Anthrax lethal toxin-induced lung injury and treatment by activating MK2.
Anthrax lethal toxin-induced lung injury and treatment by activating MK2.
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炭疽致死毒素引起的肺损伤以及通过激活 MK2 进行治疗。
DOI：
10.1152/japplphysiol.00335.2015
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Kayyali,UsamahS
中科院分区：
文献类型：
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作者：
Liu,Tiegang;Warburton,RodR;Hill,NicholasS;Kayyali,UsamahS
炭疽病与严重的血管渗漏有关，这是由细菌致死毒素（LeTx）引起的。炭疽引起的胸腔积液和肺水肿被认为是炭疽毒素引起的内皮损伤的反映。由于血管渗漏也可以观察到一致的大鼠静脉注射LeTx，后者可能会提出一个简单的生理相关的急性肺损伤（ALI）的动物模型。这种模型可用于评估和开发更好的治疗ALI或急性呼吸窘迫综合征（ARDS），因为其他可用的啮齿动物模型不一致地产生内皮渗透性，这是ARDS的主要组成部分。LeTx的生物活性存在于特异性降解MAP激酶激酶（MKK）的致死因子金属蛋白酶中。最近，我们发现，通过在肺血管内皮细胞中降解MKK 3，LeTx使p38 MAP激酶信号转导失活可能与内皮渗透性屏障受损有关。LeTx效应与阻断p38底物和MAP激酶活化的蛋白激酶2（MAPKAPK 2或MK 2）的活化以及后者的底物热休克蛋白27（HSP 27）的磷酸化特异性相关。我们现在已经设计了一种肽，可以直接特异性地激活MK2，在细胞和体内引起HSP 27磷酸化。MK2激活肽（MK2-AP）还可以阻断LeTx对培养细胞内皮屏障的影响，并减少LeTx诱导的大鼠肺血管渗漏。因此，MK2-AP具有对抗炭疽或肺水肿和由于其他原因引起的血管渗漏的治疗潜力。
Anthrax is associated with severe vascular leak, which is caused by the bacterial lethal toxin (LeTx). Pleural effusions and pulmonary edema that occur in anthrax are believed to reflect endothelial injury caused by the anthrax toxin. Since vascular leak can also be observed consistently in rats injected intravenously with LeTx, the latter might present a simple physiologically relevant animal model of acute lung injury (ALI). Such a model could be utilized in evaluating and developing better treatment for ALI or acute respiratory distress syndrome (ARDS), as other available rodent models do not consistently produce the endothelial permeability that is a major component of ARDS. The biological activity of LeTx resides in the lethal factor metalloprotease that specifically degrades MAP kinase kinases (MKKs). Recently, we showed that LeTx inactivation of p38 MAP kinase signaling via degradation of MKK3 in pulmonary vascular endothelial cells can be linked to compromise of the endothelial permeability barrier. LeTx effects were linked specifically to blocking activation of p38 substrate and MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2) and phosphorylation of the latter's substrate, heat shock protein 27 (HSP27). We have now designed a peptide that directly and specifically activates MK2, causing HSP27 phosphorylation in cells and in vivo. The MK2-activating peptide (MK2-AP) also blocks the effects of LeTx on endothelial barriers in cultured cells and reduces LeTx-induced pulmonary vascular leak in rats. Hence, MK2-AP has the therapeutic potential to counteract anthrax or pulmonary edema and vascular leak due to other causes.