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血红素加氧酶-1 的部分抑制可减轻 HMP 诱导的肝再生对大鼠肝损伤的作用。

Partial Inhibition of HO-1 Attenuates HMP-Induced Hepatic Regeneration against Liver Injury in Rats.

机构信息

Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.

Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, China.

出版信息

Oxid Med Cell Longev. 2018 Apr 15;2018:9108483. doi: 10.1155/2018/9108483. eCollection 2018.

DOI:10.1155/2018/9108483
PMID:29849924
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5925174/
Abstract

We found better liver graft regeneration with hypothermic machine perfusion (HMP) compared with static cold storage (SCS) for the first time in our pilot study, but the underlying mechanisms are unknown. Upregulated heme oxygenase- (HO-) 1 expression has been reported to play a pivotal role in promoting hepatocyte proliferation. Here, we evaluated the novel role of HO-1 in liver graft protection by HMP. Rats with a heterozygous knockout of HO-1 (HO-1) were generated and subjected to 3 h of SCS or HMP pre-half-size liver transplantation (HSLT) in vivo or 6 h of SCS or HMP in vitro; control rats were subjected to the same conditions (HO-1). We found that HSLT induced significant elevation of the HO-1 protein level in the regenerated liver and that HO-1 haplodeficiency resulted in decreased proliferation post-HSLT. Compared with SCS, HMP induced significant elevation of the HO-1 protein level along with better liver recovery, both of which were reduced by HO-1 haplodeficiency. HO-1 haplodeficiency-induced decreased proliferation was responsible for the attenuated regenerative ability of HMP. Mechanistically, HO-1 haploinsufficiency resulted in suppression of hepatocyte growth factor (HGF)/Akt activity. Our results suggest that inhibition of HO-1 mitigates HMP-induced liver recovery effects related to proliferation, in part, by downregulating the HGF-Akt axis.

摘要

在我们的初步研究中，我们首次发现与静态冷保存（SCS）相比，低温机器灌注（HMP）可实现更好的肝移植物再生，但其中的机制尚不清楚。有报道称，上调血红素加氧酶-1（HO-1）的表达在促进肝细胞增殖方面起着关键作用。在此，我们评估了 HMP 中 HO-1 在肝移植物保护中的新作用。生成 HO-1 杂合敲除（HO-1）大鼠，并在体内进行 3 小时 SCS 或 HMP 预半肝移植（HSLT）或在体外进行 6 小时 SCS 或 HMP；对照组大鼠接受相同的条件（HO-1）。我们发现，HSLT 可诱导再生肝中 HO-1 蛋白水平的显著升高，而 HO-1 单倍体缺乏可导致 HSLT 后增殖减少。与 SCS 相比，HMP 诱导了 HO-1 蛋白水平的显著升高以及更好的肝恢复，而这两者均因 HO-1 单倍体缺乏而降低。HO-1 单倍体缺乏诱导的增殖减少是 HMP 减弱再生能力的原因。从机制上讲，HO-1 单倍体不足会抑制肝细胞生长因子（HGF）/Akt 活性。我们的研究结果表明，抑制 HO-1 可减轻与增殖相关的 HMP 诱导的肝恢复作用，部分原因是下调 HGF-Akt 轴。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5040/5925174/e00c51b360c9/OMCL2018-9108483.008.jpg
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