An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.
An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.
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内皮 TLR4-VEGFR2 通路介导肺保护免受氧化诱导的损伤。
DOI：
10.1096/fj.15-275024
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Lee,PattyJ
中科院分区：
文献类型：
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作者：
Takyar,Seyedtaghi;Zhang,Yi;Haslip,Maria;Jin,Lei;Shan,Peiying;Zhang,Xuchen;Lee,PattyJ
TLR4缺乏导致对氧化性损伤的敏感。我们利用使用过的骨髓嵌合体研究了TLR4在肺保护中的作用；细胞特异性转基因建模；和慢病毒在体内传递，以敲低或表达TLR4在各个肺室；和肺特异性VEGF转基因小鼠，研究TLR4对VEGF介导的保护作用。C57/BL6小鼠在封闭的室内暴露于100%氧气中，评估存活和肺损伤。原代内皮细胞用重组VEGF刺激，并暴露于高氧或过氧化氢中。人TLR4的内皮特异性表达（相对于其在上皮细胞或免疫细胞中的表达）使TLR4缺陷小鼠在高氧环境下的存活率提高了24小时，暴露72小时后LDH释放和肺细胞凋亡减少了30%。TLR4的表达对于VEGF在肺和培养的原代内皮细胞中的保护作用是必要和充分的。TLR4敲低可抑制肺和原代内皮细胞中通过VEGF受体2 （VEGFR2）、Akt和ERK途径传递的VEGF信号，降低细胞表面VEGFR2的可用性。这些发现证明了TLR4（一种先天模式受体）与内皮细胞存活途径相互作用的新机制。-Takyar， S.，张艳，Haslip， M.，靳玲，单鹏，张晓霞，李鹏军。内皮细胞TLR4-VEGFR2通路在肺氧化损伤中的保护作用。
TLR4 deficiency causes hypersusceptibility to oxidant-induced injury. We investigated the role of TLR4 in lung protection, using used bone marrow chimeras; cell-specific transgenic modeling; and lentiviral delivery in vivo to knock down or express TLR4 in various lung compartments; and lung-specific VEGF transgenic mice to investigate the effect of TLR4 on VEGF-mediated protection. C57/BL6 mice were exposed to 100% oxygen in an enclosed chamber and assessed for survival and lung injury. Primary endothelial cells were stimulated with recombinant VEGF and exposed to hyperoxia or hydrogen peroxide. Endothelium-specific expression of human TLR4 (as opposed to its expression in epithelium or immune cells) increased the survival of TLR4-deficent mice in hyperoxia by 24 h and decreased LDH release and lung cell apoptosis after 72 h of exposure by 30%. TLR4 expression was necessary and sufficient for the protective effect of VEGF in the lungs and in primary endothelial cells in culture. TLR4 knockdown inhibited VEGF signaling through VEGF receptor 2 (VEGFR2), Akt, and ERK pathways in lungs and primary endothelial cells and decreased the availability of VEGFR2 at the cell surface. These findings demonstrate a novel mechanism through which TLR4, an innate pattern receptor, interacts with an endothelial survival pathway.—Takyar, S., Zhang, Y., Haslip, M., Jin L., Shan P., Zhang, X., Lee, P. J. An endothelial TLR4-VEGFR2 pathway mediates lung protection against oxidant-induced injury.