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远程缺血预处理通过血红素加氧酶-1诱导的自噬保护肝脏免受缺血再灌注损伤。

Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy.

作者信息

Wang Yun, Shen Jian, Xiong Xuanxuan, Xu Yonghua, Zhang Hai, Huang Changjun, Tian Yuan, Jiao Chengyu, Wang Xuehao, Li Xiangcheng

机构信息

Department of Oncological Surgery 2, Xuzhou City Central Hospital, The Affiliated Hospital of the Southeast University Medical School (Xuzhou), The Tumor Research Institute of the Southeast University (Xuzhou), Xuzhou, Jiangsu Province, China.

Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.

出版信息

PLoS One. 2014 Jun 10;9(6):e98834. doi: 10.1371/journal.pone.0098834. eCollection 2014.

DOI:10.1371/journal.pone.0098834
PMID:24914543
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4051645/
Abstract

BACKGROUND

Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy.

METHODS

RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro.

RESULTS

In liver IR, the expression of LC3-II peaked 12-24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA.

CONCLUSIONS

RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.

摘要

背景

越来越多的证据表明自噬与肝脏缺血/再灌注（IR）预处理的保护作用有关。血红素加氧酶-1（HO-1）在限制炎症和防止对IR的凋亡反应中至关重要。我们之前证明，远程缺血预处理（RIPC）后肝脏移植物中HO-1上调。本研究的目的是证实RIPC通过HO-1介导的自噬来保护肝脏免受IR损伤。

方法

在肝脏缺血前对肢体进行局部缺血以进行RIPC，并在术前抑制HO-1活性。通过轻链3-II（LC3-II）的表达评估自噬。在自噬模型和体外矿物油诱导的IR中检测HO-1/细胞外信号调节激酶（ERK）/p38/丝裂原活化蛋白激酶（MAPK）途径。

结果

在肝脏IR中，LC3-II的表达在IR后12 - 24小时达到峰值，超微结构显示IR后肝细胞中有大量自噬体。当HO-1失活时自噬受到抑制，我们认为这导致体内肝脏IR损伤（IRI）加重。血红素诱导的自噬在体外也保护大鼠肝细胞免受IRI，而HO-1 siRNA可消除这种保护作用。在血红素预处理的肝细胞中p38-MAPK和ERK1/2的磷酸化上调，在用HO-1 siRNA处理后下调。

结论

RIPC可能通过诱导HO-1/p38-MAPK依赖性自噬来保护肝脏免受IRI损伤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/1d85ecfd5229/pone.0098834.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/fe531181e1dd/pone.0098834.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/61d863cfab50/pone.0098834.g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/e25c7959389f/pone.0098834.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/e87d79af6026/pone.0098834.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/8ee9dc47f3dc/pone.0098834.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/1d85ecfd5229/pone.0098834.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/fe531181e1dd/pone.0098834.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/61d863cfab50/pone.0098834.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/aaba81cb083d/pone.0098834.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/e25c7959389f/pone.0098834.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/e87d79af6026/pone.0098834.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/8ee9dc47f3dc/pone.0098834.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc2e/4051645/1d85ecfd5229/pone.0098834.g007.jpg

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