A rodent model of intra-amniotic inflammation/infection, induced by the administration of inflammatory agent in a gestational sac, associated with preterm delivery: a systematic review

Rodents are the most commonly used animals in the study of spontaneous preterm delivery (PTD). Intra-amniotic inflammation/infection is a frequent and important cause of PTD. Intraperitoneal and intrauterine administrations of inflammatory agents are traditional methods to establish a rodent model of PTD associated with inflammation and infection. The intra-amniotic administration of inflammatory or infectious triggering agents to rodents can be useful to study not only intra-amniotic inflammatory response but also PTD associated with intra-amniotic inflammation/infection. This systematic review aimed mainly to assess and analyze all described methods of intra-amniotic administration of infectious and/or inflammatory agents to create a rodent model of intra-amniotic inflammation associated with PTD. A literature search through two electronic databases from their earliest entries to February 2019 was performed. The selection criteria were as follows: (1) rodents as model animals, (2) a model of intra-amniotic inflammation/infection associated with PTD, and (3) intra-amniotic administration of triggering agents. Data extraction included specification of the study (author and year of publication), characteristics of study animals (species, strain, and number of animals), characteristics of intervention (timing and used technique), substance used for induction of intra-amniotic inflammation/infection, and outcome assessment. The search identified a total of 4673 articles, of which 118 were selected for full-text reading, but only 13 studies were included in the review. Intra-amniotic administration was used only in the articles that were published beyond 2004. Two different approaches were identified: (1) open surgery with direct puncture of the amniotic sacs and (2) transabdominal ultrasound-guided puncture of the gestational sacs. Live microorganisms (<i>Ureaplasma parvum</i>), bacterial products (extracellular membrane vesicles), and pathogen-associated (lipopolysaccharide) and damage-associated molecular patterns (high mobility group box-1, S100B, and surfactant protein A) were used to simulate intra-amniotic inflammation/infection. Differences in the effect on intra-amniotic inflammation/infection associated with PTD in the mouse model were identified among triggering agents. Intra-amniotic application of lipopolysaccharide in the rat model caused intra-amniotic inflammation, but it did not lead to PTD. The intra-amniotic administration of the triggering agents can be used to study intra-amniotic inflammatory response and intra-amniotic inflammation/infection in the rodents model.

啮齿类动物是自发性早产（spontaneous preterm delivery, PTD）研究中最常用的实验动物。羊膜腔内炎症/感染（intra-amniotic inflammation/infection）是引发PTD的常见且关键诱因。传统构建与炎症、感染相关PTD啮齿类动物模型的方法为腹腔内与子宫内给予炎性制剂。而对啮齿类动物实施羊膜腔内给予炎性或感染性触发剂的造模策略，不仅可用于探究羊膜腔内炎症反应，亦能为研究与羊膜腔内炎症/感染相关的PTD提供支撑。
本系统综述旨在系统性评估并分析所有已报道的、通过羊膜腔内给予感染性和/或炎性制剂以构建与PTD相关的羊膜腔内炎症啮齿类动物模型的方法。研究检索了2个电子数据库自建库至2019年2月的全部相关文献。纳入标准如下：（1）实验动物为啮齿类；（2）构建与PTD相关的羊膜腔内炎症/感染模型；（3）采用羊膜腔内给予触发剂的造模方式。
数据提取涵盖研究基本信息（作者及发表年份）、实验动物特征（物种、品系及动物数量）、干预措施特征（干预时机与操作技术）、用于诱导羊膜腔内炎症/感染的制剂类型，以及结局评估指标。
本次检索共获取4673篇文献，其中118篇经全文阅读后进行详细评估，但最终仅13项研究被纳入本综述。所有采用羊膜腔内给药造模的文献均发表于2004年之后。研究共识别出两种不同的给药途径：（1）开放式手术直接穿刺羊膜囊；（2）经腹超声引导下穿刺妊娠囊。
研究中用于模拟羊膜腔内炎症/感染的制剂包括活微生物（微小脲原体<i>Ureaplasma parvum</i>）、细菌产物（细胞外膜囊泡）、病原体相关分子模式（代表性物质为脂多糖（lipopolysaccharide））以及损伤相关分子模式（涵盖高迁移率族蛋白B1（high mobility group box-1）、S100B及表面活性蛋白A）。
不同触发剂对小鼠模型中与PTD相关的羊膜腔内炎症/感染的调控效果存在显著差异。在大鼠模型中，经羊膜腔内给予脂多糖可诱发羊膜腔内炎症，但无法诱导PTD。综上，羊膜腔内给予触发剂的方法可有效应用于啮齿类动物模型的羊膜腔内炎症反应及羊膜腔内炎症/感染相关研究。