散寒化湿颗粒对流感病毒与呼吸道合胞病毒致小鼠肺炎模型的作用机理研究

doi:10.19803/j.1672-8629.20250031

摘要/Abstract

摘要： 目的研究散寒化湿颗粒对小鼠感染甲型H1N1流感病毒及呼吸道合胞病毒（RSV）所致肺炎模型的治疗作用机理。方法通过采用甲型H1N1流感病毒FM1（H1N1/FM1）毒株及RSV以滴鼻的方式感染小鼠,构建病毒性肺炎小鼠模型;建模后,取小鼠肺组织,计算小鼠的肺指数及其抑制率。甲型H1N1流感病毒感染模型及RSV感染模型均设立正常组,模型组,连花清瘟组,散寒化湿高剂量组（52.8 g·kg^-1·d^-1）、中剂量组（26.4 g·kg^-1·d^-1）、低剂量组（13.2 g·kg^-1·d^-1）,甲型H1N1流感病毒感染模型以奥司他韦组为模型组,RSV感染模型利巴韦林组为模型组,建模并给药后,针对甲型H1N1流感病毒FM1毒株感染的小鼠,将其肺内细支气管及肺组织进行苏木精-伊红（HE）染色处理,在显微镜下详细观察病变情况,并依据既定的标准进行等级评分,并对RSV滴鼻感染小鼠的肺组织中白细胞介素-4（IL-4）、白细胞介素-33（IL-33）的水平进行检测。结果散寒化湿颗粒中剂量组可显著降低H1N1/FM1模型组小鼠肺指数（P<0.05）,显著改善小鼠肺内细支气管及肺组织的病变程度,肺部及支气管病变等级显著降低。散寒化湿颗粒高剂量组可显著降低RSV感染小鼠肺指数（P<0.05）,且散寒化湿颗粒3个剂量组均可明显升高RSV感染小鼠IL-4含量、降低IL-33含量,模型组、散寒化湿低剂量组、中剂量组及高剂量组的IL-4含量依次为（50.20±2.22）、）、（61.63±1.34）、（71.46±2.39）、（56.74±1.24）pg·mL^-1,IL-33含量依次为（1 787.37±60.59）、（1 273.10±378.04）、（1 532.38±337.96）、（1 347.33±345.39）pg·mL^-1,均与模型组比较,差异具有统计学意义（P<0.01,P<0.05）。结论散寒化湿颗粒可改善小鼠肺内细支气管及肺组织的病变程度,使肺部及支气管病变等级显著降低,显著降低病毒性肺炎模型小鼠的肺指数,且能使得小鼠肺脏IL-4含量升高、IL-33含量降低。

关键词: 散寒化湿颗粒, 甲型H1N1流感病毒, 呼吸道合胞病毒, 病毒性肺炎, 小鼠

Abstract: Objective To study the therapeutic mechanism of Sanhan Huashi granules (SHG) on a pneumonia model induced by influenza A (H1N1) virus and respiratory syncytial virus (RSV) in mice. Methods The mice were infected with the FM1 strain of influenza A (H1N1) virus and respiratory syncytial virus (RSV) by nasal drip to construct a mouse model of viral pneumonia. Both influenza A (H1N1) virus group and the RSV group were divided into normal group, model group, Lianhua Qingwen group(LHG), SHG groups with high-dose(52.8 g·kg^-1·d^-1), medium-dose(26.4 g·kg^-1·d^-1), and low-dose (13.2 g·kg^-1·d^-1). And oseltamivir group was served as the control group in the influenza A (H1N1) virus group, ribavirin group was served as the control group in the RSV group. After modelling and intragastric administration, the lung tissues of the mice were taken to accurately calculate the lung index and its inhibition rate. For mice infected with the FM1 strain of influenza A (H1N1) virus, hematoxylin-eosin (HE) staining was performed on the bronchioles and lung tissues. The pathological changes were observed under a microscope, and the grades were scored by the established standards. At the same time, the levels of interleukin-4 (IL-4) and interleukin-33 ( IL-33 ) in lung tissues of mice infected with RSV were detected. Results A medium dose of SHG could significantly reduce the lung index of mice in the H1N1/FM1 model group (P <0.05), improve the pathological changes of bronchioles and lung tissues, and reduce the grade of lung and bronchial lesions while a high dose of SHG could significantly reduce the lung index of RSV-infected mice (P<0.05). The three doses of SHG could significantly increase the content of IL-4 but reduce the content of IL-33 in RSV-infected mice. The contents of IL-4 in the model group, the low-dose group, the medium-dose group and the high-dose group were（50.20±2.22）,（61.63±1.34）,（71.46±2.39）and（56.74±1.24）pg·mL^-1 respectively, compared with(1 787.37±60.59), (1 273.10±378.04), (1 532.38±337.96) and(1 347.33±345.39)pg·mL^-1for IL-33, all of which were significantly different from those of the control group (P<0.01, P<0.05). Conclusion SHG can mitigate the severity of pathological changes of bronchioles and lung tissues of mice, significantly reduce the grade of lung and bronchial lesions, significantly lower the lung index of viral pneumonia in model mice, and increase the content of IL-4 in the lungs of mice while decreasing the content of IL-33.

Key words: Sanhan Huashi Granules, H1N1 Influenza A Virus, Respiratory Syncytial Virus, Viral Pneumonia, Mice

中图分类号:

赵荣华, 朱春旭, 孙静, 包蕾, 王馨蔚, 耿子涵, 张敬升, 郭姗姗, 李舒冉, 王道涵, 崔晓兰. 散寒化湿颗粒对流感病毒与呼吸道合胞病毒致小鼠肺炎模型的作用机理研究[J]. 中国药物警戒, 2025, 22(5): 488-494.

ZHAO Ronghua, ZHU Chunxu, SUN Jing, BAO Lei, WANG Xinwei, GENG Zihan, ZHANG Jingsheng, GUO Shanshan, LI Shuran, WANG Daohan, CUI Xiaolan. Mechanisms of Sanhan Huashi Granules on a Respiratory Syncytial Virus and Influenza Virus and Respiratory Syncytial Virus Induced Pneumonia Model in Mice[J]. Chinese Journal of Pharmacovigilance, 2025, 22(5): 488-494.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://zgywjj.magtechjournal.com/CN/10.19803/j.1672-8629.20250031

https://zgywjj.magtechjournal.com/CN/Y2025/V22/I5/488

参考文献

[1] LI YY, LI Y, DU H, et al.Analysis on the Clinical Epidemiological Characteristics of Respiratory Syncytial Virus in a Children’s Hospital in Hubei Province from 2020 to 2023[J]. Chinese Journal of Preventive Medicine(中华预防医学杂志), 2024, 58(2): 213-218.
[2] ZOU XH, CHANG K, FAN GH, et al.A Randomized, Open-Label, Multicenter Clinical Study Evaluating the Efficacy and Safety of Sanhan Huashi Granules Versus Nirmatrelvir-Ritonavir in the Treatment of Mild/Moderate COVID-19[J]. Science Bulletin, 2024, 69(12): 1954-1963.
[3] GUZMÁN-BELTRÁN S, HERRERA MT, TORRES M, et al. CD33 Is Downregulated by Influenza Virus H1N1pdm09 and Induces ROS and the TNF-α, IL-1β, and IL-6 Cytokines in Human Mononuclear Cells[J]. Brazilian Journal of Microbiology, 2022, 53(1): 89-97.
[4] LE GOFFIC R, ARSHAD MI, RAUCH M, et al.Infection with Influenza Virus Induces IL-33 in Murine Lungs[J]. American Journal of Respiratory Cell and Molecular Biology, 2011, 45(6): 1125-1132.
[5] YU X, ZHANG X, ZHAO B, et al.Intensive Cytokine Induction in Pandemic H1N1 Influenza Virus Infection Accompanied by Robust Production of IL-10 and IL-6[J]. Public Library of Science One, 2011, 6(12): e28680.
[6] VARGAS JE, DE SOUZA AP, PORTO BN, et al.Immunomodulator Plasmid Projected by Systems Biology as a Candidate for the Development of Adjunctive Therapy for Respiratory Syncytial Virus Infection[J]. Medical Hypotheses, 2016, 88: 86-90.
[7] NIU M, JIANG Z, XIN X, et al.Effect of HMGB1 on Monocyte Immune Function in Respiratory Syncytial Virus Bronchiolitis[J]. Experimental and Therapeutic Medicine, 2021, 21(1): 75.
[8] CHEN YQ, ZHOU Y, WANG QL, et al.Conciliatory Anti-Allergic Decoction Attenuates Pyroptosis in RSV-Infected Asthmatic Mice and Lipopolysaccharide (LPS)-Induced 16HBE Cells by Inhibiting TLR3/NLRP3/NF-κB/IRF3 Signaling Pathway[J]. Journal of Immunology Research, 2022, 2022, 1800401.
[9] HAMID S, WINN A, PARIKH R, et al.Seasonality of Respiratory Syncytial Virus-United States, 2017 to 2023[J]. Morbidity and Mortality Weekly Report, 2023, 72(14): 355-361.
[10] LIU S, XU LC, ZENG HS, et al.Evolutionary Analysis of Influenza a (H1N1) Virus in Futian District, Shenzhen in 2023[J]. Chinese Journal of Viral Diseases(中国病毒病杂志), 2024, 14(4): 351-357.
[11] National Children’s Health and Disease Medical Research Center, Infection Group of Pediatrics Branch of Chinese Medical Association, Infectious Diseases Branch of Shanghai Medical Association. Chinese Expert Consensus on Clinical Diagnosis and Treatment of Respiratory Syncytial Virus Infection in Children (2023 Edition)[J]. Journal of Clinical Pediatrics(临床儿科杂志), 2024, 42(1): 1-14.
[12] FECHNER H, PINKERT S, GEISLER A, et al.Pharmacological and Biological Antiviral Therapeutics for Cardiac Coxsackievirus Infections[J]. Molecules, 2011, 16(10): 8475-8503.
[13] CROTTY S, ANDINO R.Implications of High RNA Virus Mutation Rates: Lethal Mutagenesis and the Antiviral Drug Ribavirin[J]. Microbes and Infection, 2002, 4(13): 1301-1307.
[14] DING Y, ZENG L, LI R, et al.The Chinese Prescription Lianhua-qingwen Capsule Exerts Anti-Influenza Activity through the Inhibition of Viral Propagation and Impacts Immune Function[J]. BMC Complementary and Alternative Medicine, 2017, 17(1): 130.
[15] WU J, WANG Q, YANG L, et al.Potency of Lianhua Qingwen Granule Combined with Paramivir Sodium Chloride Injection in Treating Influenza and Level Changes of Serum Inflammatory Factors[J]. American Journal of Translational Research, 2021, 13(6): 6790-6795.
[16] YAO W, WANG JJ, LI YG.Clinical Observation on 40 Cases of Infantile Bronchiolitis Treated with Lianhua Qingwen Granules As Adjuvant Therapy[J]. Hebei Journal of Traditional Chinese Medicine(河北中医), 2014, 36(8): 1218-1219.
[17] MARTINEZ FO, GORDON S.The M1 and M2 Paradigm of Macrophage Activation: Time for Reassessment[J]. F1000Prime Reports, 2014, 6: 13.
[18] SNELGROVE RJ, GREGORY LG, PEIRÓ T, et al. Alternaria-Derived Serine Protease Activity Drives IL-33-Mediated Asthma Exacerbations[J]. Journal of Allergy and Clinical Immunology, 2014, 134(3): 583-592.e6.
[19] SCHMITZ J, OWYANG A, OLDHAM E, et al.IL-33, an Interleukin-1-Like Cytokine that Signals via the IL-1 Receptor-Related Protein ST2 and Induces T Helper Type 2-Associated Cytokines[J]. Immunity, 2005, 23(5): 479-490.
[20] CHEN LT.Study on the Correlation between Serum Interleukin-17, Interleukin-33 and Chronic Cough[D]. Jilin: Jilin University, 2017.
[21] LI JY, LI PZ, QIU YM, et al.Expression of IL-33/ST2 in Peripheral Blood of Children with Mycoplasma Pneumoniae Pneumonia[J]. Chinese Journal of Child Health Care(中国儿童保健杂志) , 2021, 29(3): 332-334, 338.
[22] MYERS MA, SMITH AP, LANE LC, et al.Dynamically Linking Influenza Virus Infection Kinetics, Lung Injury, Inflammation, and Disease Severity[J]. eLife, 2021, 10: e68864.