Original articles

Jinxin oral liquid (金欣口服液) reduced lung inflammation in influenza A virus infected mice through inhibiting NOD-like receptor protein 3 pathway

  • Tao LI ,
  • Xianzheng WANG ,
  • Yingcai XIONG ,
  • Qigang DAI ,
  • Shouchuan WANG ,
  • Jianjian JI
Expand
  • 1 Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
    2 Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
    3 Basic Medical College of Hebei University of Traditional Chinese Medicine, Shijiazhuang 050200, China

Received date: 2023-12-06

  Accepted date: 2024-05-15

  Online published: 2025-03-10

Supported by

Young Elite Scientists Sponsorship Program by Chinese Association for Clinical Medicine(2021-QNRC2-B14);Colleges and universities in Jiangsu Province Natural Science Research: Investigating the Mechanism of Jinping Decoction Inhibiting the Differentiation of Myeloid-derived Suppressor Cells and Regulating Lipid Metabolism(22KJA360004);Jiangsu Graduate Practice Innovation Program: A Study on the Mechanism of Xiaofeng Xuanqiao Decoction in Treating Pediatric Rhinitis based on Interleukin-33/Suppression of Tumorigenicity 2(SJCX23_0803);Wuxi Health Commission Scientific Research Project: Observation on the Efficacy of Xiaofeng Xuanqiao Decoction in Treating Pediatric Rhinitis (Wind-Phlegm Obstructing Orifices Syndrome) and Its Influence on Serum IgE and Related Inflammatory Cytokine Levels(M202035);High-level Construction of Key Traditional Chinese Medicine (TCM) Disciplines, China: Research on Tic Disorders from the Perspective of the Five Viscera Syndrome Treatment(NZYEK004);High-level Construction of Key TCM Disciplines, China: Research on the Mechanism of Xiaofeng Xuanqiao Decoction in Treating Allergic Rhinitis based on the Interleukin-33/ST2 Axis(NZYEK006)

Abstract

OBJECTIVE: To investigate the therapeutic effects of Jinxin oral liquid (金欣口服液, JX) on influenza A virus(H1N1)influenza virus infected mice.

METHODS: We established a model of by intranasally infecting the mice with H1N1 virus. The mice were then orally administered JX or ribavirin to evaluate their therapeutic effects in vivo. We conducted histologic and immunohistochemical analyses, enzyme linked immunosorbent assay or quantitative real-time polymerase chain reaction to assess lung damage and the expression of inflammatory cytokines. Western blot (WB) experiments was conducted to measure the activation of NOD-like receptor protein 3 (NLRP3) pathway. Flow cytometry was employed to quantify the populations of alveolar macrophages (AMs). To block the NLRP3 pathway, mice were treated with MCC950. For AMs depletion, mice were intranasally administered a single dose of clodronate liposome.

RESULTS: Administration of JX demonstrated a protective effect against H1N1-induced lung pathology by reducing lung injury, suppressing lung inflammation, and decreasing viral titer. JX significantly inhibited the production of pro-inflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor-ɑ, in H1N1-infected mice. JX inhibits the activation of NOD-like receptor protein 3 (NLRP3)/apoptosis-associated speck-like protein containing a caspase recruitment domain/ caspase 1 pathway in the lungs and AMs of H1N1-infected mice. The inhibitory effect of JX on IL-1β secretion was mediated by blocking the NLRP3 pathway activation in AMs.

CONCLUSIONS: These findings suggest that JX holds promise as a potential therapeutic agent for suppressing the aggressive pro-inflammatory response induced by H1N1 infection. Further research and development are warranted to explore the full potential of JX in the prevention and treatment of H1N1 infection

Cite this article

Tao LI , Xianzheng WANG , Yingcai XIONG , Qigang DAI , Shouchuan WANG , Jianjian JI . Jinxin oral liquid (金欣口服液) reduced lung inflammation in influenza A virus infected mice through inhibiting NOD-like receptor protein 3 pathway[J]. Journal of Traditional Chinese Medicine, 2025 , 45(2) : 281 -290 . DOI: 10.19852/j.cnki.jtcm.2025.02.022

References

1. Brody H. Influenza. Nature 2019; 573: S49.
2. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol 2016; 13: 3-10.
3. Guo XJ, Thomas PG. New fronts emerge in the influenza cytokine storm. Semin Immunopathol 2017; 39: 541-50.
4. Chen S, Liu G, Chen J, et al. Ponatinib protects mice from lethal influenza infection by suppressing cytokine storm. Front Immunol 2019; 10: 1393.
5. Fajgenbaum DC, June CH. Cytokine Storm. N Engl J Med 2020; 383: 2255-73.
6. Teijaro JR, Walsh KB, Rice S, Rosen H, Oldstone MB. Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection. Proc Natl Acad Sci USA 2014; 111: 3799-804.
7. Teijaro JR. The role of cytokine responses during influenza virus pathogenesis and potential therapeutic options. Curr Top Microbiol Immunol 2015; 386: 3-22.
8. Hartshorn KL. Innate immunity and influenza A virus pathogenesis: lessons for COVID-19. Front Cell Infect Microbiol 2020; 10: 563850.
9. Wang S, Le TQ, Kurihara N, et al. Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza. J Infect Dis 2010; 202: 991-1001.
10. Hsieh CF, Lo CW, Liu CH, et al. Mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus. J Ethnopharmacol 2012; 143: 57-67.
11. Nosaka N, Martinon D, Moreira D, Crother TR, Arditi M, Shimada K. Autophagy protects against developing increased lung permeability and hypoxemia by down regulating inflammasome activity and IL-1β in LPS plus mechanical ventilation-induced acute lung injury. Front Immunol 2020; 11: 207.
12. Tuku B, Stanelle-Bertram S, Sellau J, et al. Testosterone Protects against severe influenza by reducing the pro-inflammatory cytokine response in the murine lung. Front Immunol 2020; 11: 697.
13. Peiro T, Patel DF, Akthar S, et al. Neutrophils drive alveolar macrophage IL-1 beta release during respiratory viral infection. Thorax 2018; 73: 546-56.
14. Kuriakose T, Kanneganti TD. Regulation and functions of NLRP3 inflammasome during influenza virus infection. Mol Immunol 2017; 86: 56-64.
15. Huang Y, Xu W, Zhou R. NLRP3 inflammasome activation and cell death. Cell Mol Immunol 2021; 18: 2114-27.
16. Lin L, Xu L, Lv W, et al. An NLRP3 inflammasome-triggered cytokine storm contributes to streptococcal toxic shock-like syndrome (STSLS). Plos Pathog 2019; 15: e1007795.
17. Freeman TL, Swartz TH. Targeting the NLRP3 Inflammasome in Severe COVID-19. Front Immunol 2020; 11: 1518.
18. Coates BM, Staricha KL, Ravindran N, et al. Inhibition of the NOD-like receptor protein 3 inflammasome is protective in juvenile influenza A virus infection. Front Immunol 2017; 8: 782.
19. Xiong Y, Li NX, Duan N, et al. Traditional Chinese Medicine in treating influenza: from basic science to clinical applications. Front Pharmacol 2020; 11: 575803.
20. Chen ZG, Luo H, Wang SC, Xu JY, Li JX. Antiviral effects of Jinxin oral liquid against respiratory syncytial virus infection in the BALB/c mice model. J Ethnopharmacol 2015; 162: 287-95.
21. Shen C, Zhang Z, Xie T, et al. Jinxin oral liquid inhibits human respiratory syncytial virus-induced excessive inflammation associated with blockade of the NLRP3/ASC/Caspase-1 pathway. Biomed Pharmacother 2018; 103: 1376-83.
22. Jiang L, Deng L, Wu T. Chinese medicinal herbs for influenza. Cochrane Database Syst Rev 2013; 2013: D4559.
23. Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages. Curr Protoc Immunol 2008; Chapter 14: 11-4.
24. Kolli D, Gupta MR, Sbrana E, et al. Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection. Am J Respir Cell Mol Biol 2014; 51: 502-15.
25. Coll RC, Hill JR, Day CJ, et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol 2019; 15: 556-59.
26. Coates BM, Staricha KL, Wiese KM, Ridge KM. Influenza A virus infection, innate immunity, and childhood. JAMA Pediatr 2015; 169: 956-63.
27. Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol 2016; 12: 259-68.
28. Allen IC, Scull MA, Moore CB, et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 2009; 30: 556-65.
29. Thomas PG, Dash P, Aldridge JJ, et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 2009; 30: 566-75.
30. McAuley JL, Tate MD, MacKenzie-Kludas CJ, et al. Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease. Plos Pathog 2013; 9: e1003392.
31. Tate MD, Ong J, Dowling JK, et al. Reassessing the role of the NLRP 3 inflammasome during pathogenic influenza A virus infection via temporal inhibition. Sci Rep 2016; 6: 27912.
32. Park HS, Liu G, Thulasi RS, Landreth SL, Liu Q, Zhou Y. NS1 protein of 2009 pandemic influenza A virus inhibits porcine NLRP3 inflammasome-mediated interleukin-1 beta production by suppressing ASC ubiquitination. J Virol 2018; 92.
33. Liesman RM, Buchholz UJ, Luongo CL, et al. RSV-encoded NS2 promotes epithelial cell shedding and distal airway obstruction. J Clin Invest 2014; 124: 2219-33.
34. Huanbo C, Hui HU, Daihua S, Guangzhong W. Anti-inflammatory, anti-tussive effects and toxicity evaluation of Qingfei Dayuan granules. J Tradit Chin Med 2023; 43: 1110-17.
35. Rong F, Haoyu HE, Tao T, Hanjin C. Long-term effects of Qingfei Paidu decoction in patients with coronavirus disease 2019 acute pneumonia after treatment: a protocol for systematic review and Meta-analysis. J Tradit Chin Med 2023; 43: 1068-71.
Outlines

/