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LPS诱导的炎症驱动型子痫前期小鼠模型中多器官炎症表型及转录组特征分析

王宁^1,2, 冯静秋², 谢英², 孙梦灿², 王琪², 王哲², 高路^2,*

¹上海大学医学院，上海 201900；²海军军医大学生理学教研室，上海 200433

摘要

子痫前期(preeclampsia, PE)是一种妊娠中晚期严重并发症，以高血压和蛋白尿为主要特征，其中免疫驱动亚型表现为胎盘促炎细胞因子过表达及慢性炎性损伤。为揭示此类PE亚型的病理机制，本研究通过腹腔注射脂多糖(lipopolysaccharide, LPS)构建炎症驱动的PE小鼠模型，系统评估母鼠心脏、肝脏、肺脏、肾脏及胎盘的组织病理变化，并整合转录组学分析以阐明分子机制。结果显示，LPS稳定诱导母鼠高血压和蛋白尿，再现PE核心表型，但对母鼠器官重量及胎儿体重无显著影响。组织学分析显示母体肺脏、肾脏及胎盘呈现显著炎性损伤，其中肺脏损伤最为严重，表现为炎性细胞浸润、肺泡壁增厚及间质水肿，挑战了传统PE研究中以胎盘和肾脏为核心靶器官的观点。胎盘迷路区及连接区显示广泛结构破坏与坏死，提示功能严重受损。转录组分析鉴定出27个炎症相关基因在多组织中一致上调，蛋白质相互作用网络进一步筛选出Il1β、Il6、Ccl5、Ccl2、Cxcl10、Tlr2 和Icam1 等关键基因。定量PCR验证表明，Tlr2在LPS诱导的PE小鼠肺组织、肾脏及胎盘中显著上调，而Cxcl10 在胎盘中特异性上调，提示两者在胎盘病理中可能形成协同炎症轴。本研究首次系统揭示了肺脏在炎症驱动型PE中的关键作用，重塑了对PE多器官炎性损伤的认识，并提出Tlr2 和Cxcl10 作为潜在诊断标志物与治疗靶点，为PE的精准干预提供了新视角。

关键词： 子痫前期; 炎症驱动; 肺损伤; 转录组分析; Tlr2/Cxcl10

Multi-organ inflammatory phenotypes and transcriptomic characterization in an inflammation-driven mouse model of preeclampsia induced by LPS

WANG Ning^1,2, FENG Jing-Qiu², XIE Ying², SUN Meng-Can², WANG Qi², WANG Zhe², GAO Lu^2,*

¹School of Medicine, Shanghai University, Shanghai 201900, China；²Department of Physiology, Naval Medical University, Shanghai 200433, China

Abstract

Preeclampsia (PE) is a severe gestational disorder characterized by hypertension and proteinuria, with a subset of cases exhibiting an immune-driven phenotype marked by placental overexpression of proinflammatory cytokines and chronic inflammatory damage, profoundly impacting fetal development. To elucidate the pathophysiology of this PE subtype, we established an inflammation-driven PE mouse model via lipopolysaccharide (LPS) intraperitoneal injection, systematically evaluating histopathological changes in maternal heart, liver, lung, kidney, and placenta, and integrating transcriptomic profiling to uncover molecular mechanisms. LPS administration robustly induced maternal hypertension and proteinuria, hallmarks of PE, without significantly altering organ or fetal weights. Histological analyses revealed pronounced inflammatory damage in the maternal lung, kidney, and placenta, with the lung exhibiting the most severe pathology, characterized by inflammatory cell infiltration, alveolar wall thickening, and interstitial edema—challenging the conventional focus on placental and renal primacy in PE. Placental labyrinth and junctional zones displayed extensive structural disruption and necrosis, indicating functional impairment. Transcriptomic analysis identified inflammation-related genes consistently upregulated across tissues, with protein-protein interaction networks pinpointing Il1β, Il6, Ccl5, Ccl2, Cxcl10, Tlr2, and Icam1 as hub genes. Quantitative PCR validation confirmed Tlr2 as a central regulator, evidenced by significant upregulation of Tlr2 in lung, kidney, and placenta of LPS-induced PE mice, while Cxcl10 exhibited placenta-specific upregulation, suggesting a synergistic inflammatory axis in placental pathology. These findings highlight the lung as a critical, yet underappreciated, target in inflammation-driven PE, reframe the multi-organ inflammatory landscape of the disease, and nominate Tlr2 and Cxcl10 as potential diagnostic biomarkers and therapeutic targets, offering new avenues for precision intervention in PE.

Key words: preeclampsia; inflammation-driven; lung injury; transcriptomic analysis; Tlr2/Cxcl10

收稿日期：　　录用日期：

通讯作者：高路　　E-mail:

DOI: 10.13294/j.aps.2025.0042

引用本文：

王宁, 冯静秋, 谢英, 孙梦灿, 王琪, 王哲, 高路. LPS诱导的炎症驱动型子痫前期小鼠模型中多器官炎症表型及转录组特征分析[J]. 生理学报 2025; 77 (5): 775-791.

WANG Ning, FENG Jing-Qiu, XIE Ying, SUN Meng-Can, WANG Qi, WANG Zhe, GAO Lu. Multi-organ inflammatory phenotypes and transcriptomic characterization in an inflammation-driven mouse model of preeclampsia induced by LPS. Acta Physiol Sin 2025; 77 (5): 775-791 (in Chinese with English abstract).