Study on Lipid Metabolism Regulated by Polygonum Cuspidatum in the Treatment of Pulmonary Fibrosis Model of Respiratory Syncytial Virus Infection in Mice
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摘要:
目的 研究虎杖对呼吸道合胞病毒(Respiratory syncytial virus, RSV)感染的肺纤维化小鼠肺组织脂质代谢及炎症过程的影响。 方法 采用50 μL RSV病毒液(4×106 PFU · mL-1)联合博来霉素(Bleomycin, 2 mg · mL-1)气管滴注C57BL/6雄性小鼠, 建立RSV感染肺纤维化小鼠模型, 小鼠随机分为空白组、博来霉素诱导肺纤维化组、RSV感染肺纤维化组、虎杖(4.55 g · kg-1 · d-1)治疗组。造模第21天后采集各组小鼠的肺组织, 观察其病理改变及检测白细胞介素(IL)-6、肿瘤坏死因子(TNF)-α等炎症因子水平, 同时采用超高效液相色谱-四极杆-静电场轨道阱高分辨质谱联用(UPLC-Q Exactive Orbitrap/MS)技术进行脂质组学分析。 结果 与空白组相比, 博来霉素诱导肺纤维化组和RSV感染肺纤维化组肺组织病理可见明显胶原纤维沉积及炎症浸润, 伴肺部炎症因子如IL-6、TNF-α水平显著升高(P < 0.05)。与博来霉素诱导肺纤维化组相比, RSV感染肺纤维化组呈现显著脂质代谢异常(P < 0.05), 具体表现为神经酰胺(Cer)、磷脂酰胆碱(PC)、磷脂酰乙醇胺(PE)、磷脂酰肌醇(PI)、酰基乙醇胺(NAE)、鞘磷脂(SM)、甘油二酯(DG)、甘油三酯(TG)、心磷脂(CL)、脂肪酸(FA)等脂质代谢紊乱。经虎杖(4.55 g · kg-1 · d-1)干预后, 上述指标均呈现显著回调趋势。 结论 RSV可加重肺纤维化进程, 虎杖通过调控脂质代谢, 减轻RSV感染肺纤维化小鼠的肺组织炎症反应和胶原沉积, 改善小鼠肺组织纤维化进程。 Abstract:OBJECTIVE To investigate the effects of Polygonum Cuspidatum in the treatment of lung fibrosis mice infected with the respiratory syncytial virus (RSV) in terms of altered lipids and the inflammatory process in the lung. METHODS C57BL/6 mice were given a tracheal drip of 50 μL RSV venom (4×106 PFU·mL-1) combined with bleomycin (2 mg·mL-1). The mice were randomly divided into blank group, bleomycin induced pulmonary fibrosis group, RSV infected pulmonary fibrosis group and Polygonum Cuspidatum (4.55 g·kg-1·d-1) treatment group. To assess changes in pathological and pro-inflammatory cytokine levels (IL-6, and TNF-α), lung tissues from each group were removed 21 days after modeling. Lipidomics analysis was then completed using UPLC-Q Exactive Orbitrap/MS. RESULTS In comparison to the blank group, the lungs of the bleomycin induced pulmonary fibrosis group and RSV infected pulmonary fibrosis group showed prominent collagen fiber deposition and inflammatory infiltration, and the levels of lung inflammatory factors like IL-6 and TNF-α were noticeably higher (P < 0.05). The lipid metabolism of the RSV infected pulmonary fibrosis group differed significantly from that of the bleomycin induced pulmonary fibrosis group, with abnormal levels of ceramide (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), acylethanolamine (NAE), sphingomyelin (SM), diglyceride (DG), triglyceride (TG) and fatty acid (FA). The above indexes showed a significant trend of correction after the intervention of Polygonum Cuspidatum (4.55 g·kg-1·d-1). CONCLUSION RSV has the potential to accelerate the progression of pulmonary fibrosis. Polygonum Cuspidatum reduces inflammation and collagen deposition in the lung tissue of RSV-infected mice with pulmonary fibrosis by regulating lipid metabolism, and it slows the progression of pulmonary fibrosis in mice. -
Key words:
- RSV /
- pulmonary fibrosis /
- Polygonum Cuspidatum /
- lipids
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图 1 各组病理HE、Masson染色结果(×200)
Figure 1. Results of pathology in different groups using HE and Masson staining(×200)
图 2 各组小鼠肺组织肺纤维化程度比较
注: 与空白组比较, * *P < 0.01;与博来霉素诱导肺纤维化组比较, #P < 0.05;与RSV感染肺纤维化组比较, △△△P < 0.001。
Figure 2. Comparison of pulmonary fibrosis degree in lung tissue of mice in each group
图 3 各组小鼠肺组织IL-6、TNF-α水平比较
注: 与空白组比较, *P < 0.05, * * *P < 0.001;与RSV感染肺纤维化组比较, △P < 0.05, △△△P < 0.001。
Figure 3. Comparison of IL-6 and TNF-α levels in lung tissue of mice in each group
图 4 QC样本和各组小鼠肺组织PCA图
注: A.正离子模式; B.负离子模式
Figure 4. PCA of lung tissue in different groups of QC samples
图 5 小鼠肺组织总离子流图
注: A.正离子模式; B.负离子模式
Figure 5. Total ion chromatograms (TIC) of mouse lung tissue
图 6 各组小鼠肺组织PCA图
注: C.空白组; BL.博来霉素诱导肺纤维化组; RB.RSV感染肺纤维化组; RBH.虎杖(4.55 g·kg-1·d-1)治疗组
Figure 6. PCA of lung tissue in different groups of mice
图 7 RSV感染肺纤维化小鼠肺组织差异性脂质热图
注: 热图中红色代表上调趋势；蓝色代表下调趋势; C.空白组; BL.博来霉素诱导肺纤维化组; RB.RSV感染肺纤维化组
Figure 7. Differential lipid heatmap of lung tissue in RSV-infected mice with pulmonary fibrosis
图 8 虎杖干预后RSV感染肺纤维化小鼠肺组织差异性脂质热图
注: 红色代表上调趋势；蓝色代表下调趋势; C.空白组; RB.RSV感染肺纤维化组; RBH.虎杖(4.55 g·kg-1·d-1) 治疗组
Figure 8. Differential lipid heatmap of lung tissue of RSV-infected mice with pulmonary fibrosis after intervention of Polygonum Cuspidatum
表 1 RSV感染肺纤维化小鼠肺组织差异性脂质
Table 1. Differential lipids in lung tissue of RSV-infected mice with pulmonary fibrosis
差异性脂质 保留时间/min 质荷比
m/z加和离子 化学结构式 博来霉素诱导肺纤维化组/空白组 RSV感染肺纤维化组/
博来霉素诱导肺纤维化组FC P值 FC P值 FA 20∶3;4O 0.53 369.229 9 [M-H]- C20H34O6 0.83 0.002 2 1.50 0.004 3 FA 18∶1;3O 0.55 329.234 1 [M-H]- C18H34O5 0.57 0.002 2 1.82 0.002 2 LPE 20∶5 0.62 500.279 6 [M+H]+ C25H42NO7P 0.58 0.026 0 7.78 0.002 2 NAE 14∶0 0.79 272.259 1 [M+H]+ C16H33NO2 1.82 0.002 2 1.93 0.015 2 FA 16∶1;O 0.81 269.212 3 [M-H]- C16H30O3 0.78 0.015 2 1.68 0.002 2 FA 18∶1;O 1.19 297.243 6 [M-H]- C18H34O3 0.77 0.015 2 1.34 0.026 0 DG 40∶6 3.06 691.531 3 [M+Na]+ C43H72O5 0.51 0.041 1 7.73 0.002 2 DG 16∶0_24∶6 3.06 686.574 7 [M+NH4]+ C43H72O5 0.36 0.041 1 14.33 0.002 2 PC 39∶9 3.78 836.547 9 [M+Na]+ C47H76NO8P 0.59 0.008 7 5.04 0.002 2 NAE 23∶1 4.17 396.382 7 [M+H]+ C25H49NO2 0.71 0.002 2 3.66 0.002 2 PI 38∶6 4.94 900.553 7 [M+NH4]+ C47H79O13P 1.79 0.015 2 1.80 0.041 1 PI 16∶0_22∶6 5.05 881.515 8 [M-H]- C47H79O13P 2.07 0.015 2 1.36 0.004 3 PI 18∶0_18∶2 5.69 861.553 4 [M-H]- C45H83O13P 27.19 0.041 1 1.61 0.041 1 PC 14∶0_16∶0 5.73 706.536 8 [M+H]+ C38H76NO8P 2.83 0.004 3 1.83 0.015 2 PI 40∶5 5.74 930.607 2 [M+NH4]+ C49H85O13P 0.52 0.008 7 1.60 0.015 2 CL 20∶4_22∶6_22∶6_22∶6 6.36 807.486 3 [M-2H]2- C95H142O17P2 1.19 0.041 1 0.76 0.041 1 PE 18∶0_22∶6 6.56 790.536 6 [M-H]- C45H78NO8P 0.82 0.041 1 0.83 0.008 7 PE O-18∶1_20∶3 7.35 752.563 4 [M-H]- C43H80NO7P 0.48 0.015 2 0.29 0.002 2 SM 42∶2;2O 7.49 835.665 2 [M+Na]+ C47H93N2O6P 0.31 0.015 2 3.81 0.026 0 PE O-20∶1_22∶5 7.81 804.588 0 [M-H]- C47H84NO7P 0.78 0.026 0 0.49 0.002 2 PC O-39∶0 8.60 818.691 4 [M+H]+ C47H96NO7P 0.35 0.015 2 3.55 0.015 2 TG 14∶0_16∶0_18∶2;2O 8.64 852.731 6 [M+NH4]+ C51H94O8 1.87 0.041 1 2.65 0.026 0 TG 16∶0_18∶2_18∶3 10.60 870.747 3 [M+NH4]+ C55H96O6 2.18 0.026 0 0.34 0.015 2 TG 18∶2_18∶2_20∶4 10.63 920.766 7 [M+NH4]+ C59H98O6 1.19 0.041 1 0.48 0.002 2 TG 18∶1_18∶2_18∶3 10.95 896.768 3 [M+NH4]+ C57H98O6 2.18 0.041 1 0.40 0.026 0 TG 16∶0_18∶1_22∶6 11.30 922.789 0 [M+NH4]+ C59H100O6 1.94 0.008 7 0.57 0.008 7 TG 16∶0_18∶2_20∶4 11.31 896.770 0 [M+NH4]+ C57H98O6 2.24 0.004 3 0.45 0.004 3 TG O-22∶1_18∶5_18∶5 11.48 933.721 7 [M+Na]+ C61H98O5 1.27 0.041 1 0.41 0.002 2 TG 18∶1_18∶1_20∶4 11.55 924.805 1 [M+NH4]+ C59H102O6 1.85 0.026 0 0.37 0.002 2 TG 16∶0_18∶0_18∶0 12.59 880.825 6 [M+NH4]+ C55H106O6 2.23 0.002 2 1.65 0.041 1 TG 16∶0_18∶2_18∶2 12.85 872.771 4 [M+NH4]+ C55H98O6 1.95 0.026 0 0.41 0.015 2 TG 18∶1_34∶1_18∶2 13.21 1 125.055 1 [M+NH4]+ C73H134O6 0.36 0.041 1 0.30 0.015 2 注: 统计方法采用非参数检验法(Kruskal-Wallis test), 根据FC、P值筛选差异性代谢物。选取P < 0.05, 当FC>1.2或FC < 0.83, 提示该代谢物具有统计学意义。 
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表 2 虎杖干预后RSV感染肺纤维化小鼠肺组织差异性脂质
Table 2. Differential lipids in lung tissue of RSV-infected mice with pulmonary fibrosis after intervention of Polygonum Cuspidatum
差异性脂质 保留时间/min 质荷比
m/z加和离子 化学结构式 RSV感染肺纤维化组/空白组 虎杖(4.55 g·kg-1·d-1)治疗组/RSV感染肺纤维化组 FC FDR值 FC FDR值 NAGly 16∶1;O 0.49 328.244 6 [M+H]+ C18H33NO4 3.25 0.033 2 0.11 0.004 1 LPE 20∶5 0.62 500.279 6 [M+H]+ C25H42NO7P 4.50 0.033 2 0.30 0.004 1 FA 16∶0;2O 0.67 287.224 5 [M-H]- C16H32O4 0.52 0.010 1 3.44 0.025 4 NAE 16∶2 0.70 296.255 8 [M+H]+ C18H33NO2 2.69 0.042 5 0.26 0.004 1 NAE 16∶0 0.71 300.288 4 [M+H]+ C18H37NO2 2.37 0.042 5 0.14 0.004 1 NAE 14∶0 0.79 272.259 1 [M+H]+ C16H33NO2 3.51 0.033 2 0.16 0.004 1 NAE 18∶2 1.02 324.287 6 [M+H]+ C20H37NO2 3.44 0.033 2 0.15 0.004 1 LPE 20∶4 1.17 500.277 0 [M-H]- C25H44NO7P 1.53 0.010 1 1.43 0.016 5 LPE 22∶5 1.27 528.310 6 [M+H]+ C27H46NO7P 2.01 0.042 5 0.29 0.004 1 NAE 20∶1 1.40 354.334 6 [M+H]+ C22H43NO2 4.64 0.033 2 0.09 0.004 1 LPC 18∶1 1.68 522.355 8 [M+H]+ C26H52NO7P 2.92 0.033 2 0.13 0.004 1 NAE 21∶1 2.34 368.350 6 [M+H]+ C23H45NO2 3.65 0.042 5 0.12 0.004 1 DG 42∶10 3.72 711.499 6 [M+Na]+ C45H68O5 3.92 0.033 2 0.08 0.004 1 DG 30∶3 3.81 557.414 0 [M+Na]+ C33H58O5 2.81 0.042 5 0.13 0.004 1 PC O-38∶9 3.83 786.530 6 [M+H]+ C46H76NO7P 4.46 0.033 2 0.38 0.037 1 PC O-40∶9 3.87 814.562 0 [M+H]+ C48H80NO7P 3.15 0.042 5 0.15 0.004 1 DG 46∶9 3.97 769.575 1 [M+Na]+ C49H78O5 4.41 0.042 5 0.24 0.022 4 SM 38∶7;2O 4.15 747.529 9 [M+H]+ C43H75N2O6P 3.40 0.033 2 0.11 0.004 1 DG 38∶8 4.20 659.481 9 [M+Na]+ C41H64O5 2.96 0.033 2 0.14 0.004 1 PC O-42∶10 4.47 840.574 6 [M+H]+ C50H82NO7P 3.88 0.042 5 0.25 0.022 4 PG 18∶2_22∶6 4.63 817.500 4 [M-H]- C46H75O10P 1.71 0.010 1 0.61 0.016 5 BMP 18∶2_20∶4 4.72 812.544 8 [M+NH4]+ C44H75O10P 4.07 0.033 2 0.11 0.004 1 PG 18∶2_18∶2 4.78 769.502 9 [M-H]- C42H75O10P 1.71 0.010 1 0.57 0.016 5 PC O-42∶9 4.80 842.590 0 [M+H]+ C50H84NO7P 4.13 0.033 2 0.15 0.004 1 PI 16∶0_22∶6 5.05 881.515 8 [M-H]- C47H79O13P 2.80 0.010 1 0.64 0.016 5 PG 18∶2_22∶4 5.08 821.532 4 [M-H]- C46H79O10P 3.84 0.010 1 0.57 0.025 4 PC 32∶3 5.09 728.518 8 [M+H]+ C40H74NO8P 2.81 0.042 5 0.01 0.004 1 PC 14∶0_14∶0 5.11 678.506 4 [M+H]+ C36H72NO8P 2.46 0.033 2 0.18 0.004 1 SM 42∶4;3O 5.19 825.650 8 [M+H]+ C47H89N2O7P 4.04 0.042 5 0.16 0.004 1 PC 30∶1 5.22 704.519 0 [M+H]+ C38H74NO8P 3.02 0.033 2 0.18 0.004 1 PG 16∶0_22∶6 5.23 793.504 4 [M-H]- C44H75O10P 0.64 0.010 1 1.71 0.016 5 BMP 18∶1_18∶2 5.24 790.557 5 [M+NH4]+ C42H77O10P 4.05 0.033 2 0.08 0.004 1 PI 16∶0_18∶2 5.26 833.520 8 [M-H]- C43H79O13P 1.52 0.010 1 0.52 0.016 5 PE 16∶0_20∶3;2O 5.28 772.518 7 [M-H]- C41H76NO10P 1.49 0.010 1 0.64 0.037 6 PC 16∶1_16∶1 5.34 730.536 7 [M+H]+ C40H76NO8P 2.65 0.033 2 0.17 0.004 1 PI 18∶1_18∶2 5.35 859.537 8 [M-H]- C45H81O13P 1.60 0.010 1 0.63 0.025 4 DG 28∶2 5.37 531.410 1 [M+Na]+ C31H56O5 2.53 0.042 5 0.41 0.013 4 SM 42∶3;3O 5.56 827.656 3 [M+H]+ C47H91N2O7P 4.64 0.033 2 0.31 0.013 4 PI 34∶1 5.69 854.567 8 [M+NH4]+ C43H81O13P 3.19 0.042 5 0.15 0.004 1 PC 14∶0_16∶0 5.73 706.536 8 [M+H]+ C38H76NO8P 5.18 0.033 2 0.24 0.004 1 SMGDG 40∶10 5.81 887.507 0 [M-H]- C49H76O12S 4.73 0.016 3 0.51 0.016 5 SM 34∶0;2O 5.86 727.568 2 [M+Na]+ C39H81N2O6P 2.59 0.042 5 0.13 0.004 1 PS 18∶0_16∶1 5.86 760.513 0 [M-H]- C40H76NO10P 0.83 0.041 1 1.54 0.016 5 HexCer 18∶1;2O/16∶0 5.86 700.572 3 [M+H]+ C40H77NO8 3.50 0.033 2 0.19 0.004 1 DG 39∶10 5.95 669.451 5 [M+Na]+ C42H62O5 4.23 0.042 5 0.28 0.037 1 PC O-30∶0 6.13 692.561 7 [M+H]+ C38H78NO7P 2.94 0.033 2 0.17 0.004 1 PI 36∶1 6.28 882.601 6 [M+NH4]+ C45H85O13P 2.89 0.042 5 0.12 0.004 1 CL 18∶0_18∶0_28∶0_20∶3 6.32 812.583 9 [M-2H]2- C93H176O17P2 1.64 0.016 3 0.72 0.037 6 PS 40∶4 6.33 840.573 8 [M+H]+ C46H82NO10P 0.34 0.042 5 0.43 0.022 4 PE O-16∶1_22∶4 6.95 750.548 2 [M-H]- C43H78NO7P 0.30 0.010 1 2.10 0.025 4 PE O-16∶1_18∶1 7.02 700.533 8 [M-H]- C39H76NO7P 0.67 0.010 1 1.30 0.037 6 PS 18∶1_22∶1 7.15 842.589 4 [M-H]- C46H86NO10P 0.70 0.041 1 1.62 0.037 6 PE O-18∶1_20∶4 7.20 750.541 6 [M-H]- C43H78NO7P 0.52 0.010 1 0.01 0.016 5 PE 34∶0 7.20 742.535 1 [M+Na]+ C39H78NO8P 2.69 0.033 2 0.02 0.004 1 PE O-18∶1_20∶3 7.35 752.563 4 [M-H]- C43H80NO7P 0.14 0.010 1 2.64 0.037 6 PE 22∶5_16∶2;O 7.39 776.498 4 [M-H]- C43H72NO9P 1.92 0.016 3 0.07 0.016 5 Cer 18∶2;2O/24∶2 7.42 644.600 8 [M+H]+ C42H77NO3 2.79 0.033 2 0.08 0.004 1 DG 50∶9 7.75 825.624 3 [M+Na]+ C53H86O5 0.14 0.033 2 3.94 0.007 3 PE O-20∶1_22∶5 7.81 804.588 0 [M-H]- C47H84NO7P 0.38 0.010 1 2.68 0.016 5 SM 44∶2;2O 8.26 841.712 0 [M+H]+ C49H97N2O6P 2.88 0.033 2 0.01 0.004 1 PE 18∶0_18∶0 8.39 746.581 1 [M-H]- C41H82NO8P 3.15 0.025 4 0.08 0.016 5 HexCer 18∶1;2O/24∶0 8.59 812.698 7 [M+H]+ C48H93NO8 2.46 0.033 2 0.22 0.004 1 Cer 18∶1;2O/24∶1 8.72 646.616 9 [M-H]- C42H81NO3 1.56 0.025 4 0.44 0.016 5 Cer 20∶1;2O/32∶1;O 9.23 804.782 0 [M+H]+ C52H101NO4 6.24 0.033 2 0.02 0.004 1 Cer 18∶0;2O/24∶0 9.48 652.660 8 [M+H]+ C42H85NO3 2.22 0.033 2 0.22 0.004 1 Cer 20∶0;2O/24∶0 10.08 680.689 2 [M+H]+ C44H89NO3 2.26 0.042 5 0.38 0.004 1 TG 18∶1_18∶2_22∶5 11.16 948.800 5 [M+NH4]+ C61H102O6 0.60 0.033 2 2.99 0.007 3 TG O-22∶1_18∶5_18∶5 0.49 933.721 7 [M+Na]+ C61H98O5 3.25 0.033 2 0.11 0.004 1 TG 18∶0_18∶1_22∶5 0.62 952.823 4 [M+NH4]+ C61H106O6 4.50 0.033 2 0.30 0.004 1 TG 18∶0_18∶1_22∶4 0.67 954.843 8 [M+NH4]+ C61H108O6 0.52 0.010 1 3.44 0.025 4 Cer 20∶2;2O/52∶3;2O 0.70 1 095.044 0 [M+H]+ C72H135NO5 2.69 0.042 5 0.26 0.004 1 TG 18∶1_30∶1_18∶2 0.71 1 068.982 0 [M+NH4]+ C69H126O6 2.37 0.042 5 0.14 0.004 1 TG 16∶1_18∶1_32∶1 0.79 1 071.007 0 [M+NH4]+ C69H128O6 3.51 0.033 2 0.16 0.004 1 TG 18∶1_34∶1_18∶2 1.02 1 125.055 0 [M+NH4]+ C73H134O6 3.44 0.033 2 0.15 0.004 1 注: 统计方法采用非参数检验法(Kruskal-Wallis test), 根据FC、FDR值筛选差异性代谢物, FDR采用Benjamini & Hochberg检验法。选取FDR < 0.05, 当FC>1.2或FC < 0.83, 提示该代谢物具有统计学意义。
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