Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Korean Red Ginseng suppresses emphysematous lesions induced by cigarette smoke condensate through inhibition of macrophage-driven apoptosis pathways

  • Jeong-Won Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Jin-Hwa Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Chang-Yeop Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Ji-Soo Jeong (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Je-Won Ko (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University) ;
  • Tae-Won Kim (College of Veterinary Medicine (BK21 FOUR Program), Chungnam National University)
  • Received : 2022.09.20
  • Accepted : 2023.11.02
  • Published : 2024.03.01
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Abstract

Background: Cigarette smoke is generally accepted as a major contributor to chronic obstructive pulmonary disease (COPD), which is characterized by emphysematous lesions. In this study, we investigated the protective effects of Korean Red Ginseng (KRG) against cigarette smoke condensate (CSC)-induced emphysema. Methods: Mice were instilled with 50 mg/kg of CSC intranasally once a week for 4 weeks, KRG was administered to the mice once daily for 4 weeks at doses of 100 or 300 mg/kg, and dexamethasone (DEX, positive control) was administered to the mice once daily for 2 weeks at 3 mg/kg. Results: KRG markedly decreased the macrophage population in bronchoalveolar lavage fluid and reduced emphysematous lesions in the lung tissues. KRG suppressed CSC-induced apoptosis as revealed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining and Caspase 3 immunohistochemistry. Additionally, KRG effectively inhibited CSC-mediated activation of Bcl-2-associated X protein/Caspase 3 signaling, followed by the induction of cell survival signaling, including vascular endothelial growth factor/phosphoinositide 3-kinase/protein kinase B in vivo and in vitro. The DEX group also showed similar improved results in vivo and in vitro. Conclusion: Taken together, KRG effectively inhibits macrophage-mediated emphysema induced by CSC exposure, possibly via the suppression of pro-apoptotic signaling, which results in cell survival pathway activation. These findings suggest that KRG has therapeutic potential for the prevention of emphysema in COPD patients.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (MOE).

References

  1. World Health Organization. The top 10 causes of death. 2019 November. https://www.who.int/en/news-room/fact-sheets/detail/the-top-10-causes-of-death.
  2. Collaborators GBD. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392(10159):1789-858. https://doi.org/10.1016/S0140-6736(18)32279-7
  3. World Health Organization. COPD management. 2019 December. https://www.who.int/respiratory/copd/management/en/.
  4. Kurashima K, Takaku Y, Ohta C, Takayanagi N, Yanagisawa T, Kanauchi T, Takahashi O. Smoking history and emphysema in asthma-COPD overlap. Int J Chron Obstr Pulmon Dis 2017;12:3523-32. https://doi.org/10.2147/COPD.S149382
  5. Goldklang M, Stockley R. Pathophysiology of emphysema and implications. Chronic Obstr Pulm Dis 2016;3(1):454-8. https://doi.org/10.15326/jcopdf.3.1.2015.0175
  6. Gwinn MR, Vallyathan V. Respiratory burst: role in signal transduction in alveolar macrophages. J Toxicol Environ Health B Crit Rev 2006;9(1):27-39. https://doi.org/10.1080/15287390500196081
  7. Grashoff WF, Sont JK, Sterk PJ, Hiemstra PS, de Boer WI, Stolk J, Han J, van Krienken JM. Chronic obstructive pulmonary disease: role of bronchiolar mast cells and macrophages. Am J Pathol 1997;151(6):1785-90.
  8. Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, Mapp CE, Fabbri LM, Donner CF, Saetta M. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998;158:1277-85. https://doi.org/10.1164/ajrccm.158.4.9802078
  9. Choi MK, Song IS. Interactions of ginseng with therapeutic drugs. Arch Pharm Res 2019;42(10):862-78. https://doi.org/10.1007/s12272-019-01184-3
  10. In G, Seo HK, Park HW, Jang KH. A metabolomic approach for the discrimination of red ginseng root parts and targeted validation. Molecules 2017;22(3):471.
  11. So SH, Lee JW, Kim YS, Hyun SH, Han CK. Red ginseng monograph. J Ginseng Res 2018;42(4):549-61. https://doi.org/10.1016/j.jgr.2018.05.002
  12. 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 Transl Med 2021;19(1):96.
  13. Kim JH, Kim JW, Kim CY, Jeong JS, Lim JO, Ko JW, Kim TW. Korean red ginseng ameliorates allergic asthma through reduction of lung inflammation and oxidation. Antioxidants 2022;11:1422.
  14. Shergis JL, Di YM, Zhang AL, Vlahos R, Helliwell R, Ye JM, Xue CC. Therapeutic potential of Panax ginseng and ginsenosides in the treatment of chronic obstructive pulmonary disease. Complement Ther Med 2014;22(5):944-53. https://doi.org/10.1016/j.ctim.2014.08.006
  15. Guan S, Xu W, Han F, Gu W, Song L, Ye W, Liu Q, Guo X. Ginsenoside Rg1 attenuates cigarette smoke-induced pulmonary epithelial-mesenchymal transition via inhibition of the TGF-β1/smad pathway. Biomed Res Int 2017;2017:7171404.
  16. Kim S, Kim N, Jeong J, Lee S, Kim W, Ko SG, Kim B. Anti-cancer effect of Panax ginseng and its metabolites: from traditional medicine to modern drug discovery. Processes 2021;9:1344.
  17. Lim JO, Kim WI, Lee SJ, Pak SW, Cho YK, Kim JC, Kim JS, Shin IS. The involvement of PDE4 in the protective effects of melatonin on cigarette-smoke-induced chronic obstructive pulmonary disease. Molecules 2021;26(21):6588.
  18. Park SJ, Noh J, Jeong EJ, Kim YS, Han BC, Lee SH, Moon KS. Subchronic oral toxicity study of Korean red ginseng extract in Sprague-Dawley rats with a 4-week recovery period. Regul Toxicol Pharmacol 2018;92:83-93. https://doi.org/10.1016/j.yrtph.2017.11.007
  19. Kim CY, Kim JW, Kim JH, Jeong JS, Lim JO, Ko JW, Kim TW. Inner shell of the chestnut (Castanea crenatta) suppresses inflammatory responses in ovalbumin-induced allergic asthma mouse model. Nutrients 2022;14:2067.
  20. Hsia CC, Hyde DM, Ochs M, Weibel ER. An official Research policy statement of the American thoracic society/European respiratory society: standards for quantitative assessment of lung structure. Am J Respir Care Med 2010;181(4):394-418. https://doi.org/10.1164/rccm.200809-1522ST
  21. Ko JW, Shin NR, Jung TY, Shin IS, Moon C, Kim SH, Lee IC, Kim SH, Yun WK, Kim HC, et al. Melatonin attenuates cisplatin-induced acute kidney injury in rats via induction of anti-aging protein. Klotho. Food Chem Toxicol 2019;129:201-10. https://doi.org/10.1016/j.fct.2019.04.049
  22. Sharafkhaneh A, Hanania NA, Kim V. Pathogenesis of emphysema: from the bench to the bedside. Proc Am Thorac Soc 2008;5(4):475-7. https://doi.org/10.1513/pats.200708-126ET
  23. Akata K, van Eeden SF. Lung macrophage functional properties in chronic obstructive pulmonary disease. Int J Mol Sci 2020;21(3):853.
  24. Shapiro SD. The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:S29-32. https://doi.org/10.1164/ajrccm.160.supplement_1.9
  25. Vlahos R, Bozinovski S. Role of alveolar macrophages in chronic obstructive pulmonary disease. Front Immunol 2014;5:435.
  26. Miyata R, van Eeden SF. The innate and adaptive immune response induced by alveolar macrophages exposed to ambient particulate matter. Toxicol Appl Pharmacol 2011;257(2):209-26. https://doi.org/10.1016/j.taap.2011.09.007
  27. Hu G, Dong T, Wang S, Jing H, Chen J. Vitamin D3-vitamin D receptor axis suppresses pulmonary emphysema by maintaining alveolar macrophage homeostasis and function. EBioMedicne 2019;45:563-77. https://doi.org/10.1016/j.ebiom.2019.06.039
  28. Pesci A, Balbi B, Cacciani G, Bertacco S, Alciato P, Donner CF. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 1998;12(2):380-6. https://doi.org/10.1183/09031936.98.12020380
  29. Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med 1995;152:1666-72. https://doi.org/10.1164/ajrccm.152.5.7582312
  30. Goldsmith CA, Imrich A, Danaee H, Ning YY, Kobzik L. Analysis of air pollution particulate-mediated oxidant stress in alveolar macrophages. J Toxicol Environ Health A 1998;54:529-45.
  31. Martinou JC, Youle RJ. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 2011;21(1):92-101. https://doi.org/10.1016/j.devcel.2011.06.017
  32. Lan CH, Sheng JQ, Fang DC, Meng QZ, Fan LL, Huang ZR. Involvement of VDAC1 and Bcl-2 family of proteins in VacA-induced cytochrome c release and apoptosis of gastric epithelial carcinoma cells. J Dig Dis 2010;11(1):43-9. https://doi.org/10.1111/j.1751-2980.2009.00412.x
  33. Chambers E, Rounds S, Lu Q. Pulmonary endothelial cell apoptosis in emphysema and acute lung injury. Adv Anat Embryol Cell Biol 2018;228:63-86. https://doi.org/10.1007/978-3-319-68483-3_4
  34. Demedts IK, Demoor T, Bracke KR, Joos GF, Brusselle GG. Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res 2006;7(1):53.
  35. Matsuyama S, Palmer J, Bates A, Poventud-Fuentes I, Wong K, Ngo J, Matsutama M. Bax-induced apoptosis shortens the life span of DNA repair defect Ku70-knockout mice by inducing emphysema. Exp Biol Med 2016;241(12):1265-71. https://doi.org/10.1177/1535370216654587
  36. Morissette MC, Vachon-Beaudoin G, Parent J, Chakir J, Milot J. Increased p53 level, Bax/Bcl-x(L) ratio, and TRAIL receptor expression in human emphysema. Am J Respir Crit Care Med 2008;178(3):240-7. https://doi.org/10.1164/rccm.200710-1486OC
  37. Zhou Y, Tan X, Kuang W, Liu L, Wan L. Erythromycin ameliorates cigarette-smoke-induced emphysema and inflammation in rats. Transl Res 2012;159(6):464-72. https://doi.org/10.1016/j.trsl.2011.09.007
  38. Su X, Taniuchi N, Jin E, Fujiwara M, Zhang L, Ghazizadeh M, Tashimo H, Yamashita N, Ohta K, Kawanami O. Spatial and phenotypic characterization of vascular remodeling in a mouse model of asthma. Pathobiology 2008;75:42-56. https://doi.org/10.1159/000113794
  39. Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 2011;4:51.
  40. Peng N, Gao S, Guo X, Wang G, Cheng C, Li M. Silencing of VEGF inhibits human osteosarcoma angiogenesis and promotes cell apoptosis via VEGF/PI3K/AKT signaling pathway. Am J Transl Res 2016;8:1005-15.
  41. Sun S, Gong F, Liu P, Miao Q. Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway. Gene 2018;664:50-7. https://doi.org/10.1016/j.gene.2018.04.045
  42. Golpon HA, Fadok VA, Taraseviciene-Stewart L, Scerbavicius R, Sauer C, Welte T, Henson PM, Voelkel NF. Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth. FASEB J 2004;18(14):1716-8. https://doi.org/10.1096/fj.04-1853fje
  43. Kranenburg AR, de Boer WI, Alagappan VK, Sterk PJ, Sharma HS. Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease. Thorax 2005;60:106-13. https://doi.org/10.1136/thx.2004.023986
  44. Tsurutani J, Castillo SS, Brognard J, Granville CA, Zhang C, Gills JJ, Sayyah J, Dennis PA. Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis 2005;26(7):1182-95. https://doi.org/10.1093/carcin/bgi072
  45. Wen N, Guo B, Zheng H, Xu L, Liang H, Wang Q, Wang D, Chen X, Zhang S, Li Y, et al. Bromodomain inhibitor jq1 induces cell cycle arrest and apoptosis of glioma stem cells through the VEGF/PI3K/AKT signaling pathway. Int J Oncol 2019;55(4):879-95. https://doi.org/10.3892/ijo.2019.4863
  46. Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41(4):435-43. https://doi.org/10.1016/j.jgr.2016.08.004
  47. Jiang Y, Zhou Z, Meng QT, Sun Q, Su W, Lei S, Xia Z, Xia ZY. Ginsenoside Rb1 treatment attenuates pulmonary inflammatory cytokine release and tissue injury following intestinal ischemia reperfusion injury in mice. Oxid Med Cell Longev 2015;2015:843721.
  48. Fu Z, Xu YS, Cai CQ. Ginsenoside Rg3 inhibits pulmonary fibrosis by preventing HIF-1α nuclear localisation. BMC Pulm Med 2021;21(1):70.