Biotrauma hypothesis of ventilator-induced lung injury.
Biotrauma hypothesis of ventilator-induced lung injury.
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DOI：
10.1164/ajrccm.169.2.950
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发表时间：
2004-01
影响因子：
24.7
通讯作者：
S. Uhlig;M. Ranieri;Arthur S Slutsky
中科院分区：
文献类型：
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作者：
S. Uhlig;M. Ranieri;Arthur S Slutsky
在最近的观点中，Dreyfuss及其同事（1）质疑细胞因子在呼吸机诱导的肺损伤（VILI）中的存在和作用，这与他们在介质和生物创伤领域唯一发表的工作一致，他们未能证实我们的一些发现（见参考文献25，Dreyfuss及其同事）。我们对他们的观点的批评不仅在于它关注了许多琐碎的所谓研究内部和研究之间的不一致，而且它没有一个概念框架。如果规定以下三个概念，就可以澄清许多误解。首先，Dreyfuss及其同事（1）没有系统地区分生物创伤假说的两个独立部分：（1）通气可能导致介质的释放，以及（2）这些介质具有生物学作用。由于生物创伤假说是相当新的，到目前为止，大多数工作都与该假说的第一部分有关，并且有充分的证据（2003年美国胸科学会国际会议上有大量此类研究）支持通气或拉伸可以激活细胞并促进介质释放。研究之间的差异或对照受试者的非零基线水平并不能使这一普遍概念无效，现在的问题不是通气是否引起介质释放，而是通气如何引起介质释放。可以说更重要的问题涉及这些介质的生物学作用。这一问题最近才开始得到解决，但至少有三项健康动物研究表明，通气诱导的肺损伤显然不是由机械力本身直接引起的，而是由响应这些力而产生的介质引起的（2，3，参考文献50，Dreyfuss及其同事）。其中一项研究显示巨噬细胞炎性蛋白（MIP）-2受体（CXCR 2）在小鼠VILI模型中的关键作用（参考文献50，Dreyfuss及其同事），Dreyfuss及其同事（1）用以下声明驳回：“受伤的肺最终招募嗜中性粒细胞并不令人惊讶。”关键点是，中性粒细胞在损伤前被募集到肺中，如中性粒细胞隔离被阻断时肺损伤的预防所证明的。这正是生物创伤假说所预测的。第二，认为这“不足为奇”的评估是基于本审查的第二个概念缺陷，即它没有系统地区分一次打击和两次打击模式。在1996年之前，几乎所有的工作都使用了两次打击模型，通常是肺灌洗模型，然后是不同的通气策略。在许多二次打击模型中已经观察到由有害的刺激策略引起的细胞因子水平增加，但是第一次打击（例如灌洗或酸吸入）和第二次打击（通气）之间的相互作用非常复杂，并且难以定义介质释放和白细胞活化的初始刺激。因此，研究人员开始研究通气对健康肺的影响（一次性模型）。而在一次打击模型中，很难始终检测到肿瘤坏死因子（TNF; Dreyfuss及其同事过分强调了这一点），经常发现许多其他介质，如白细胞介素（IL）-6，MIP-2，MIP-1，有时甚至是TNF（3，4，Dreyfuss及其同事的参考文献50）。
In a recent perspective, Dreyfuss and colleagues (1) question the existence and role of cytokines during ventilator-induced lung injury (VILI), in agreement with their only published work in the field of mediators and biotrauma, in which they failed to confirm some of our findings (see Reference 25 in Dreyfuss and colleagues). Our criticism of their perspective is not only that it focused on many trivial so-called inconsistencies within and between studies, but that it did so without a conceptual framework. Provision for the following three concepts would have clarified many misconceptions. First, Dreyfuss and colleagues (1) do not systematically distinguish between the two independent parts of the biotrauma hypothesis:(1) that ventilation may cause release of mediators, and (2) that these mediators have biological actions. Because the biotrauma hypothesis is rather new, until now most work has been concerned with the first part of this hypothesis and ample evidence (the 2003 American Thoracic Society International Conference was abound in such studies) exists to support that ventilation or stretch can activate cells and promote mediator release. Differences among studies or nonzero baseline levels in control subjects do not invalidate this general notion, and the problem now is not whether, but how ventilation causes mediator release. The arguably more important question concerns the biological role of these mediators. This problem has only recently begun to be addressed, and yet there are already at least three studies in healthy animals where ventilation-induced lung injury was apparently not caused directly by the mechanical forces themselves, but by the mediators produced in response to these forces (2, 3, Reference 50 in Dreyfuss and colleagues). One of these studies, showing the pivotal role of macrophage inffammatory protein (MIP)-2 receptors (CXCR2) in a murine VILI model (Reference 50 in Dreyfuss and colleagues) is dismissed by Dreyfuss and colleagues (1) with the statement:“It is not very surprising that injured lungs eventually recruit neutrophils.” The critical point is that neutrophils were recruited to the lungs before injury, as demonstrated by the prevention of lung injury when neutrophil sequestration was blocked. This is exactly what the biotrauma hypothesis would predict. Second, the assessment that this is “not surprising” is based on the second conceptual deficit of this review, namely that it does not systematically distinguish between one-hit and two-hit models. Almost all of the work before 1996 used two-hit models, typically the lung lavage model followed by different ventilation strategies. Increased cytokine levels caused by injurious ventilatory strategies have been observed in a number of two-hit models, but the interaction between the first (eg, lavage or acid aspiration) and the second hit (ventilation) is very complex, and the initial stimulus for mediator release and leukocyte activation is difficult to define. Therefore, investigators have started to investigate the effects of ventilation in healthy lungs (one-hit model). And whereas in the one-hit models it has been difficult to always detect tumor necrosis factor (TNF; which is overemphasized by Dreyfuss and colleagues), many other mediators were frequently found such as interleukin (IL)-6, MIP-2, MIP-1, and sometimes even TNF (3, 4, Reference 50 in Dreyfuss and colleagues).