Moving forward in sepsis research.
Moving forward in sepsis research.
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脓毒症研究取得进展。
DOI：
10.1164/rccm.201305-0810le
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发表时间：
2013
影响因子：
24.7
通讯作者：
Parikh,SamirM
中科院分区：
文献类型：
--
作者：
Karumanchi,SAnanth;Parikh,SamirM
1264 美国呼吸与重症监护医学杂志第188卷2013年获2011年诺贝尔生理学或医学奖（4）。科学界应该如何解决这个悖论？ Seok 及其同事对表达阵列的跨物种比较为正在进行的对话注入了新的重要数据 (2)。正如 Perlman 及其同事的社论 (1) 中提出的方法论问题所强调的那样，证明小鼠和人类之间不存在关联是很困难的。鉴于 Seok 及其同事的文章的深远影响，对危重疾病感兴趣的临床医生和研究人员可能会从作者更加努力地“同类比较”中受益。我们建议另外两项实验将加强他们的结论，特别是关于白细胞对内毒素反应的差异。首先，Seok 及其同事发现，小鼠对内毒素的转录反应在 TLR4 下游立即显着减弱 (2)。因为小鼠版本的 TLR4 被认为是人类基因的真正直系同源物，这一令人惊讶的结果让我们想知道是否实现了充分的内毒素暴露，或者小鼠中高 TLR4 表达细胞（例如单核细胞）的转录特征是否被低表达细胞（例如淋巴细胞）淹没。如果 Seok 和同事能够调整内毒素的剂量或持续时间，以在他们自己的读数中实现可比的 TLR4 信号反应，那么随后的阴性结果将得到极大的支持。其次，Seok 及其同事可以比较不同物种间同源细胞类型对内毒素的转录反应，例如，用相同的内毒素血清型刺激的每个物种中分离出的单核细胞，在相当的剂量和暴露时间下进行分析。如果离体曲线出乎意料地相似，那么读者就可以更深入地解释体内的差异，例如，通过提高小鼠和人类对内毒素的反应在最初的分子事件中不会出现分歧的可能性，而是在它们对体内发现的细胞间网络的后续影响中出现分歧。总的来说，我们赞扬 Seok 和同事对小鼠脓毒症模型问题采取的细致入微的方法。我们相信，有充足的证据支持使用小鼠作为发现工具，但未来脓毒症的机制研究应强调在人类环境中的早期验证 (5)。该领域的基础和临床研究人员不应推迟概念验证人体研究，而应尽早进行广泛合作，以确保最“可转化”的科学不断向前发展。
1264 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 188 2013 by the 2011 Nobel Prize in Physiology or Medicine (4). How should the scientific community resolve this paradox? The cross-species comparison of expression arrays by Seok and colleagues has injected new, important data into this ongoing conversation (2). Proving the absence of an association between mouse and human is difficult, as highlighted by the methodological issues raised in Perlman and colleagues’ editorial (1). Given the profound implications of Seok and colleagues’ article, clinicians and researchers interested in critical illness would have benefited from an even more intense effort by the authors to compare “apples to apples.” We propose that two additional experiments would have strengthened their conclusions, particularly regarding the dissimilarity in leukocyte responses to endotoxin. First, Seok and colleagues showed that the mouse transcriptional response to endotoxin was markedly attenuated immediately downstream of TLR4 (2). Because the murine version of TLR4 is considered the true ortholog of the human gene, this surprising result made us wonder whether an adequate exposure to endotoxin was achieved or whether the transcriptional signature of high-TLR4-expressing cells in mice (eg, monocytes) was swamped out by lower-expressing cells (eg, lymphocytes). Had Seok and colleagues been able to adjust endotoxin dose or duration to achieve comparable TLR4 signaling responses in their own readout, the subsequent negative findings would have been greatly bolstered. Second, Seok and colleagues could have compared transcriptional responses to endotoxin of homologous cell types between species—for example, monocytes isolated from each species stimulated with the same endotoxin serotype analyzed at comparable doses and durations of exposure. Had the ex vivo profiles been unexpectedly similar, readers could then have interpreted the in vivo dissimilarity more deeply, for example, by raising the possibility that mouse and human responses to endotoxin do not diverge at the initial molecular events, but rather, in their subsequent effects on the intercellular network found within the body. Overall, we commend Seok and colleagues on their nuanced approach to the mouse-as-sepsis-model question. We believe that ample evidence exists to support use of the mouse as a discovery tool, but that future mechanistic studies in sepsis should emphasize early validation in the human setting (5). Rather than delaying proof-of-concept human studies, basic and clinical researchers in this field should collaborate early and extensively to ensure that the most “translatable” science is moving forward.