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Pulmonary Protective Functions of Rare Ginsenoside Rg4 on Particulate Matter-induced Inflammatory Responses

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Abstract

Inhalation of fine particulate matter (PM2.5) is associated with an increase in lung injury caused by the loss of integrity of the vascular barrier. The rare ginsenoside Rg4 is a main protopanaxatriol type ginsenoside of black ginseng (BG). The aim of this study was to investigate the beneficial effects of Rg4 on PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated EC and mice. Rg4 significantly scavenged PM2.5-induced ROS, inhibited ROS-induced activation of p38 mitogen-activated protein kinase (MAPK), activated Akt in purified pulmonary endothelial cells, which helped maintain endothelial integrity. Further, Rg4 reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in PM-induced mouse lung tissues. Data suggested that Rg4 might exhibit protective effects in PM-induced inflammatory lung injury and vascular hyperpermeability.

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References

  1. Liu, Q., C. Xu, G. Ji, H. Liu, W. Shao, C. Zhang, A. Gu, and P. Zhao (2017) Effect of exposure to ambient PM2.5 pollution on the risk of respiratory tract diseases: a meta-analysis of cohort studies. J. Biomed. Res. 31: 130–142.

    PubMed  PubMed Central  Google Scholar 

  2. Xing, Y. F., Y. H. Xu, M. H. Shi, and Y. X. Lian (2016) The impact of PM2.5 on the human respiratory system. J. Thorac. Dis. 8: E69–74.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rao, X., J. Zhong, R. D. Brook, and S. Rajagopalan (2018) Effect of particulate matter air pollution on cardiovascular oxidative stress pathways. Antioxid. Redox Signal. 28: 797–818.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brook, R. D., B. Franklin, W. Cascio, Y. Hong, G. Howard, M. Lipsett, R. Luepker, M. Mittleman, J. Samet, S. C. Smith, Jr., and I. Tager (2004) Air pollution and cardiovascular disease: a statement for healthcare professionals from the expert panel on population and prevention science of the American heart association. Circulation. 109: 2655–2671.

    Article  PubMed  Google Scholar 

  5. Araujo, J. A., and A. E. Nel (2009) Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress. Part. Fibre Toxicol. 6: 24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. de Kok, T. M., L. G. Engels, E. J. Moonen, and J. C. Kleinjans (2005) Inflammatory bowel disease stimulates formation of carcinogenic N-nitroso compounds. Gut. 54: 731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sun, Y., Y. Yin, J. Zhang, H. Yu, X. Wang, J. Wu, and Y. Xue (2008) Hydroxyl radical generation and oxidative stress in Carassius auratus liver, exposed to pyrene. Ecotoxicol. Environ. Saf. 71: 446–453.

    Article  CAS  PubMed  Google Scholar 

  8. Wu, S., F. Deng, Y. Hao, X. Wang, C. Zheng, H. Lv, X. Lu, H. Wei, J. Huang, Y. Qin, M. Shima, and X. Guo (2014) Fine particulate matter, temperature, and lung function in healthy adults: findings from the HVNR study. Chemosphere 108: 168–174.

    Article  CAS  PubMed  Google Scholar 

  9. Shusterman, D. (2011) The effects of air pollutants and irritants on the upper airway. Proc. Am. Thorac. Soc. 8: 101–105.

    Article  CAS  PubMed  Google Scholar 

  10. Deng, X., F. Zhang, W. Rui, F. Long, L. Wang, Z. Feng, D. Chen, and W. Ding (2013) PM2.5-induced oxidative stress triggers autophagy in human lung epithelial A549 cells. Toxicol. In Vitro. 27: 1762–1770.

    Article  CAS  PubMed  Google Scholar 

  11. Kelly, F. J. and J. C. Fussell (2015) Linking ambient particulate matter pollution effects with oxidative biology and immune responses. Ann. N. Y. Acad. Sci. 1340: 84–94

    Article  CAS  PubMed  Google Scholar 

  12. Dong, H., L. P. Bai, V. K. Wong, H. Zhou, J. R. Wang, Y. Liu, Z. H. Jiang, and L. Liu (2011) The in vitro structure-related anticancer activity of ginsenosides and their derivatives. Molecules 16: 10619–10630.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wu, J. Y., B. H. Gardner, C. I. Murphy, J. R. Seals, C. R. Kensil, J. Recchia, G. A. Beltz, G. W. Newman, and M. J. Newman (1992) Saponin adjuvant enhancement of antigen-specific immune responses to an experimental HIV-1 vaccine. J. Immunol. 148: 1519–1525.

    CAS  PubMed  Google Scholar 

  14. Nag, S. A., J. J. Qin, W. Wang, M. H. Wang, H. Wang, and R. W. Zhang (2012) Ginsenosides as anticancer agents: in vitro and in vivo activities, structure-activity relationships, and molecular mechanisms of action. Front. Pharmacol. 3.

  15. Park, J. D., D. K. Rhee, and Y. H. Lee (2005) Biological Activities and Chemistry of Saponins from Panax ginseng C. A. Meyer. Phytochem. Rev 4: 159–175.

    Article  CAS  Google Scholar 

  16. Kang, O. H., M. Y. Shon, R. Kong, Y. S. Seo, T. Zhou, D. Y. Kim, Y. S. Kim, and D. Y. Kwon (2017) Anti-diabetic effect of black ginseng extract by augmentation of AMPK protein activity and upregulation of GLUT2 and GLUT4 expression in db/db mice. BMC Complem. Altern. M. 17: 341.

    Article  CAS  Google Scholar 

  17. Park, J. Y., D. S. Lee, C. E. Kim, M. S. Shin, C. S. Seo, H. K. Shin, G. S. Hwang, J. M. An, S. N. Kim, and K. S. Kang (2018) Effects of fermented black ginseng on wound healing mediated by angiogenesis through the mitogen-activated protein kinase pathway in human umbilical vein endothelial cells. J. Ginseng Res. 42: 524–531.

    Article  PubMed  Google Scholar 

  18. Saba, E., Y. Y. Lee, M. Kim, S. H. Kim, S. B. Hong, and M. H. Rhee (2018) A comparative study on immune-stimulatory and antioxidant activities of various types of ginseng extracts in murine and rodent models. J. Ginseng Res. 42: 577–584.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sun, B. S., L. J. Gu, Z. M. Fang, C. Y. Wang, Z. Wang, M. R. Lee, Z. Li, J. J. Li, and C. K. Sung (2009) Simultaneous quantification of19 ginsenosides in black ginseng developed from Panax ginseng by HPLC-ELSD. J. Pharm. Biomed. Anal. 50: 15–22.

    Article  CAS  PubMed  Google Scholar 

  20. Cho, J. H., H. Y. Chun, J. S. Lee, J. H. Lee, K. J. Cheong, Y. S. Jung, T. G. Woo, M. H. Yoon, A. Y. Oh, S. M. Kang, C. Lee, H. Sun, J. Hwang, G. Y. Song, and B. J. Park (2016) Prevention effect of rare ginsenosides against stress-hormone induced MTOC amplification. Oncotarget 7: 35144–35158.

    PubMed  PubMed Central  Google Scholar 

  21. Lee, J. H., H. Lim, O. Shehzad, Y. S. Kim, and H. P. Kim (2014) Ginsenosides from Korean red ginseng inhibit matrix metalloproteinase-13 expression in articular chondrocytes and prevent cartilage degradation. Eur. J. Pharmacol. 724: 145–151.

    Article  CAS  PubMed  Google Scholar 

  22. Chen, B., Y. P. Shen, D. F. Zhang, J. Cheng, and X. B. Jia (2013) The apoptosis-inducing effect of ginsenoside F4 from steamed notoginseng on human lymphocytoma JK cells. Nat. Prod. Res. 27: 2351–2354.

    Article  CAS  PubMed  Google Scholar 

  23. Wang, H., L. Song, W. Ju, X. Wang, L. Dong, Y. Zhang, P. Ya, C. Yang, and F. Li (2017) The acute airway inflammation induced by PM2.5 exposure and the treatment of essential oils in Balb/c mice. Sci. Rep-UK. 7: 44256.

    Article  Google Scholar 

  24. Kovacs-Kasa, A., M. N. Varn, A. D. Verin, and J. N. Gonzales (2017) Method for the culture of mouse pulmonary microvascular endothelial cells. Sci. Pages Pulmonol. 1: 7–18.

    PubMed  PubMed Central  Google Scholar 

  25. Kim, J. E., W. Lee, S. Yang, S. H. Cho, M. C. Baek, G. Y. Song, and J. S. Bae (2019) Suppressive effects of rare ginsenosides, Rk1 and Rg5, on HMGB1-mediated septic responses. Food Chem. Toxicol. 124: 45–53.

    Article  CAS  PubMed  Google Scholar 

  26. Lee, I. C., and J. S. Bae (2019) Pelargonidin protects against renal injury in a mouse model of sepsis. J. Med. Food. 22: 57–61.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, L., and M. C. Wang (2018) Growth Inhibitory Effect of Mangiferin on Thyroid Cancer Cell Line TPC1. Biotechnol. Bioproc. E. 23: 649–654.

    Article  CAS  Google Scholar 

  28. Jang, M. H., N. H. Kang, S. Mukherjee, and J. W. Yun (2018) Theobromine, a methylxanthine in cocoa bean, stimulates thermogenesis by inducing white fat browning and activating brown adipocytes. Biotechnol. Bioproc E. 23: 617–626.

    Article  CAS  Google Scholar 

  29. Piao, M. J., M. J. Ahn, K. A. Kang, Y. S. Ryu, Y. J. Hyun, K. Shilnikova, A. X. Zhen, J. W. Jeong, Y. H. Choi, H. K. Kang, Y. S. Koh, and J. W. Hyun (2018) Particulate matter 2.5 damages skin cells by inducing oxidative stress, subcellular organelle dysfunction, and apoptosis. Arch. Toxicol. 92: 2077–2091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ozdulger, A., I. Cinel, O. Koksel, L. Cinel, D. Avlan, A. Unlu, H. Okcu, M. Dikmengil, and U. Oral (2003) The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model. Shock 19: 366–372.

    Article  CAS  PubMed  Google Scholar 

  31. Wang, T., Y. Shimizu, X. Wu, G. T. Kelly, X. Xu, L. Wang, Z. Qian, Y. Chen, and J. G. N. Garcia (2017) Particulate matter disrupts human lung endothelial cell barrier integrity via Rhodependent pathways. Pulm. Circ. 7: 617–623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang, T., E. T. Chiang, L. Moreno-Vinasco, G. D. Lang, S. Pendyala, J. M. Samet, A. S. Geyh, P. N. Breysse, S. N. Chillrud, V. Natarajan, and J. G. Garcia (2010) Particulate matter disrupts human lung endothelial barrier integrity via ROS- and p38 MAPK-dependent pathways. Am. J. Respir. Cell Mol. Biol. 42: 442–449.

    Article  CAS  PubMed  Google Scholar 

  33. Qin, Y. H., S. M. Dai, G. S. Tang, J. Zhang, D. Ren, Z. W. Wang, and Q. Shen (2009) HMGB1 enhances the proinflammatory activity of lipopolysaccharide by promoting the phosphorylation of MAPK p38 through receptor for advanced glycation end products. J. Immunol. 183: 6244–6250.

    Article  CAS  PubMed  Google Scholar 

  34. Sun, C., C. Liang, Y. Ren, Y. Zhen, Z. He, H. Wang, H. Tan, X. Pan, and Z. Wu (2009) Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Res. Cardiol. 104: 42–49.

    Article  CAS  PubMed  Google Scholar 

  35. Zhao, Y., P. V. Usatyuk, I. A. Gorshkova, D. He, T. Wang, L. Moreno-Vinasco, A. S. Geyh, P. N. Breysse, J. M. Samet, E. W. Spannhake, J. G. Garcia, and V. Natarajan (2009) Regulation of COX-2 expression and IL-6 release by particulate matter in airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 40: 19–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Xu, C., Q. Shi, L. Zhang, and H. Zhao (2018) High molecular weight hyaluronan attenuates fine particulate matter-induced acute lung injury through inhibition of ROS-ASK1-p38/JNK-mediated epithelial apoptosis. Environ. Toxicol. Pharmacol. 59: 190–198.

    Article  CAS  PubMed  Google Scholar 

  37. Gualtieri, M., E. Longhin, M. Mattioli, P. Mantecca, V. Tinaglia, E. Mangano, M. C. Proverbio, G. Bestetti, M. Camatini, and C. Battaglia (2012) Gene expression profiling of A549 cells exposed to Milan PM2.5. Toxicol. Lett. 209: 136–145.

    Article  CAS  PubMed  Google Scholar 

  38. Bellacosa, A., T. O. Chan, N. N. Ahmed, K. Datta, S. Malstrom, D. Stokoe, F. McCormick, J. N. Feng, and P. Tsichlis (1998) Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17: 313–325.

    Article  CAS  PubMed  Google Scholar 

  39. Singleton, P. A., S. Chatchavalvanich, P. Fu, J. Xing, A. A. Birukova, J. A. Fortune, A. M. Klibanov, J. G. Garcia, and K. G. Birukov (2009) Akt-mediated transactivation of the S1P1 receptor in caveolin-enriched microdomains regulates endothelial barrier enhancement by oxidized phospholipids. Circ. Res. 104: 978–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shiojima, I. and K. Walsh (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ. Res. 90: 1243–1250.

    Article  CAS  PubMed  Google Scholar 

  41. Komarova, Y. A., D. Mehta, and A. B. Malik (2007) Dual regulation of endothelial junctional permeability. Sci. STKE. 2007: re8.

    Article  PubMed  Google Scholar 

  42. Curry, F. R. and R. H. Adamson (2013) Tonic regulation of vascular permeability. Acta Physiol. (Oxf) 207: 628–649.

    Article  CAS  Google Scholar 

  43. Mehta, D., K. Ravindran, and W. M. Kuebler (2014) Novel regulators of endothelial barrier function. Am. J. Physiol. Lung Cell. Mol. Physiol. 307: L924–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Dominici, F., R. D. Peng, M. L. Bell, L. Pham, A. McDermott, S. L. Zeger, and J. M. Samet (2006) Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. JAMA 295: 1127–1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Peng, R. D., H. H. Chang, M. L. Bell, A. McDermott, S. L. Zeger, J. M. Samet, and F. Dominici (2008) Coarse particulate matter air pollution and hospital admissions for cardiovascular and respiratory diseases among Medicare patients. JAMA 299: 2172–2179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schicker, B., M. Kuhn, R. Fehr, L. M. Asmis, C. Karagiannidis, and W. H. Reinhart (2009) Particulate matter inhalation during hay storing activity induces systemic inflammation and platelet aggregation. Eur. J. Appl. Physiol. 105: 771–778.

    Article  CAS  PubMed  Google Scholar 

  47. Mutlu, G. M., D. Green, A. Bellmeyer, C. M. Baker, Z. Burgess, N. Rajamannan, J. W. Christman, N. Foiles, D. W. Kamp, A. J. Ghio, N. S. Chandel, D. A. Dean, J. I. Sznajder, and G. R. Budinger (2007) Ambient particulate matter accelerates coagulation via an IL-6-dependent pathway. J. Clin. Invest. 117: 2952–2961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Baccarelli, A., P. A. Cassano, A. Litonjua, S. K. Park, H. Suh, D. Sparrow, P. Vokonas, and J. Schwartz (2008) Cardiac autonomic dysfunction: effects from particulate air pollution and protection by dietary methyl nutrients and metabolic polymorphisms. Circulation 117: 1802–1809.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Wang, T., L. Moreno-Vinasco, Y. Huang, G. D. Lang, J. D. Linares, S. N. Goonewardena, A. Grabavoy, J. M. Samet, A. S. Geyh, P. N. Breysse, Y. A. Lussier, V. Natarajan, and J. G. Garcia (2008) Murine lung responses to ambient particulate matter: genomic analysis and influence on airway hyperresponsiveness. Environ. Health Perspect. 116: 1500–1508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Garcon, G., Z. Dagher, F. Zerimech, F. Ledoux, D. Courcot, A. Aboukais, E. Puskaric, and P. Shirali (2006) Dunkerque City air pollution particulate matter-induced cytotoxicity, oxidative stress and inflammation in human epithelial lung cells (L132) in culture. Toxicol In Vitro 20: 519–528.

    Article  CAS  PubMed  Google Scholar 

  51. Pozzi, R., B. De Berardis, L. Paoletti, and C. Guastadisegni (2003) Inflammatory mediators induced by coarse (PM2.5–10) and fine (PM2.5) urban air particles in RAW 264.7 cells. Toxicology 183: 243–254.

    Article  CAS  PubMed  Google Scholar 

  52. Hulsmann, A. R., H. R. Raatgeep, J. C. den Hollander, T. Stijnen, P. R. Saxena, K. F. Kerrebijn, and J. C. de Jongste (1994) Oxidative epithelial damage produces hyperresponsiveness of human peripheral airways. Am. J. Respir. Crit. Care Med. 149: 519–525.

    Article  CAS  PubMed  Google Scholar 

  53. Kreyling, W. G., M. Semmler, F. Erbe, P. Mayer, S. Takenaka, H. Schulz, G. Oberdorster, and A. Ziesenis (2002) Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. J. Toxicol. Environ. Health A 65: 1513–1530.

    Article  CAS  PubMed  Google Scholar 

  54. Karoly, E. D., Z. Li, L. A. Dailey, X. Hyseni, and Y. C. Huang (2007) Up-regulation of tissue factor in human pulmonary artery endothelial cells after ultrafine particle exposure. Environ. Health Perspect. 115: 535–540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Walters, D. M., P. N. Breysse, and M. Wills-Karp (2001) Ambient urban Baltimore particulate-induced airway hyperresponsiveness and inflammation in mice. Am. J. Respir. Crit. Care Med. 164: 1438–1443.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.2018R1A5A2025272 and 2017R1A5A2015385).

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  1. First three authors contributed equally to this work.

Authors and Affiliations

  1. Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, 34141, Korea

    Wonhwa Lee & Jong-Sup Bae

  2. College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Korea

    Wonhwa Lee

  3. Department of Histology and Anatomy, College of Korean Medicine, Daegu Haany University, Gyeongsan, 38610, Korea

    Sae-Kwang Ku

  4. College of Pharmacy, Chungnam National University, Daejon, 34134, Korea

    Ji-Eun Kim, Ga-Eun Choi & Gyu-Yong Song

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  1. Wonhwa Lee
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Correspondence to Gyu-Yong Song or Jong-Sup Bae.

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Lee, W., Ku, SK., Kim, JE. et al. Pulmonary Protective Functions of Rare Ginsenoside Rg4 on Particulate Matter-induced Inflammatory Responses. Biotechnol Bioproc E 24, 445–453 (2019). https://doi.org/10.1007/s12257-019-0096-4

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