Bocharov Alexander V, Wu Tinghuai, Baranova Irina N, Birukova Anna A, Sviridov Denis, Vishnyakova Tatyana G, Remaley Alan T, Eggerman Thomas L, Patterson Amy P, Birukov Konstantin G
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; National Heart, Lung, and Blood Institute, Bethesda, MD 20892;
Lung Injury Center, The University of Chicago, Chicago, IL 60637;
J Immunol. 2016 Jul 15;197(2):611-9. doi: 10.4049/jimmunol.1401028. Epub 2016 Jun 17.
Synthetic amphipathic helical peptides (SAHPs) designed as apolipoprotein A-I mimetics are known to bind to class B scavenger receptors (SR-Bs), SR-BI, SR-BII, and CD36, receptors that mediate lipid transport and facilitate pathogen recognition. In this study, we evaluated SAHPs, selected for targeting human CD36, by their ability to attenuate LPS-induced inflammation, endothelial barrier dysfunction, and acute lung injury (ALI). L37pA, which targets CD36 and SR-BI equally, inhibited LPS-induced IL-8 secretion and barrier dysfunction in cultured endothelial cells while reducing lung neutrophil infiltration by 40% in a mouse model of LPS-induced ALI. A panel of 20 SAHPs was tested in HEK293 cell lines stably transfected with various SR-Bs to identify SAHPs with preferential selectivity toward CD36. Among several SAHPs targeting both SR-BI/BII and CD36 receptors, ELK-B acted predominantly through CD36. Compared with L37pA, 5A, and ELK SAHPs, ELK-B was most effective in reducing the pulmonary barrier dysfunction, neutrophil migration into the lung, and lung inflammation induced by LPS. We conclude that SAHPs with relative selectivity toward CD36 are more potent at inhibiting acute pulmonary inflammation and dysfunction. These data indicate that therapeutic strategies using SAHPs targeting CD36, but not necessarily mimicking all apolipoprotein A-I functions, may be considered a possible new treatment approach for inflammation-induced ALI and pulmonary edema.
设计为载脂蛋白A-I模拟物的合成两亲性螺旋肽（SAHP）已知可与B类清道夫受体（SR-B）、SR-BI、SR-BII和CD36结合，这些受体介导脂质转运并促进病原体识别。在本研究中，我们通过评估SAHP减轻脂多糖（LPS）诱导的炎症、内皮屏障功能障碍和急性肺损伤（ALI）的能力，来筛选靶向人类CD36的SAHP。L37pA对CD36和SR-BI具有同等靶向性，可抑制LPS诱导的培养内皮细胞中白细胞介素-8（IL-8）分泌和屏障功能障碍，同时在LPS诱导的ALI小鼠模型中使肺中性粒细胞浸润减少40%。在稳定转染了各种SR-B的人胚肾293（HEK293）细胞系中测试了一组20种SAHP，以鉴定对CD36具有优先选择性的SAHP。在几种同时靶向SR-BI/BII和CD36受体的SAHP中，ELK-B主要通过CD36起作用。与L37pA、5A和ELK SAHP相比，ELK-B在减轻LPS诱导的肺屏障功能障碍、中性粒细胞向肺内迁移和肺部炎症方面最有效。我们得出结论，对CD36具有相对选择性的SAHP在抑制急性肺部炎症和功能障碍方面更有效。这些数据表明，使用靶向CD36的SAHP的治疗策略，不一定模仿所有载脂蛋白A-I的功能，可能被认为是治疗炎症诱导的ALI和肺水肿的一种新的治疗方法。
