Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Inhalation of panaxadiol alleviates lung inflammation via inhibiting TNFA/TNFAR and IL7/IL7R signaling between macrophages and epithelial cells

  • Yifan Wang (Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health) ;
  • Hao Wei (Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health) ;
  • Zhen Song (Department of Molecular Bioinformatics, Institute of Computer Science, Goethe University Frankfurt) ;
  • Liqun Jiang (Department of Pharmacy, Xuzhou Medical University) ;
  • Mi Zhang (Department of Pharmacy, Xuzhou Medical University) ;
  • Xiao Lu (Shenyang Pharmaceutical University) ;
  • Wei Li (Shenyang Pharmaceutical University) ;
  • Yuqing Zhao (Shenyang Pharmaceutical University) ;
  • Lei Wu (Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health) ;
  • Shuxian Li (Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health) ;
  • Huijuan Shen (The Second Affiliated Hospital, Zhejiang University School of Medicine) ;
  • Qiang Shu (Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health) ;
  • Yicheng Xie (Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health)
  • Received : 2023.02.15
  • Accepted : 2023.09.13
  • Published : 2024.01.01
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Abstract

Background: Lung inflammation occurs in many lung diseases, but has limited effective therapeutics. Ginseng and its derivatives have anti-inflammatory effects, but their unstable physicochemical and metabolic properties hinder their application in the treatment. Panaxadiol (PD) is a stable saponin among ginsenosides. Inhalation administration may solve these issues, and the specific mechanism of action needs to be studied. Methods: A mouse model of lung inflammation induced by lipopolysaccharide (LPS), an in vitro macrophage inflammation model, and a coculture model of epithelial cells and macrophages were used to study the effects and mechanisms of inhalation delivery of PD. Pathology and molecular assessments were used to evaluate efficacy. Transcriptome sequencing was used to screen the mechanism and target. Finally, the efficacy and mechanism were verified in a human BALF cell model. Results: Inhaled PD reduced LPS-induced lung inflammation in mice in a dose-dependent manner, including inflammatory cell infiltration, lung tissue pathology, and inflammatory factor expression. Meanwhile, the dose of inhalation was much lower than that of intragastric administration under the same therapeutic effect, which may be related to its higher bioavailability and superior pharmacokinetic parameters. Using transcriptome analysis and verification by a coculture model of macrophage and epithelial cells, we found that PD may act by inhibiting TNFA/TNFAR and IL7/IL7R signaling to reduce macrophage inflammatory factor-induced epithelial apoptosis and promote proliferation. Conclusion: PD inhalation alleviates lung inflammation and pathology by inhibiting TNFA/TNFAR and IL7/IL7R signaling between macrophages and epithelial cells. PD may be a novel drug for the clinical treatment of lung inflammation.

Keywords

Acknowledgement

The language is edited by the American Journal Experts (AJE) with the verification code 2BCO-5BFF-9962-4659-86A3.

References

  1. Cui S, Wu J, Wang J, Wang X. Discrimination of American ginseng and Asian ginseng using electronic nose and gas chromatography-mass spectrometry coupled with chemometrics. J Ginseng Res 2017;41:85-95. https://doi.org/10.1016/j.jgr.2016.01.002
  2. Boonlert W, Benya AH, Umka WJ, Rodsiri R. Ginseng extract G115 attenuates ethanol-induced depression in mice by increasing brain BDNF levels. Nutrients 2017;9.
  3. Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003;31:1065-71. https://doi.org/10.1124/dmd.31.8.1065
  4. Hsu BY, Lu TJ, Chen CH, Wang SJ, Hwang LS. Biotransformation of ginsenoside Rd in the ginseng extraction residue by fermentation with lingzhi (Ganoderma lucidum). Food Chemistry 2013;141:4186-93. https://doi.org/10.1016/j.foodchem.2013.06.134
  5. Lin XH, Cao MN, He WN, Yu SW, Guo DA, Ye M. Biotransformation of 20(R)-panaxadiol by the fungus Rhizopus chinensis. Phytochemistry 2014;105:129-34. https://doi.org/10.1016/j.phytochem.2014.06.001
  6. Lee HJ, Kim SR, Kim JC, Kang CM, Lee YS, Jo SK, Kim TH, Jang JS, Nah SY, Kim SH. In Vivo radioprotective effect of Panax ginseng C.A. Meyer and identification of active ginsenosides. Phytother Res 2006;20:392-5. https://doi.org/10.1002/ptr.1867
  7. Liang X, Yao Y, Lin Y, Kong L, Xiao H, Shi Y, Yang J. Panaxadiol inhibits synaptic dysfunction in Alzheimer's disease and targets the Fyn protein in APP/PS1 mice and APP-SH-SY5Y cells. Life Sci 2019;221:35-46. https://doi.org/10.1016/j.lfs.2019.02.012
  8. Kwon BM, Kim MK, Baek NI, Kim DS, Park JD, Kim YK, Lee HK, Kim SI. Acyl-CoA: cholesterol acyltransferase inhibitory activity of ginseng sapogenins, produced from the ginseng saponins. Bioorg Med Chem Lett 1999;9:1375-8. https://doi.org/10.1016/S0960-894X(99)00208-5
  9. Quinton LJ, Walkey AJ, Mizgerd JP. Integrative physiology of pneumonia. Physiol Rev 2018;98:1417-64.
  10. Scherer PM, Chen DL. Imaging pulmonary inflammation. J. Nucl. Med. : Official Publication, Society of Nuclear Medicine 2016;57:1764-70. https://doi.org/10.2967/jnumed.115.157438
  11. Zhang G, Mo S, Fang B, Zeng R, Wang J, Tu M, Zhao J. Pulmonary delivery of therapeutic proteins based on zwitterionic chitosan-based nanocarriers for treatment on bleomycin-induced pulmonary fibrosis. Int J Biol Macromol 2019;133:58-66. https://doi.org/10.1016/j.ijbiomac.2019.04.066
  12. Thakur AK, Chellappan DK, Dua K, Mehta M, Satija S, Singh I. Patented therapeutic drug delivery strategies for targeting pulmonary diseases. Expert Opinion on Therapeutic Patents 2020;30:375-87. https://doi.org/10.1080/13543776.2020.1741547
  13. Li J, Lu K, Sun F, Tan S, Zhang X, Sheng W, Hao W, Liu M, Lv W, Han W. Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway. J. Translat. Med. 2021;19:1-14. https://doi.org/10.1186/s12967-020-02683-4
  14. Xie YC, Dong XW, Wu XM, Yan XF, Xie QM. Inhibitory effects of flavonoids extracted from licorice on lipopolysaccharide-induced acute pulmonary inflammation in mice. Int. Immunoph. 2009;9:194-200. https://doi.org/10.1016/j.intimp.2008.11.004
  15. Rankin JA, Marcy T, Rochester CL, Sussman J, Smith S, Buckley P, Lee D. Human airway macrophages. A technique for their retrieval and a descriptive comparison with alveolar macrophages. Am Rev Respir Dis 1992;145:928-33. https://doi.org/10.1164/ajrccm/145.4_Pt_1.928
  16. Zhang C, Li W, Li X, Wan D, Mack S, Zhang J, Wagner K, Wang C, Tan B, Chen J. Novel aerosol treatment of airway hyper-reactivity and inflammation in a murine model of asthma with a soluble epoxide hydrolase inhibitor. PloS One 2022;17:e0266608.
  17. Gao S, Hu J, Wu X, Liang Z. PMA treated THP-1-derived-IL-6 promotes EMT of SW48 through STAT3/ERK-dependent activation of Wnt/beta-catenin signaling pathway. Biomed Pharmacother 2018;108:618-24. https://doi.org/10.1016/j.biopha.2018.09.067
  18. Tonder A, Joubert AM, Cromarty AD. Limitations of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay when compared to three commonly used cell enumeration assays. BMC Res Notes 2015;8:47.
  19. Gong L, Zhu T, Chen C, Xia N, Yao Y, Ding J, Xu P, Li S, Sun Z, Dong X, et al. Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-kappaB pathway and iNOS production. Neurobiol Dis 2022;172:105823.
  20. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, Galon J. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 2009;25:1091-3. https://doi.org/10.1093/bioinformatics/btp101
  21. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, McCastlain K, Edmonson M, Pounds SB, Shi L, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 2017;49:1211-8. https://doi.org/10.1038/ng.3909
  22. Fan EKY, Fan J. Regulation of alveolar macrophage death in acute lung inflammation. Respir Res 2018;19:50.
  23. Cosio MG, Guerassimov A. Chronic obstructive pulmonary disease. Inflammation of small airways and lung parenchyma. Am. J. Respirat. Critical Care Med. 1999;160:S21-5. https://doi.org/10.1164/ajrccm.160.supplement_1.7
  24. Liu C, Xiao K, Xie L. Progress in preclinical studies of macrophage autophagy in the regulation of ALI/ARDS. Front Immunol 2022;13:922702.
  25. Mokra D, Kosutova P. Biomarkers in acute lung injury. Respir Physiol Neurobiol 2015;209:52-8.
  26. Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017;377:562-72. https://doi.org/10.1056/NEJMra1608077
  27. Byrne AJ, Mathie SA, Gregory LG, Lloyd CM. Pulmonary macrophages: key players in the innate defence of the airways. Thorax 2015;70:1189-96. https://doi.org/10.1136/thoraxjnl-2015-207020
  28. Yu X, Buttgereit A, Lelios I, Utz SG, Cansever D, Becher B, Greter M. The cytokine TGF-beta promotes the development and homeostasis of alveolar macrophages. Immunity 2017;47:903-912 e4.
  29. Huang X, Xiu H, Zhang S, Zhang G. The role of macrophages in the pathogenesis of ALI/ARDS. Mediators Inflamm 2018;2018:1264913.
  30. Li W, Li D, Chen Y, Abudou H, Wang H, Cai J, Wang Y, Liu Z, Liu Y, Fan H. Classic signaling pathways in alveolar injury and repair involved in sepsis-induced ALI/ARDS: new research progress and prospect. Dis Markers 2022;2022:6362344.
  31. Luh SP, Chiang CH. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): the mechanism, present strategies and future perspectives of therapies. J Zhejiang Univ Sci B 2007;8:60-9. https://doi.org/10.1631/jzus.2007.B0060
  32. Mohan A, Agarwal S, Clauss M, Britt NS, Dhillon NK. Extracellular vesicles: novel communicators in lung diseases. Respir Res 2020;21:175.
  33. Gschwend J, Sherman SPM, Ridder F, Feng X, Liang HE, Locksley RM, Becher B, Schneider C. Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth. J Exp Med 2021:218.
  34. Bissonnette EY, Lauzon JJF, Debley JS, Ziegler SF. Cross-talk between alveolar macrophages and lung epithelial cells is essential to maintain lung homeostasis. Front Immunol 2020;11:583042.
  35. Tao H, Xu Y, Zhang S. The role of macrophages and alveolar epithelial cells in the development of ARDS. Inflammation 2023;46:47-55. https://doi.org/10.1007/s10753-022-01726-w
  36. Mu M, Gao P, Yang Q, He J, Wu F, Han X, Guo S, Qian Z, Song C. Alveolar epithelial cells promote IGF-1 production by alveolar macrophages through TGF-beta to suppress endogenous inflammatory signals. Front Immunol 2020;11:1585.
  37. Baloglu E, Velineni K, Ermis KE, Mairbaurl H. Hypoxia aggravates inhibition of alveolar epithelial Na-transport by lipopolysaccharide-stimulation of alveolar macrophages. Int. J. Molecul. Sci. 2022;23.
  38. Sadikot RT, Bedi B, Li J, Yeligar SM. Alcohol-induced mitochondrial DNA damage promotes injurious crosstalk between alveolar epithelial cells and alveolar macrophages. Alcohol 2019;80:65-72. https://doi.org/10.1016/j.alcohol.2018.08.006
  39. Du J, Li G, Jiang L, Zhang X, Xu Z, Yan H, Zhou Z, He Q, Yang X, Luo P. Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib. Toxicol Lett 2021;338:1-9. https://doi.org/10.1016/j.toxlet.2020.11.011
  40. Conlon TM, Schuster JG, Heide D, Pfister D, Lehmann M, Hu Y, Ertuz Z, Lopez MA, Ansari M, Strunz M, et al. Inhibition of LTbetaR signalling activates WNT-induced regeneration in lung. Nature 2020;588:151-6. https://doi.org/10.1038/s41586-020-2882-8
  41. Wang X, Chang S, Wang T, Wu R, Huang Z, Sun J, Liu J, Yu Y, Mao Y. IL7R is correlated with immune cell infiltration in the tumor microenvironment of lung adenocarcinoma. Front Pharmacol 2022;13:857289.
  42. Guo D, Dunbar JD, Yang CH, Pfeffer LM, Donner DB. Induction of Jak/STAT signaling by activation of the type 1 TNF receptor. J Immunol 1998;160:2742-50. https://doi.org/10.4049/jimmunol.160.6.2742
  43. Li WQ, Jiang Q, Khaled AR, Keller JR, Durum SK. Interleukin-7 inactivates the pro-apoptotic protein Bad promoting T cell survival. Journal of Biological Chemistry 2004;279:29160-6.
  44. Armant M, Delespesse G, Sarfati M. IL-2 and IL-7 but not IL-12 protect natural killer cells from death by apoptosis and up-regulate bcl-2 expression. Immunology 1995;85:331.
  45. Sammicheli S, Dang Vu Phuong L, Ruffin N, Pham Hong T, Lantto R, Vivar N, Chiodi F, Rethi B. IL-7 promotes CD95-induced apoptosis in B cells via the IFN-γ/STAT1 pathway. PloS One 2011;6:e28629.
  46. Yan M, Yang Y, Zhou Y, Yu C, Li R, Gong W, Zheng J. Interleukin-7 aggravates myocardial ischaemia/reperfusion injury by regulating macrophage infiltration and polarization. J Cell Mol Med 2021;25:9939-52. https://doi.org/10.1111/jcmm.16335
  47. Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov 2007;6:67-74. https://doi.org/10.1038/nrd2153