Toll-like Receptor 4 Inhibitor TAK-242 Treatment Does Not Influence Perfusion Recovery in Tissue Ischemia
Toll-like Receptor 4 Inhibitor TAK-242 Treatment Does Not Influence Perfusion Recovery in Tissue Ischemia
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Toll 样受体 4 抑制剂 TAK-242 治疗不影响组织缺血的灌注恢复
DOI：
10.1097/fjc.0000000000000019
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发表时间：
2014
影响因子：
3
通讯作者：
G. Pasterkamp
中科院分区：
文献类型：
--
作者：
P. van den Borne;A. Bastiaansen;M. D. de Vries;P. Quax;I. Hoefer;G. Pasterkamp
toll样受体（TLRs）在先天性免疫应答中起重要作用，在侧支动脉形成（动脉发生）中起关键作用。后肢缺血的TLR4 - / -小鼠表现为灌注恢复减少，并伴有炎症细胞浸润受损。目前正在开发和测试TLR拮抗剂，目的是抑制器官损伤性免疫反应的急性加重。然而，先天免疫反应的全身性抑制可能对动脉生成产生负面影响。在这项研究中，我们评估了一种有效的TLR4抑制剂（TAK-242）对TLR4的抑制是否会对小鼠动脉生成模型的灌注恢复产生负面影响。在TAK-242孵育后，用TLR4配体脂多糖刺激人和小鼠全血。刺激后，采用荧光活化细胞分选法测定细胞TLR4活化情况，采用酶联免疫吸附法测定肿瘤坏死因子α释放情况。接下来，在小鼠动脉生成模型中测试TAK-242对灌注恢复的影响。长期刺激后，TAK-242可抑制人和小鼠血液中肿瘤坏死因子α水平测量的TLR4反应。TAK-242在体内减弱了TLR4的反应，但不抑制小鼠的灌注恢复。综上所述，尽管TAK-242具有抑制TLR4的特性，但它不会对后肢缺血后的灌注恢复产生负面影响。
Abstract: Toll-like receptors (TLRs) are important in innate immune responses, which are crucial in collateral artery formation (arteriogenesis). TLR4−/− mice undergoing hind limb ischemia show decreased perfusion recovery accompanied by an impaired infiltration of inflammatory cells. TLR antagonists are currently developed and tested with the objective to inhibit acute exacerbation of organ damaging immune responses. However, systemic inhibition of innate immune responses may negatively influence arteriogenesis. In this study, we evaluated if TLR4 inhibition by a potent TLR4 inhibitor (TAK-242) would negatively influence perfusion recovery in a mouse model for arteriogenesis. Whole blood from human and mouse origin was stimulated with the TLR4 ligand lipopolysaccharide following TAK-242 incubation. After stimulation, cellular TLR4 activation was measured using fluorescence-activated cell sorting and tumor necrosis factor alpha release was measured using enzyme-linked immunosorbent assay. Next, the effect of TAK-242 was tested in a mouse model for arteriogenesis on perfusion recovery. TLR4 responses measured by tumor necrosis factor alpha levels were inhibited by TAK-242 in human and mouse blood after long-term stimulation. TAK-242 attenuated TLR4 responses in vivo but did not inhibit perfusion recovery in mice. In conclusion, TAK-242 does not negatively influence perfusion recovery following hind limb ischemia despite its TLR4 inhibiting properties.
影响因子：
4
作者：
Lu, Zhongyang;Zhang, Xiaoming;Huang, Yan
通讯作者：
Huang, Yan