The Translational Value of Rodent Models of Sepsis.
The Translational Value of Rodent Models of Sepsis.
复制标题
脓毒症啮齿动物模型的转化价值。
DOI：
10.1164/rccm.202308-1489vp
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发表时间：
2024
影响因子：
24.7
通讯作者：
Martin,ThomasR
中科院分区：
文献类型：
--
作者：
Matthay,MichaelA;Schmidt,EricP;Bastarache,JulieA;Calfee,CarolynS;Frevert,CharlesW;Martin,ThomasR
脓毒症仍然是世界范围内发病率和死亡率的主要原因(1)，但在确定有效治疗方法方面进展缓慢(2)，这不仅反映了脓毒症临床表现的可变性（如休克、肾功能衰竭、呼吸衰竭、凝血功能障碍），也反映了患者水平的生物学异质性和致病过程的复杂性，导致了不同的临床表现。尽管人们普遍认为需要对脓毒症患者和动物模型的临床异质性进行更多的研究（https://www）。美国国家。国家卫生研究院。gov/News/Documents)，基于动物和人类基因组反应的差异，一些研究者质疑动物模型对这项研究的价值(3)，而另一些人则强调动物模型的重要性和进一步完善的必要性（4,5）。本观点阐述了小动物模型在败血症的正向和反向转化研究中的价值，特别关注它们在推进疾病发病机制的理解和新疗法的临床前测试方面的重要性，以及努力提高啮齿动物模型与人类败血症问题的相关性。在小鼠、大鼠和人类中，许多（但不是全部）对败血症和严重感染的生物学反应在进化上是保守的。尽管一些基因组反应不同，但在小鼠和人类的蛋白质组学、脂质组学和糖组学特征之间存在相似之处（3,6,7）。小鼠在解剖人类对感染的反应方面具有不可估量的价值，包括获得诺贝尔奖的toll样受体的发现(8)。此外，患有败血症的啮齿动物会出现急性器官衰竭，如呼吸衰竭和休克，并表现出器官损伤的异质性，就像在人类身上看到的那样。鉴于这些重要的相似性，败血症的啮齿动物模型为人类研究的科学基础（和理由）做出了贡献，这些研究导致了危重病人治疗的根本进步。大鼠和小鼠模型提供了关键的临床前证据（9,10），导致了具有里程碑意义的急性呼吸窘迫综合征（脓毒症的常见后遗症）肺保护性机械通气的临床试验，该试验确定死亡率绝对降低9%(40-31%)（11）。脓毒症小鼠模型证明了糖皮质激素的潜在价值（12），为最近的一项临床试验提供了临床前证据，该试验报告了氢化可的松对危重患者的严重社区获得性肺炎合并脓毒症的主要发病率和死亡率的益处（13）。小鼠研究已经提供了重要证据，证明细胞因子依赖通路在败血症和器官损伤中的重要性，包括IL-6通路的重要性，阻断IL-6通路已被证明有益于严重冠状病毒病（COVID-19）肺炎（14）。此外，小鼠模型对于开发应对COVID-19所需的疫苗和抗病毒疗法至关重要（15）。与所有模型一样，啮齿动物脓毒症模型也有局限性（4,5）。啮齿类动物模型通常不包含在患者身上看到的许多临床合并症或临床护理中使用的治疗方法，包括机械通气、血管加压剂和营养。然而，正在努力在小鼠实验中模拟合并症，包括使用年轻和老年小鼠；不同性别的小鼠；而患有糖尿病、肥胖或吸烟的小鼠，更接近于模拟人类败血症的异质性（16）。此外，啮齿动物模型的临床价值随着监测氧合能力的提高而提高，包括抗生素和液体治疗。
Sepsis remains a major cause of morbidity and mortality worldwide (1), but progress in identifying effective therapies has been slow (2), reflecting not only the variability of the clinical manifestations of sepsis (eg, shock, renal failure, respiratory failure, coagulopathy) but also the patient-level biological heterogeneity and complexity of the pathogenic processes responsible for varied clinical manifestations. Although there is a widely accepted need for more research into the clinical heterogeneity of sepsis in both patients and animal models (https://www. nigms. nih. gov/News/Documents), the value of animal models to this research effort has been questioned by some investigators on the basis of differences in genomic responses between animals and humans (3), whereas others have stressed the importance of animal models and the need for further refinements (4, 5). This Viewpoint addresses the value of small animal models in both forward-and reverse-translational investigations of sepsis, with specific attention to their importance in advancing the understanding of disease pathogenesis and preclinical testing of new therapeutics, as well as efforts to improve the relevance of rodent models for the problem of human sepsis. Many, but not all, biological responses to sepsis and severe infection are evolutionarily conserved in mice, rats, and humans. Although some genomic responses differ, there are similarities between proteomic, lipidomic, and glycomic signatures in mice and humans (3, 6, 7). Mice have been invaluable in dissecting human responses to infection, including the Nobel Prize–winning discovery of Toll-like receptors (8). Moreover, rodents with sepsis develop acute organ failures, such as respiratory failure and shock, and demonstrate heterogeneity in organ injury, as seen in humans. Given these important similarities, rodent models of sepsis have contributed to the scientific foundations of (and justification for) human studies that have led to fundamental advances in therapy of critically ill patients. Rat and mouse models provided the critical preclinical evidence (9, 10) that led to the landmark clinical trial of lungprotective mechanical ventilation for acute respiratory distress syndrome, a common sequela of sepsis, which identified a 9% absolute decrease in mortality (40–31%)(11). Mouse models of sepsis demonstrated the potential value of glucocorticoids (12), providing preclinical evidence supporting a recent clinical trial that reported the major morbidity and mortality benefit of hydrocortisone in severe communityacquired pneumonia with sepsis in critically ill patients (13). Mouse studies have provided important evidence about the importance of cytokine-dependent pathways in sepsis and organ injury, including the importance of the IL-6 pathway, the blockade of which has proven to benefit severe coronavirus disease (COVID-19) pneumonia (14). Furthermore, mouse models were critical for developing vaccines and antiviral therapies necessary to respond to COVID-19 (15).Like all models, rodent models of sepsis have limitations (4, 5). Rodent models do not typically incorporate the many clinical comorbidities seen in patients or the treatments used in clinical care, including mechanical ventilation, vasopressors, and nutrition. However, efforts are being made to model comorbidities in mouse experiments, including using mice of younger and older ages; mice of different genders; and mice with diabetes, obesity, or cigarette smoke exposure, to more closely mimic the heterogeneity of human sepsis (16). In addition, the clinical value of rodent models has improved with the ability to monitor oxygenation and include antibiotics and fluid therapy …