VEGFR1-positive macrophages facilitate liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion injury.
VEGFR1-positive macrophages facilitate liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion injury.
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DOI：
10.1371/journal.pone.0105533
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Majima M
中科院分区：
文献类型：
--
作者：
Ohkubo H;Ito Y;Minamino T;Eshima K;Kojo K;Okizaki S;Hirata M;Shibuya M;Watanabe M;Majima M
急性肝损伤后的肝修复以肝细胞增殖、坏死组织清除、肝细胞和肝脏微血管构筑重建为特征。巨噬细胞募集是肝组织修复和损伤恢复所必需的；然而，其潜在的机制尚不清楚。通过血管内皮生长因子受体1(VEGFR1)传递的信号被认为在巨噬细胞迁移和血管生成中发挥作用。本研究旨在探讨血管内皮生长因子受体1在肝脏缺血/再灌注后肝修复和肝窦重建中的作用。对VEGFR1酪氨酸激酶基因敲除小鼠(VEGFR1TK-/-小鼠)和野生型(WT)小鼠进行肝脏温热I/R，观察肝脏修复和肝窦重建过程。与WT小鼠相比，VEGFR1 TK-/-小鼠在肝脏I/R后表现出延迟的肝修复，表达VEGFR1的巨噬细胞被招募到受损的肝脏中，表皮生长因子(EGF)的表达减少。VEGFR1 TK-/-小鼠也显示出持续的正弦状功能和结构损伤，以及促血管生成因子的表达减少。EGF治疗VEGFR1 TK-/-小鼠可减轻肝脏I/R期间的肝细胞和肝窦损伤。VEGFR1 TK-/-骨髓(BM)嵌合小鼠表现出肝脏修复和血窦重建受损，表达VEGFR1的巨噬细胞向受损肝脏募集的减少。VEGFR1-巨噬细胞在肝脏I/R期间被招募到肝脏，有助于肝脏修复和肝窦重建。VEGFR1活化是促进急性肝损伤后肝修复和肝窦重建的潜在治疗策略。
Liver repair after acute liver injury is characterized by hepatocyte proliferation, removal of necrotic tissue, and restoration of hepatocellular and hepatic microvascular architecture. Macrophage recruitment is essential for liver tissue repair and recovery from injury; however, the underlying mechanisms are unclear. Signaling through vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to play a role in macrophage migration and angiogenesis. The aim of the present study was to examine the role of VEGFR1 in liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion (I/R). VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice) and wild-type (WT) mice were subjected to hepatic warm I/R, and the processes of liver repair and sinusoidal reconstruction were examined. Compared with WT mice, VEGFR1 TK-/- mice exhibited delayed liver repair after hepatic I/R. VEGFR1-expressing macrophages recruited to the injured liver showed reduced expression of epidermal growth factor (EGF). VEGFR1 TK-/- mice also showed evidence of sustained sinusoidal functional and structural damage, and reduced expression of pro-angiogenic factors. Treatment of VEGFR1 TK-/- mice with EGF attenuated hepatoceullar and sinusoidal injury during hepatic I/R. VEGFR1 TK-/- bone marrow (BM) chimeric mice showed impaired liver repair and sinusoidal reconstruction, and reduced recruitment of VEGFR1-expressing macrophages to the injured liver. VEGFR1-macrophages recruited to the liver during hepatic I/R contribute to liver repair and sinusoidal reconstruction. VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury.
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