2016年6月22日 讯 /生物谷BIOON/ --载脂蛋白是一类与脂蛋白相互作用的蛋白质，它们能够稳定脂蛋白的结构，同时介导受体依赖性的脂蛋白识别过程（例如低密度脂蛋白受体以及B型清道夫受体等）。栽脂蛋白A-I（ApoA-I）是高密度脂蛋白的主要组成成分，它对于胆固醇的反向转运以及抗炎具有重要的作用。
过表达ApoA-I的小鼠体内高密度脂蛋白的水平有明显升高，同时其慢性炎症以及心血管硬化的病情都会明显减轻。这一效应部分依赖于ApoA-I能够阻断DAMP的信号转导过程。此前研究发现，一类叫做“SAHP”的双亲性多肽（一种ApoA-I的类似物），能够竞争性地与ApoA-I的多类受体结合，包括SR-BI、SR-BII以及CD36。由于SR-B广泛表达在肺部表皮细胞以及巨噬细胞表面， 因此其在急性肺病发病过程中可能具有重要的作用。进而，ApoA-I与SAHP对于表皮细胞的功能也可能具有一定的影响。
急性的炎症反应几乎都伴随着内皮细胞屏障的损坏并且会面临高致死风险。最近研究表明CD36正向调节了包括内毒素血症以及脓毒症在内的多种炎症反应。另一方面，由于ApoA-I以及SAHP具有明显的抗炎效果，基于两者的新型抗炎疗法的开发也是十分有前景的课题。针对以上问题，来自美国NIH的Konstantin G. Birukov课题组进行了深入研究，相关结果发表在最近一期的《Journal of Immunology》杂志上。
首先，作者在分别过表达了SR-BI，SR-BII以及CD36的HELA细胞系上检测了荧光标记的载脂蛋白L37pA。结果显示，L37pA均能够与上述过表达的细胞系结合。进一步，作者利用人源肺脏表皮细胞系进行试验，发现L37pA能够有效降低LPS引起的IL-8的分泌，而且效果优于SAHP。
之后，作者通过体外实验发现L37pA能够有效降低由LPS引发的表皮细胞的损伤程度。进一步，作者通过体内试验也证明了L37pA能够有效降低炎症反应带来的表皮细胞的损伤。
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Alexander V. Bocharov, Tinghuai Wu, Irina N. Baranova, Anna A. Birukova, Denis Sviridov, Tatyana G. Vishnyakova, Alan T. Remaley, Thomas L. Eggerman, Amy P. Patterson and Konstantin G. Birukov
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.