating P-selectin-dependent and -independent pathways.

1 Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China.

2 Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, The Third Xiangya Hospital of Central South University, Changsha, China.

Received 23 August 2018. Revision received 1 January 2019.

Accepted 4 January 2019.

This study was supported by the National Natural Science Foundation of China-Xinjiang joint fund (grant [U1403222]) and the National Natural Science Foundation of China (grant [81570079]).

The authors declare no conflicts of interest.

X.Z. and Y.W. designed the experiments; M.L. and Z.F. analyzed the data; X.Z., S.X., W.L., C.Z., and L.F. performed the experiments; X.Z. and M.L. wrote the paper; X.F., Y.X., Y.W., and Q.Y. supervised the study; Y.W. and Q.Y. acquired the funding.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Qifa Ye, PhD, MD, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China. (yqf_china@163.com)

Yanfeng Wang, MD, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, China. (1370261793@qq.com).

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