背景:动物实验研究对肿瘤坏死因子(TNF)在脓毒症和内毒素血症中的作用产生了相互矛盾的结果,一些人报告了适应性,另一些人报告了不适当的效果。对现有文献进行荟萃分析,以确定解释这种差异的因素。
方法:本研究遵循系统评价和荟萃分析(PRISMA)声明的首选报告项目。该协议在数据收集之前在PROSPERO(CRD42020167384)注册。PubMed和Embase是查询的数据库。使用SYRCLE偏差风险工具评估偏差风险。所有调查脓毒症相关死亡率和改良TNF信号的动物研究都被认为是合格的。排除标准是: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%,没有英文摘要。根据实验方案确定TNF的作用,使用了三种方法:第一种是基于每个实验的统计意义的方法,然后计算汇总死亡率,最后评估了死亡率的加权风险比。
结果:共175项研究纳入分析,总共包括760个实验,涉及19,899只动物。使用的主要物种是小鼠(77%)和大鼠(21%)。TNF途径调节的最常见方法是TNF途径失活,其主要与TNF的不适当分泌有关。在对面,TNF注射与TNF的适应性作用相关。脂多糖(LPS)注射是建立感染模型的最常用刺激(42%),并且与TNF的不适当作用密切相关。相反,活细菌模型,尤其是盲肠结扎和穿孔(CLP)模型,肺炎,脑膜炎,和胃肠道感染,与适应性角色相关。这对单核细胞增生李斯特菌尤其明显,肺炎链球菌。
结论:TNF在感染过程中的作用因使用的实验模型而异。模拟临床条件的模型,基于即使在低接种量下也会导致高死亡率的有毒细菌,证明了TNF的适应性作用。相反,基于LPS或低致病性活菌的模型,以远高于生理阈值的剂量给药,并结合早期抗生素治疗,与不适当的角色有关。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.