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虫草菌丝通过抑制TLR4/NF-κB信号通路与血管生成素样蛋白4对肝纤维化小鼠模型的保护作用
DOI: 10.3969/j.issn.1001-5256.2022.07.016
伦理学声明：本研究方案于2021年1月15日通过上海中医药大学实验动物伦理委员会审查，伦理编号PZSHUTCM210115005，符合实验室动物管理与使用准则。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：张霖璋负责课题设计，资料分析，撰写论文；张定棋、徐莹、杨海琳、戚胜兰、张聪聪、陈佳美参与收集数据，修改论文；刘平、刘伟负责拟定写作思路，指导撰写文章并最后定稿。
Cultured mycelia of Cordyceps sinensis exerts a protective effect on a mouse model of liver fibrosis by inhibiting the Toll-like receptor 4/nuclear transcription factor-κB signaling pathway and angiopoietin-like protein 4
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摘要:
目的 探究虫草菌丝对CCl4诱导的肝纤维化小鼠模型的干预作用，及对Toll样受体4(TLR4)/核转录因子-κB(NF-κB)通路与血管生成素样蛋白4(ANGPTL4)的影响。 方法 将60只SPF级雄性C57/BL6J小鼠随机分为正常组、模型组、扶正化瘀方组及虫草菌丝低、中、高剂量组，每组各10只。模型组和各用药组注射15% CCl4-橄榄油，造模6周。在第4周首日开始给药，连续3周。分别采用血生化法检测小鼠血清ALT、AST、TBil水平或活性，HE和SR染色观察肝组织病理学，碱水解法测定肝组织羟脯氨酸(HYP)含量情况，PCR检测α-SMA、Col-Ⅰ的mRNA表达情况，免疫组化测定肝组织α-SMA、Col-Ⅰ与ANGPTL4蛋白表达，Western Blot检测α-SMA、ANGPTL4、TLR4、NF-κB/P-NF-κB、CD163蛋白的表达。计量资料多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。 结果 与正常组比较，模型组小鼠血清ALT、AST、TBil水平均显著增加(P值均＜0.01)；与模型组比较，虫草菌丝高剂量组显著改善小鼠肝纤维化程度，血清ALT、AST、TBil水平均显著减少(P值均＜0.05)。HE染色发现虫草菌丝高剂量组能显著减少肝组织炎性细胞浸润。SR染色发现，虫草菌丝高剂量组明显减轻肝脏胶原沉积。与正常组比较，模型组肝组织HYP含量、SR阳性染色面积比均显著增加(P值均＜0.01)；与模型组比较，虫草菌丝高剂量组肝组织HYP含量、SR阳性染色面积比均显著减小(P值均＜0.05)。与正常组比较，免疫组化、PCR和Western Blot结果显示模型组肝组织中α-SMA和Col-Ⅰ mRNA及蛋白表达显著增加(P值均＜0.01)；与模型组比较，虫草菌丝高剂量组肝组织中α-SMA、Col-Ⅰ胶原纤维表达均显著减少(P值均＜0.05)。与正常组比较，模型组肝组织ANGPTL4、TLR4、P-NF-κB/NF-κB、CD163蛋白表达均显著增加(P值均＜0.01)；与模型组比较，虫草菌丝高剂量组肝组织ANGPTL4、TLR4、P-NF-κB/NF-κB、CD163蛋白含量均显著降低(P值均＜0.05)。 结论 虫草菌丝对CCl4诱导的小鼠肝纤维化具有显著治疗作用，其机制可能与调控TLR4/NF-κB信号通路及抑制肝组织ANGPTL4表达相关。 Abstract:Objective To investigate the interventional effect of cultured mycelia of Cordyceps sinensis on a mouse model of CCl4-induced liver fibrosis and its effect on the Toll-like receptor 4 (TLR4)/nuclear transcription factor-κB (NF-κB) pathway and angiopoietin-like protein 4 (ANGPTL4). Methods A total of 60 specific pathogen-free male C57/BL6J mice were randomly divided into normal group, model group, Fuzheng Huayu group, and low-, middle-, and high-dose Cordyceps sinensis groups, with 10 mice in each group. The mice in the model group and each medication group were intraperitoneally injected with 15% CCl4-olive oil for 6 weeks of modeling, and drug intervention was started on the first day of week 4 and lasted for 3 consecutive weeks. Blood biochemistry was used to measure the serum level or activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil); HE and SR staining was used to observe liver histopathology; alkaline hydrolysis was used to measure the content of hydroxyproline (HYP) in liver tissue; PCR was used to measure the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col-Ⅰ), immunohistochemistry was used to measure the protein expression of α-SMA, Col-Ⅰ, and ANGPTL4 in liver tissue, and Western blot (WB) was used to measure the protein expression of α-SMA, ANGPTL4, TLR4, NF-κB/phosphorylated NF-κB (P-NF-κB), and CD163. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the LSD-t test was used for further comparison between two groups. Results Compared with the normal group, the model group had significant increases in the serum levels of ALT, AST, and TBil (all P < 0.01), and compared with the model group, the high-dose Cordyceps sinensis group had a significant improvement in the degree of liver fibrosis and significant reductions in the serum levels of ALT, AST, and TBil (all P < 0.05). HE staining revealed that the high-dose Cordyceps sinensis group had a significant reduction in inflammatory cell infiltration in liver tissue, and SR staining showed that high-dose Cordyceps sinensis significantly alleviated collagen deposition in the liver tissue. Compared with the normal group, the model group had significant increases in HYP content and Sirius red-positive area ratio in liver tissue (both P < 0.01), and compared with the model group, the high-dose Cordyceps sinensis group had significant reductions in HYP content and Sirius red-positive area ratio (both P < 0.05). Compared with the normal group based on the results of immunohistochemistry, PCR, and WB, the model group had significant increases in the mRNA and protein expression levels of α-SMA and Col-Ⅰ in liver tissue (all P < 0.01), and compared with the model group, the high-dose Cordyceps sinensis group had significant reductions in the expression levels of α-SMA and Col-Ⅰ(P < 0.05). Compared with the normal group, the model group had significant increases in the protein expression of ANGPTL4, TLR4, P-NF-κB/NF-κB, and CD163 in liver tissue (all P < 0.01), and compared with the model group, the high-dose Cordyceps sinensis group had significant reductions in the protein expression of ANGPTL4, TLR4, P-NF-κB/NF-κB, and CD163 in liver tissue (all P < 0.05). Conclusion Cordyceps sinensis mycelia have a marked therapeutic effect on CCl4-induced liver fibrosis in mice, possibly by regulating the TLR4/NF-κB signaling pathway and inhibiting ANGPTL4 expression in liver tissue. -
Key words:
- Liver Cirrhosis /
- Angiopoietins /
- Toll-Like Receptor 4 /
- NF-kappa B
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图 1 小鼠肝组织HE和SR染色
注：N，正常组；M，模型组；CS(400 mg/kg)，虫草菌丝低剂量组；CS(800 mg/kg)，虫草菌丝中剂量组；CS(1600 mg/kg)，虫草菌丝高剂量组；FZGY(2000 mg/kg)，扶正化瘀方组。
Figure 1. HE and SR staining of liver tissue in mice
图 2 小鼠肝组织α-SMA和Col-Ⅰ免疫组化染色
注：N，正常组；M，模型组；CS(400 mg/kg)，虫草菌丝低剂量组；CS(800 mg/kg)，虫草菌丝中剂量组；CS(1600 mg/kg)，虫草菌丝高剂量组；FZGY(2000 mg/kg)，扶正化瘀方组。
Figure 2. Immunohistochemical staining of α-SMA and Col-Ⅰ in mouse liver tissue
图 4 小鼠肝组织ANGPTL4免疫组化染色
注：N，正常组；M，模型组；CS(400 mg/kg)，虫草菌丝低剂量组；CS(800 mg/kg)，虫草菌丝中剂量组；CS(1600 mg/kg)，虫草菌丝高剂量组；FZGY(2000 mg/kg)，扶正化瘀方组。箭头所示为ANGPTL4蛋白的表达。
Figure 4. Immunohistochemical staining of ANGPTL4 in mouse liver tissue
图 5 肝组织ANGPTL4、TLR4、P-NF-κB、NF-κB、CD163蛋白表达
注：CS，虫草菌丝；FZHY，扶正化瘀方。
Figure 5. ANGPTL4, TLR4, P-NF-κB, NF-κB, CD163 protein expression in liver tissue
表 1 PCR引物序列
Table 1. PCR primer sequences
基因名称 引物序列 GAPDH 上游：5′-CATCACTGCCACCCAGAAGACTG-3′ 下游：5′-ATGCCAGTGAGCTTCCCGTTCAG-3′ α-SMA 上游：5′-ACCATCGGCAATGAGCGTTTCC-3′ 下游：5′-GCTGTTGTAGGTGGTCTCATGG-3′ Col-Ⅰ 上游：5′-CCTCAGGGTATTGCTGGACAAC-3′ 下游：5′-CAGAAGGACCTTGTTTGCCAGG-3′ 
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表 2 各组小鼠血清生化结果比较
Table 2. Comparison of serum biochemistry results of each group of mice
组别 动物数(只) ALT(U/L) AST(U/L) TBil(μmol/L) 正常组 10 33.67±5.27 176.83±22.57 1.78±0.11 模型组 10 208.67±23.141) 395.72±43.281) 4.43±0.261) 虫草菌丝低剂量组 10 191.06±19.24 317.82±53.293) 4.18±0.36 虫草菌丝中剂量组 10 178.72±25.38 287.04±38.472) 4.06±0.67 虫草菌丝高剂量组 10 133.63±17.672)4)5) 234.57±32.912)4) 3.76±0.115) 扶正化瘀方组 10 142.84±19.372)4) 250.61±61.922) 3.9±0.53 F值 53.021 22.162 28.222 P值 ＜0.001 ＜0.001 ＜0.001 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.01，3)P＜0.05；与虫草菌丝低剂量组比较，4)P＜0.01；与虫草菌丝中剂量组比较，5)P＜0.05。
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表 3 HYP含量和SR阳染面积
Table 3. HYP content and SR positive staining area
组别 动物数(只) HYP(μg/mL) SR阳染面积(%) 正常组 10 326.63±41.01 1.63±0.34 模型组 10 684.08±103.541) 6.28±1.321) 虫草菌丝低剂量组 10 628.78±65.42 5.48±0.87 虫草菌丝中剂量组 10 580.57±89.82 4.95±0.742) 虫草菌丝高剂量组 10 500.82±67.362)3) 4.38±0.722) 扶正化瘀方组 10 551.29±46.282) 4.40±0.952) F值 18.393 43.112 P值 ＜0.001 ＜0.001 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.05；与虫草菌丝低剂量组比较，3)P＜0.05。
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表 4 α-SMA和Col-Ⅰ免疫组化阳染面积
Table 4. Immunohistochemical positive staining area of α-SMA and Col-Ⅰ
组别 动物数(只) α-SMA阳染面积(%) Col-Ⅰ阳染面积(%) 正常组 10 1.00±0.31 1.00±0.41 模型组 10 6.11±0.561) 1.74±0.531) 虫草菌丝低剂量组 10 5.62±0.48 1.66±0.52 虫草菌丝中剂量组 10 5.14±0.96 1.51±0.39 虫草菌丝高剂量组 10 4.57±0.282) 1.32±0.482) 扶正化瘀方组 10 4.89±0.57 1.53±0.46 F值 69.413 10.936 P值 ＜0.001 0.032 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.05。
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表 5 α-SMA和Col- Ⅰ mRNA表达
Table 5. α-SMA and Col- Ⅰ mRNA expression
组别 动物数(只) α-SMA Col-Ⅰ 正常组 10 1.00±0.31 1.00±0.24 模型组 10 4.95±0.911) 6.77±0.811) 虫草菌丝低剂量组 10 3.94±0.72 5.62±0.63 虫草菌丝中剂量组 10 3.58±0.532) 5.31±0.532) 虫草菌丝高剂量组 10 3.22±0.582) 4.79±0.472) 扶正化瘀方组 10 3.58±0.71 5.21±0.51 F值 13.903 16.902 P值 0.026 0.019 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.05。
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表 6 α-SMA蛋白表达
Table 6. α-SMA protein expression
组别 动物数(只) α-SMA/GAPDH 正常组 10 1.00±0.56 模型组 10 2.73±0.671) 虫草菌丝低剂量组 10 2.33±0.36 虫草菌丝中剂量组 10 2.06±0.48 虫草菌丝高剂量组 10 1.55±0.612)3) 扶正化瘀方组 10 1.68±0.382)3) F值 12.433 P值 0.036 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.01；与虫草菌丝低剂量组比较，3)P＜0.05。
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表 7 ANGPTL4免疫组化阳染面积
Table 7. Immunohistochemical positive staining area of ANGPTL4
组别 动物数(只) ANGPTL4阳染面积(%) 正常组 10 1.00±0.17 模型组 10 1.82±0.321) 虫草菌丝低剂量组 10 1.73±0.28 虫草菌丝中剂量组 10 1.63±0.25 虫草菌丝高剂量组 10 1.32±0.312) 扶正化瘀方组 10 1.59±0.25 F值 12.874 P值 0.037 注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.05。
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表 8 ANGPTL4、TLR4、P-NF-κB、NF-κB、CD163蛋白表达
Table 8. ANGPTL4, TLR4, P-NF-κB, NF-κB, CD163 protein expression
组别 动物数(只) ANGPTL4/GAPDH TLR4/GAPDH P-NF-κB/NF-κB CD163/GAPDH 正常组 10 1.00±0.13 1.00±0.18 1.00±0.19 1.00±0.27 模型组 10 1.76±0.242) 1.69±0.322) 1.90±0.311) 2.12±0.341) 虫草菌丝低剂量组 10 1.63±0.29 1.61±0.21 1.78±0.21 1.95±0.28 虫草菌丝中剂量组 10 1.58±0.31 1.49±0.27 1.67±0.26 1.82±0.31 虫草菌丝高剂量组 10 1.23±0.193) 1.18±0.193) 1.35±0.283) 1.51±0.253) 扶正化瘀方组 10 1.38±0.353) 1.31±0.32 1.62±0.29 1.69±0.30 F值 12.227 22.492 15.103 11.141 P值 0.035 ＜0.001 0.021 0.039 注：与正常组比较，1)P＜0.01，2)P＜0.05；与模型组比较，3)P＜0.05。
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