Qin Kang, Liang Weiqiang, Fragoulis Athanassios, Yan Weining, Zhang Xing, Zhao Qun, Ma Chunxia, He Zhizhen, Buhl Eva Miriam, Li You, Greven Johannes
Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, Aachen, Germany.
Experimental Orthopaedics and Trauma Surgery, Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH Aachen University Hospital, Aachen, Germany.
Eur J Trauma Emerg Surg. 2025 May 23;51(1):218. doi: 10.1007/s00068-025-02890-y.
The aim of this study was to explore how sulforaphane (SFN), a well-known nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activator, regulates hepatic autophagy and apoptosis by modulating the polarization of Kupffer cells via the Nrf2/HO-1 pathway in a hemorrhagic shock/resuscitation (HS/R) model in mice.
Male c57/BL6 mice were subjected to hemorrhagic shock (HS) for 90 min under blood pressure control. Resuscitation was performed by reinfusing the withdrawn blood and infusing 0.9% NaCl, and SFN was administered intraperitoneally. All animals were euthanized 24 h after resuscitation, and liver tissue samples were collected for TUNEL staining, western blot analysis, immunohistochemical staining, immunofluorescence staining, and observation using transmission electron microscopy (TEM). Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was performed to verify the SFN distribution in the liver.
SFN reached the liver within the first hour after it was injected. SFN was found to promote the hepatic Nrf2/HO-1 pathway and the polarization of Kupffer cells to the M2 phenotype rather than the M1 phenotype after HS/R. Furthermore, SFN inhibited hepatic apoptosis after HS/R, as demonstrated by a decrease in the Bax/Bcl-2 ratio, fewer TUNEL-positive cells, and changes in cleaved caspase 3 expression. Enhanced hepatic autophagy was observed after HS/R, as shown by an increase in the number of autophagosomes, a higher LC3-II/LC3-I ratio, and decreased expression of p62 and beclin-1.
In this study, SFN administration inhibited hepatic apoptosis and promoted hepatic autophagy by inducing Kupffer cells to polarize to the M2 phenotype rather than the M1 phenotype via the Nrf2/HO-1 pathway.
本研究旨在探讨萝卜硫素（SFN），一种著名的核因子红细胞2相关因子2（Nrf2）通路激活剂，如何通过在小鼠失血性休克/复苏（HS/R）模型中经由Nrf2/HO-1通路调节库普弗细胞极化，从而调控肝脏自噬和凋亡。
雄性C57/BL6小鼠在血压控制下经历90分钟的失血性休克（HS）。通过回输抽出的血液并输注0.9%氯化钠进行复苏，并腹腔注射SFN。所有动物在复苏后24小时实施安乐死，收集肝脏组织样本用于TUNEL染色、蛋白质免疫印迹分析、免疫组织化学染色、免疫荧光染色以及使用透射电子显微镜（TEM）进行观察。采用基质辅助激光解吸/电离质谱成像（MALDI-MSI）来验证SFN在肝脏中的分布。
注射后1小时内SFN到达肝脏。研究发现，HS/R后SFN可促进肝脏Nrf2/HO-1通路以及库普弗细胞向M2表型而非M1表型极化。此外，HS/R后SFN抑制肝脏凋亡，表现为Bax/Bcl-2比值降低、TUNEL阳性细胞减少以及裂解的半胱天冬酶3表达变化。HS/R后观察到肝脏自噬增强，表现为自噬体数量增加、LC3-II/LC3-I比值升高以及p62和贝林1表达降低。
在本研究中，给予SFN可通过诱导库普弗细胞经由Nrf2/HO-1通路向M2表型而非M1表型极化，从而抑制肝脏凋亡并促进肝脏自噬。
