PNAS：小鼠模型不能很好模拟人类炎症疾病

数十年以来，在进行人体试验之前，实验小鼠模型一直被用于确认和测试候选药物，但是一项研究发现这些模型不能准确地代表人类对炎症疾病的响应。

Junhee Seok及其同事研究了创伤、烧伤和来自例如大肠杆菌等细菌的毒素是如何影响病人的遗传应答的。这组作者将观察到的模式与在小鼠模型中观察到的模式进行了比较。他们确定了来自这些小鼠模型的模式与人类响应模式匹配得不好，以至于这些结果看上去像是随机的。人类和小鼠的进化距离、小鼠对炎症刺激的显著抵抗以及其他因素可能解释了为什么这些模型不能重现人类情境。

他们呼吁在分子和遗传层次上开展着重于人类生理学和疾病如何影响人类的生物医学研究方法，而不是主要依靠小鼠模型。一个有前景的发现是，因为创伤、烧伤或其他疾病而遭受炎症的病人表现出了类似的遗传应答，尽管造成这些疾病的原因截然不同而且这些病人接受了不同的疗法。研究者说，这些发现还提示针对多个截然不同的炎症疾病的药物可能为大批病人带来改良的疗法。

doi:10.1073/pnas.1222878110
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Genomic responses in mouse models poorly mimic human inflammatory diseases

Junhee Seok, H. Shaw Warren, Alex G. Cuenca, Michael N. Mindrinos, Henry V. Baker, Weihong Xu, Daniel R. Richards, Grace P. McDonald-Smith, Hong Gao, Laura Hennessy, Celeste C. Finnerty, Cecilia M. López, Shari Honari, Ernest E. Moore, Joseph P. Minei, Joseph Cuschieri, Paul E. Bankey, Jeffrey L. Johnson, Jason Sperry, Avery B. Nathens, Timothy R. Billiar, Michael A. West, Marc G. Jeschke, Matthew B. Klein, Richard L. Gamelli, Nicole S. Gibran, Bernard H. Brownstein, Carol Miller-Graziano, Steve E. Calvano, Philip H. Mason, J. Perren Cobb, Laurence G. Rahme, Stephen F. Lowry, Ronald V. Maier, Lyle L. Moldawer, David N. Herndon, Ronald W. Davis, Wenzhong Xiao, Ronald G. Tompkins

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.