军事医学2026，Vol.50Issue(1)：17-23,7.DOI:10.7644/j.issn.1674-9960.2025-00139
库普弗细胞在对乙酰氨基酚诱导的急性肝损伤中的变化及功能研究
Dynamic changes and functional roles of Kupffer cells in acetaminophen-induced acute liver injury
摘要
Abstract
Objective To elucidate the spatiotemporal dynamics of Kupffer cells(KCs)in acetaminophen(APAP)-induced acute drug-induced liver injury and their regulatory mechanisms governing regional hepatocyte regeneration.Methods A Clec4f-iCre&Rosa26-tdTomato lineage-tracing mouse model was established to specifically label KCs.Acute liver injury was induced via intraperitoneal injection of acetaminophen(APAP,400 mg/kg).Liver tissues and blood samples were collected at 0,1,2,3 and 7 days post-APAP administration.Histopathological examinations(H&E staining,TUNEL assay for apoptosis detection),serum biochemical analyses(ALT and AST),and immunofluo-rescence staining were employed to find out about the spatiotemporal migration patterns of KCs,their phenotypic transition,and spatiotemporal correlations between KC dynamics and hepatocyte regeneration.Results On day 1(D1)post-APAP injury,extensive hepatocyte necrosis and apoptosis were observed in the pericentral(PC)zone,accompanied by a reduction in KCs count and their migration from the periphery toward the necrotic core.From D2 onward,repair started,with the necrotic area progressively decreasing.By D3,inflammatory cell infiltration was pronounced in the PC zone,concurrent with a peak in hepatocyte proliferation(Ki67⁺cells:approximately 22%,P<0.05).During repair,monocytes(CD11b⁺IBA-1⁻)differentiated into monocyte-derived macrophages(CD11b⁺IBA-1⁺),which synergistically promoted the regeneration of cytochrome P4502E1(CYP2E1⁺)hepatocytes in the pericentral zone.By D7,the hepatic lobular architecture was largely restored,indicating the completion of reconstruction of metabolic zonation.Conclusion KCs can regulate hepatocyte regeneration through spatiotemporal dynamics and phenotypic transitions of monocyte-derived macrophages.These findings underscore the pivotal role of macrophage spatiotemporal reprogramming in liver injury repair and may provide data for developing macrophage-targeted therapeutic interventions in hepatic injury.关键词
药物性肝损伤/库普弗细胞/代谢分区/肝再生/对乙酰氨基酚Key words
drug-induced liver injury/Kupffer cells/metabolic zonation/hepatic regeneration/acetaminophen分类
医药卫生引用本文复制引用
张祥颂,王璇,曹延楠,王韫芳,闫军..库普弗细胞在对乙酰氨基酚诱导的急性肝损伤中的变化及功能研究[J].军事医学,2026,50(1):17-23,7.基金项目
清华大学精准医学战略项目(2022ZLA006) （2022ZLA006）
