目的 探讨丹参水提物对肝窦阻塞综合征（hepatic sinusoidal obstruction syndrome，HSOS）的作用及机制。方法 以野百合碱诱导大鼠HSOS，给予丹参水提物后，通过血清生化指标检测、肝脏病理切片观察以及肝组织基质金属蛋白酶9（metalloproteinase-9，MMP-9）蛋白表达测定，评价丹参水提物对HSOS的抑制作用。通过TCMSP、HERB与GeneCards等数据库交联分析，获取丹参水提物抑制HSOS的关键靶点，并应用STRING与DAVID等数据库富集信号通路；进一步采用qRT-PCR与Western blotting对数据库结果予以验证。结果 与模型组比较，丹参水提物可显著抑制野百合碱诱导的大鼠血清中天冬氨酸氨基转移酶（aspartate aminotransferase，AST）和丙氨酸氨基转移酶（alanine aminotransferase，ALT）活力（P＜0.05、0.01），降低肝脏MMP-9蛋白表达（P＜0.05），并改善肝窦充血、中央静脉内皮脱落、III区肝细胞坏死等病变。网络药理学分析筛选得到核因子E2相关因子2（nuclear factor erythroid 2-related factor 2，Nrf2）、血红素氧合酶-1（heme oxygenase-1，HO-1）、核因子-κB p65（nuclear factor-κB p65，NF-κB p65）、肿瘤坏死因子（tumor necrosis factor，TNF）、白细胞介素-6（interleukin-6，IL-6）、IL-1β以及一氧化氮合酶2（nitricoxide synthase 2，NOS2）等关键基因，京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）分析结果表明，以上靶基因主要富集于活性氧（reactive oxygen species，ROS）、TNF和NF-κB等信号通路。丹参水提物可降低野百合碱诱导的丙二醛（malondialdehyde，MDA）和ROS含量（P＜0.05、0.01），减少F4/80、Ly6G阳性细胞浸润数目（P＜0.05、0.01），诱导Nrf2核转位（P＜0.01），促进谷氨酰半胱氨酸连接酶催化亚单位（catalytic subunit of glutamate-cysteine ligase，GCLC）、谷氨酸-半胱氨酸连接酶修饰亚基（glutamate-cysteine ligase modifier subunit，GCLM）、HO-1及醌氧化还原酶1（quinone oxidoreductase 1，NQO1）等基因的表达（P＜0.05、0.01、0.001），升高GCLC、GCLM、HO-1蛋白表达水平（P＜0.05、0.001）；并抑制NF-κB核转位（P＜0.001），降低TNF、IL-1β、IL-6、NOS2、环氧合酶-2（cyclooxygenase-2，COX-2）基因表达（P＜0.05、0.001），升高TNF-α、IL-1β、磷酸化NF-κB抑制蛋白（phosphorylated inhibitor of NF-κB，p-IκB）蛋白表达水平（P＜0.05、0.001）。结论 丹参水提物可通过激活Nrf2抗氧化信号通路，抑制NF-κB炎性信号通路，而抑制野百合碱诱导的HSOS。

Objective To explore the effct and mechanism of Salvia miltiorrhiza water extract (SWE) on inhibiting hepatic sinusoidal obstruction syndrome (HSOS). Methods Monocrotaline (MCT) was used to induce HSOS in rats, SWE was given for protection. The effect of SWE on inhibiting HSOS was evaluated through detection of serum biochemical indicators, observation of liver pathological sections, and determination of matrix metalloproteinase-9 (MMP-9) expression in liver tissue. Through cross-linking analysis of databases such as TCMSP, HERB and GeneCards, the key targets of SWE in inhibiting HSOS were obtained and databases such as STRING and DAVID were used to enrich signaling pathways. qRT-PCR and western-blotting were further used to verify the database results. Results Compared with model group, SWE significantly inhibited the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities in serum of rats induced by MCT (P < 0.05, 0.01), decreased MMP-9 expression in liver (P < 0.05), alleviated hepatic sinusoidal congestion, central vein endothelial shedding and zone III hepatocyte necrosis. Key genes were screened by network pharmacology analysis, including nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor-κB p65 (NF-κB p65), tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1β, nitric oxide synthase 2 (NOS2), etc. Kyoto encyclopedia of genes and genomes (KEGG) analysis results showed that the above target genes were mainly enriched in signaling pathways such as reactive oxygen species (ROS), TNF and NF-κB. SWE reduced the contents of malondialdehyde (MDA) and ROS induced by MCT (P < 0.05, 0.01), reduced the number of F4/80 and Ly6G positive cell infiltration (P < 0.05, 0.01), induced Nrf2 nuclear translocation (P < 0.01), and promoted the gene expressions of catalytic subunit of glutamate-cysteine ligase (GCLC), glutamate cysteine ligase modifier subunit (GCLM), HO-1, and quinone oxidoreductase 1 (NQO1) (P < 0.05, 0.01, 0.001), increased the protein expression levels of GCLC, GCLM and HO-1 (P < 0.05, 0.001), inhibited NF-κB nuclear translocation (P < 0.001), reduced TNF, IL-1β,IL-6, NOS2, cyclooxygenase-2 (COX-2) gene expressions (P < 0.05, 0.001), increased TNF-α, IL-1β and phosphorylated inhibitor of NF-κB (p-IκB) protein expression levels (P < 0.05, 0.001). Conclusion SWE can inhibit NF-κB inflammatory signaling pathway by activating Nrf2 antioxidant signaling pathway, and inhibit HSOS induced by MCT.

国家中医药管理局中医药传承与创新“百千万”人才工程青年岐黄学者计划；上海市浦江人才计划项目（22PJ1412900）