Emergency Department, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France.
Department of Anesthesiology and Surgical Intensive Care, DMU PARABOL, AP-HP, Hôpital Bichat, 75018, Paris, France.
Crit Care. 2024 Sep 4;28(1):293. doi: 10.1186/s13054-024-05057-0.
Experimental studies in animals have yielded conflicting results on the role of Tumor Necrosis Factor (TNF) in sepsis and endotoxemia, with some reporting adaptive and others inappropriate effects. A meta-analysis of the available literature was performed to determine the factors explaining this discrepancy.
The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered with PROSPERO (CRD42020167384) prior to data collection. PubMed and Embase were the databases queried. Risk of bias was evaluated using the SYRCLE Risk of Bias Tool. All animal studies investigating sepsis-related mortality and modified TNF signaling were considered eligible. The exclusion criteria were: lack of mortality data, 7-day mortality rates below 10% in both wild type and TNF-altered pathway animals, and absence of an English abstract. To determine the role of TNF according to the experimental protocol, three approaches were used: first an approach based on the statistical significance of each experiment, then the pooled mortality was calculated, and finally the weighted risk ratio for mortality was assessed.
A total of 175 studies were included in the analysis, comprising a total of 760 experiments and involving 19,899 animals. The main species used were mice (77%) and rats (21%). The most common method of TNF pathway modulation was TNF pathway inactivation that was primarily associated with an inappropriate secretion of TNF. At the opposite, TNF injection was associated with an adaptive role of TNF. Lipopolysaccharide (LPS) injection was the most used stimulus to establish an infectious model (42%) and was strongly associated with an inappropriate role of TNF. Conversely, live bacterial models, especially the cecal ligation and puncture (CLP) model, pneumonia, meningitis, and gastrointestinal infection, were associated with an adaptive role. This was particularly evident for Listeria monocytogenes, Streptococcus pneumoniae.
The role of TNF during infection varies depending on the experimental model used. Models that mimic clinical conditions, based on virulent bacteria that cause high mortality even at low inocula, demonstrated an adaptive role of TNF. Conversely, models based on LPS or low-pathogenic live bacteria, administered at doses well above physiological thresholds and combined with early antibiotic therapy, were associated with an inappropriate role.
动物实验研究表明，肿瘤坏死因子（TNF）在脓毒症和内毒素血症中的作用存在矛盾，一些研究报告 TNF 具有适应性作用，而另一些则报告其具有不适当的作用。对现有文献进行了荟萃分析，以确定解释这种差异的因素。
本研究遵循系统评价和荟萃分析的首选报告项目（PRISMA）声明。在收集数据之前，该方案已在 PROSPERO（CRD42020167384）中进行了注册。查询了 PubMed 和 Embase 数据库。使用 SYRCLE 偏倚风险工具评估了偏倚风险。所有研究脓毒症相关死亡率和 TNF 信号转导改变的动物实验均符合纳入标准。排除标准为：缺乏死亡率数据、野生型和 TNF 改变途径动物的 7 天死亡率均低于 10%，以及缺乏英文摘要。为了根据实验方案确定 TNF 的作用，采用了三种方法：首先是基于每个实验的统计学意义的方法，然后计算汇总死亡率，最后评估死亡率的加权风险比。
共纳入 175 项研究，共涉及 760 项实验，涉及 19899 只动物。主要使用的物种是小鼠（77%）和大鼠（21%）。TNF 途径调节的最常见方法是 TNF 途径失活，主要与 TNF 不适当分泌有关。相反，TNF 注射与 TNF 的适应性作用有关。脂多糖（LPS）注射是建立感染模型最常用的刺激物（42%），与 TNF 的不适当作用强烈相关。相反，活体细菌模型，特别是盲肠结扎和穿孔（CLP）模型、肺炎、脑膜炎和胃肠道感染，与适应性作用相关。这在李斯特菌、肺炎链球菌等方面尤为明显。
TNF 在感染过程中的作用取决于所使用的实验模型。模拟临床条件的模型，基于高死亡率的毒力细菌，即使在低接种量下，也显示出 TNF 的适应性作用。相反，基于 LPS 或低致病性活体细菌的模型，在远高于生理阈值的剂量下给药，并结合早期抗生素治疗，与不适当的作用相关。
