CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice
CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice
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DOI：
10.1152/ajpgi.00257.2014
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发表时间：
2015-04-15
影响因子：
4.5
通讯作者：
Lentsch, Alex B.
中科院分区：
文献类型：
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作者：
Wilson, Gregory C.;Freeman, Christopher M.;Lentsch, Alex B.
基质细胞衍生因子-1（SDF-1或CXCL12）及其受体CXC趋化因子受体-4（CXCR4）在缺血性肝损伤和恢复中的作用尚未研究。一些报告表明，这种趋化因子可能有助于肝脏再生，但其他报告则表明，它可能通过激活肝星状细胞而促进纤维化。在本研究中，我们试图阐明 SDF-1 及其受体 CXCR4 在缺血再灌注 (I/R) 后肝损伤、恢复和再生过程中的作用。使用部分（70%）I/R 的小鼠模型来诱导肝损伤并研究修复和再生反应。 CXCR4在肝脏中组成型表达，肝脏中SDF-1的水平在再灌注后8小时达到峰值，但在96小时内保持显着增加。用CXCR4拮抗剂AMD3100或激动剂SDF-1治疗小鼠对I/R后8小时评估的急性肝损伤没有影响。然而，AMD3100 治疗在再灌注 72 和 96 小时后增加了肝细胞增殖，并减少了肝坏死量。相反，SDF-1治疗显着降低了肝细胞增殖。这些影响似乎取决于肝损伤的存在，因为 AMD3100 和 SDF-1 对接受 70% 部分肝切除术的小鼠的肝细胞增殖或肝脏质量没有影响。数据表明，通过 CXCR4 的信号传导不利于 I/R 后的肝脏恢复和再生，并且使用 CXCR4 拮抗剂进行临床治疗可能会改善急性肝损伤后的肝脏恢复。
The role of stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptor CXC chemokine receptor-4 (CXCR4) in ischemic liver injury and recovery has not been studied. Some reports suggest that this chemokine may aid in liver regeneration, but others suggest that it may be profibrotic through its activation of hepatic stellate cells. In this study we sought to elucidate the role of SDF-1 and its receptor CXCR4 during liver injury, recovery, and regeneration after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. CXCR4 was expressed constitutively in the liver, and hepatic levels of SDF-1 peaked 8 h after reperfusion but remained significantly increased for 96 h. Treatment of mice with the CXCR4 antagonist AMD3100 or agonist SDF-1 had no effect on acute liver injury assessed 8 h after I/R. However, treatment with AMD3100 increased hepatocyte proliferation after 72 and 96 h of reperfusion and reduced the amount of liver necrosis. In contrast, treatment with SDF-1 significantly decreased hepatocyte proliferation. These effects appeared to be dependent on the presence of liver injury, as AMD3100 and SDF-1 had no effect on hepatocyte proliferation or liver mass in mice undergoing 70% partial hepatectomy. The data suggest that signaling through CXCR4 is detrimental to liver recovery and regeneration after I/R and that clinical therapy with a CXCR4 antagonist may improve hepatic recovery following acute liver injury.