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| 黄芪多糖调控巨噬细胞极化治疗肝纤维化的机制研究 |
| Mechanism research of astragalus polysaccharide on treating hepatic fibrosis via regulating macrophage polarization |
| 投稿时间：2024-03-22 修订日期：2024-03-22 |
| DOI： |
| 中文关键词: 黄芪多糖 四氯化碳 肝纤维化 TGF-β1/Smad2信号通路 巨噬细胞极化 |
| 英文关键词: Astragalus polysaccharide C-C chemokine ligand 4 Hepatic fibrosis TGF-β1/Smad2 signaling pathway Macrophage polarization |
| 基金项目:国家自然科学基金基于Hepcidin-FPN1轴探讨定心方调控铁稳态失衡防治动脉粥样硬化的机制研究,编号82374367；江西省教育厅科学技术研究项目基于巨噬细胞极化探讨定心方防治动脉粥样硬化机制,编号20232BAB206144；浙江省中医药卫生科技计划项目基于Let-7a探讨健脾养阴活血法对慢性萎缩性胃炎癌前病变的作用机制,编号2021FSYYZZ25 |
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| 中文摘要: |
| 目的：探讨黄芪多糖(APS)对四氯化碳(CCl4)诱导的肝纤维化(HF)大鼠的治疗作用及分子机制。方法：SD大鼠50只皮下注射CCl4建立HF动物模型,随机分为5组,每组10只。除HF模型组外,其余4组分别给予秋水仙碱 0.2 mg/kg/d和APS 200,400,800 mg/kg/d灌胃。另以SD大鼠10只设为对照组。放射免疫法检测血清III型前胶原(PCIII)、IV型胶原(IV-C)、透明质酸酶(HA)、层粘连蛋白(LN)水平；生化法检测血清丙氨酸氨基转移酶(ALT)、天冬氨酸转氨酶(AST)、总胆红素(TBIL)水平；酶联免疫吸附试验检测血清肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、白细胞介素-1β(IL-1β)水平；苏木精-伊红染色观察肝脏组织病理变化；定量实时聚合酶链式反应检测肝脏组织中诱导型一氧化氮合酶(iNOS)和精氨酸酶1(Arg-1)的mRNA表达；免疫印迹检测肝脏组织中转化生长因子-β1(TGF-β1)、磷酸化-Smad2(p-Smad2)蛋白表达。结果：与对照组比较,HF大鼠肝脏组织出现明显纤维化病理改变及炎性浸润,血清PCIII、IV-C、HA、LN、ALT、AST、TBIL、TNF-α、IL-6、IL-1β水平、肝脏组织iNOS的mRNA表达、TGF-β1、p-Smad2蛋白表达均显著增高,Arg-1的mRNA表达显著降低(P<0.01)。与HF模型组比较,APS可显著减轻大鼠肝脏组织纤维化病理改变及炎性浸润,降低血清PCIII、IV-C、HA、LN、ALT、AST、TBIL、TNF-α、IL-6、IL-1β水平、肝脏组织iNOS的mRNA、TGF-β1、p-Smad2蛋白表达,并显著增加肝脏组织Arg-1的mRNA表达(P<0.05或P<0.01)。与秋水仙碱组比较,APS高、低剂量组大鼠肝脏组织病理损伤显著加重,血清PCIII、IV-C、HA、LN、ALT、AST、TBIL、TNF-α、IL-6、IL-1β水平及肝脏组织iNOS的mRNA、TGF-β1、p-Smad2蛋白表达均显著升高,肝脏组织Arg-1的mRNA表达显著降低(P<0.05或P<0.01)。结论：APS可通过减少巨噬细胞向M1型极化,从而减轻由CCl4诱导的炎症反应以治疗HF,其机制与抑制TGF-β1/Smad2信号通路活化有关。 |
| 英文摘要: |
| Objective: To investigate the therapeutic effect and molecular mechanism of astragalus polysaccharide (APS) on C-C chemokine ligand 4 (CCl4)-induced hepatic fibrosis (HF). Methods: Fifty SD rats were subcutaneously injected with CCl4 to establish the animal model of HF and were randomly divided into 5 groups. Except HF model group, the other 4 groups were given colchicine 0.2 mg/kg/d and APS 800, 400, 200 mg/kg/d by gavage. And 10 SD rats were set as control group. Serum levels of peucedanocoumarin III (PCIII), type IV collagen (IV-C), hyaluronic acid (HA) and laminin (LN) were detected by radioimmunoassay. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels were detected by biochemical method. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by enzyme linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to observe the pathological changes of liver tissues. The mRNA expressions of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) were determined by qRT-PCR. The expressions of transforming growth factor-β1 (TGF-β1) and phosphorylated-Smad2 (p-Smad2) in liver tissues were detected by Western blot. Results: Compared with control group, the liver tissue of HF rats showed obvious fibrosis pathological changes and inflammatory infiltration, the serum levels of PCIII, IV-C, HA, LN, ALT, AST, TBIL, TNF-α, IL-6 and IL-1β, iNOS mRNA expression, TGF-β1 and p-Smad2 protein expression were elevated, the Arg-1 mRNA expression was reduced (P<0.01). Compared with HF model group, APS significantly alleviated the fibrosis pathological changes and inflammatory infiltration in liver tissues, decreased the serum levels of PCIII, IV-C, HA, LN, ALT, AST, TBIL, TNF-α, IL-6 and IL-1β, iNOS mRNA expression, TGF-β1 and p-Smad2 protein expression in liver tissues, while increased the Arg-1 mRNA expression in liver tissues (P<0.05 or P<0.01). Compared with colchicine group, the pathological injury of liver tissue in APS high and low dose groups was significantly aggravated, serum levels of PCIII, IVC, HA, LN, ALT, AST, TBIL, TNF-α, IL-6, IL-1β and iNOS mRNA, TGF-β1 and p-Smad2 protein expressions in liver were significantly increased, while the Arg-1 mRNA in liver was significantly decreased (P<0.05 or P<0.01). Conclusion: APS could reduce the fibrosis pathological changes and inflammatory infiltration induced by CCl4 to treat HF by reducing macrophage polarization to M1 type, and the mechanism is related to the inhibition of TGF-β1/Smad2 signaling pathway activation. |
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