von Willebrand factor and angiopoietin-2: toward an acute lung injury endothelial endophenotype?
von Willebrand factor and angiopoietin-2: toward an acute lung injury endothelial endophenotype?
复制标题
冯维勒布兰德因子和血管生成素-2：急性肺损伤内皮内表型？
DOI：
10.1097/ccm.0b013e31824c8fad
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发表时间：
2012
影响因子：
8.8
通讯作者：
Christie,JasonD
中科院分区：
文献类型：
--
作者：
Meyer,NualaJ;Christie,JasonD
Crit Care Med 2012，第40卷，第6期，1967年血管生成素家族，包括屏障增强分子血管生成素1(Ang1)或血管内皮生长因子，它可以改变ANG2对其受体(14)的作用，或通过受体本身，具有Ig和EGF同源结构域-2(TIE2)的酪氨酸激酶。研究发现，Ang2水平的变化与结果密切相关，并被容量策略修正，这可能表明Ang2是治疗反应的相关标记物。内皮通透性的逆转不依赖于炎症，可能是脓毒症和ALI的一种新的治疗模式(15)。在败血症和肺损伤方面的动物研究表明，使用重组Ang1或合成的TIE2受体激动剂可以获得更好的存活率，而且似乎有可能很快就可以在危重患者群体中进行临床试验(16-18)，设计用于修改Ang-tie轴的药物。虽然阻断Ang1和Ang2的药物正在开发用于癌症治疗，但似乎更适合增强Ang1对脓毒症或ALI的影响。重要的是要测试基因或基线Ang2水平是否能确定患者是否可能从这种治疗中受益，以及血浆Ang2是否可以作为反应的监测。在Calfee及其同事的研究中，vWF和Ang2的作用明显解偶联，这应该会促使进一步研究推动vWF和Ang2的表达、合成、储存、释放和血浆清除的因素。值得注意的是，尽管血浆vWF是死亡率的强烈预测因子，但低位拉伸机械通气策略并未改变血浆vWF，一些研究表明，在可能无法合成足够的ADAMTS-13(一种具有血栓反应蛋白13基序的去整合素和金属蛋白酶)的危重患者中，vWF的清除发生了改变(19)。这也可能是，血小板是血浆vWF的一个比目前认识到的更重要的来源。虽然血浆Ang2和vWF都不是一个完美的ALI生物标志物，但两者似乎都在识别长时间机械通气和死亡的高风险患者方面发挥了作用。在未来的研究中，重要的是验证这些标记物的增量预测特性，以评估在更广泛的人群中的临床实用性。此外，为了确定ALI潜在的血管损伤内表型，未来的研究可以测试这些假定的内皮因子是否与其他相关变量如肺死亡空间分数相关，以及它们是否有助于确定哪些ALI患者的增强血管屏障功能的治疗可能有效。同样重要的是，这些标记物未能告知死亡率的患者的特征；当基线vWF和Ang2水平较低的患者死于急性呼吸窘迫综合征时，这是一个具有根本不同病理生理学的患者吗？随着我们在Calfee和他的同事的研究结果的基础上发展，未来的ALI研究可能会通过在一开始就丰富他们的ALI亚型的研究人群而获得成功。
Crit Care Med 2012 Vol. 40, No. 6 1967 angiopoietin family, including the barrier enhancing molecule angiopoietin 1 (Ang1) or vascular endothelial growth factor, which may alter the action of ANG2 on its receptor (14), or by the receptor itself, tyrosine kinase with Ig and EGF homology domains-2 (TIE2). The findings that changes in Ang2 levels tracked with outcomes, and are modified by volume strategy, may indicate that Ang2 is a pertinent marker of therapy response. The reversal of endothelial permeability, independent of inflammation, may be a novel therapeutic paradigm in sepsis and ALI (15). Animal studies in sepsis and lung injury have shown better survival with recombinant Ang1 or a synthetic TIE2 receptor agonist, and it seems likely that agents designed to modify the Ang–TIE axis may soon be available for clinical trials in critically ill populations (16–18). While agents blocking both Ang1 and Ang2 are in development for cancer therapeutics, it seems more appropriate to enhance Ang1 effects for sepsis or ALI. It will be important to test whether genotype or baseline Ang2 levels identify patients likely to benefit from such therapy and whether plasma Ang2 can serve as a monitor of response. The apparent uncoupling of effects for vWF and Ang2 in the study by Calfee and colleagues should prompt further study on factors driving the expression, synthesis, storage, release, and plasma clearance of both vWF and Ang2. Notably, plasma vWF was not altered by low stretch ventilation strategy despite being a strong predictor of mortality, and some have suggested that the clearance of vWF is altered in critically ill patients who may not synthesize adequate ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motifs 13)(19). It may also be that platelets are a more important source of plasma vWF than is currently appreciated. Although neither plasma Ang2 nor vWF is a perfect ALI biomarker, both seem to have a role in identifying patients at higher risk for prolonged ventilation and death. In future studies, it will be important to validate the incremental predictive properties of these markers to assess clinical utility in broader populations. Further, to characterize a potential vascular injury endophenotype of ALI, future investigations could test whether these presumed endothelial factors associate with other relevant variables such as pulmonary dead space fraction, and whether they help to define ALI subjects in whom therapies to enhance vascular barrier function might be effective. Equally important will be the characterization of patients in whom these markers fail to inform about mortality; when a patient with low baseline vWF and Ang2 levels dies from acute respiratory distress syndrome, was this a patient with a fundamentally different pathophysiology? As we build on the findings of Calfee and colleagues, future ALI investigations may find success by enriching their study population for such ALI subtypes at the outset.