Saikosaponin a Inhibits Cigarette Smoke-Induced Oxidant Stress and Inflammatory Responses by Activation of Nrf2

  • Ru-jie Chen
  • Xian-yang Guo
  • Bi-huan Cheng
  • Yu-qiang Gong
  • Bin-yu Ying
  • Meng-xiang Lin
ORIGINAL ARTICLE

Abstract

Saikosaponin a (SSa), a triterpenoid saponin, has numerous pharmacological properties, including anti-inflammatory and antioxidant effects. The purpose of this study was to investigate whether and how SSa protected against cigarette smoke (CS)-induced lung inflammation in mice. The mice were exposed to CS and SSa was administered by an intraperitoneal (i.p.) injection 1 h before CS treatment for 5 consecutive days. The results showed that SSa significantly inhibited CS-induced inflammatory cell infiltration, NO, TNF-α, and IL-1β production in BALF. SSa also inhibited CS-induced MPO and MDA contents in lung tissues. Furthermore, SSa significantly inhibited CS-induced NF-κB and upregulated the expression of Nrf2 and HO-1. In conclusion, these results support a therapeutic potential for SSa in CS-induced lung inflammation.

KEY WORDS

Saikosaponin a cigarette smoke lung inflammation NF-κB Nrf-2 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Lopez, A.D., K. Shibuya, C. Rao, C.D. Mathers, A.L. Hansell, L.S. Held, V. Schmid, and S. Buist. 2006. Chronic obstructive pulmonary disease: current burden and future projections. The European Respiratory Journal 27: 397–412.CrossRefPubMedGoogle Scholar
  2. 2.
    Turato, G., R. Zuin, M. Miniati, S. Baraldo, F. Rea, B. Beghe, S. Monti, B. Formichi, P. Boschetto, S. Harari, et al. 2002. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. American Journal of Respiratory and Critical Care Medicine 166: 105–110.CrossRefPubMedGoogle Scholar
  3. 3.
    Pryor, W.A. 1997. Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity. Environmental Health Perspectives 105 (Suppl 4): 875–882.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sinden, N.J., and R.A. Stockley. 2010. Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 65: 930–936.CrossRefPubMedGoogle Scholar
  5. 5.
    Chung, K.F., and I.M. Adcock. 2008. Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. The European Respiratory Journal 31: 1334–1356.CrossRefPubMedGoogle Scholar
  6. 6.
    Basaria, S., J.T. Wahlstrom, and A.S. Dobs. 2001. Clinical review 138: anabolic-androgenic steroid therapy in the treatment of chronic diseases. The Journal of Clinical Endocrinology and Metabolism 86: 5108–5117.CrossRefPubMedGoogle Scholar
  7. 7.
    Sussan, T.E., T. Rangasamy, D.J. Blake, D. Malhotra, H. El-Haddad, D. Bedja, M.S. Yates, P. Kombairaju, M. Yamamoto, K.T. Liby, et al. 2009. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proceedings of the National Academy of Sciences of the United States of America 106: 250–255.CrossRefPubMedGoogle Scholar
  8. 8.
    Iizuka, T., Y. Ishii, K. Itoh, T. Kiwamoto, T. Kimura, Y. Matsuno, Y. Morishima, A.E. Hegab, S. Homma, A. Nomura, T. Sakamoto, M. Shimura, A. Yoshida, M. Yamamoto, and K. Sekizawa. 2005. Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema. Genes to Cells 10: 1113–1125.CrossRefPubMedGoogle Scholar
  9. 9.
    Harvey, C.J., R.K. Thimmulappa, S. Sethi, X. Kong, L. Yarmus, R.H. Brown, D. Feller-Kopman, R. Wise, and S. Biswal. 2011. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Science Translational Medicine 3: 78ra32.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wu, S.J., K.W. Tam, Y.H. Tsai, C.C. Chang, and J.C. Chao. 2010. Curcumin and saikosaponin a inhibit chemical-induced liver inflammation and fibrosis in rats. The American Journal of Chinese Medicine 38: 99–111.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhu, J., C. Luo, P. Wang, Q. He, J. Zhou, and H. Peng. 2013. Saikosaponin A mediates the inflammatory response by inhibiting the MAPK and NF-kappaB pathways in LPS-stimulated RAW 264.7 cells. Experimental and Therapeutic Medicine 5: 1345–1350.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Fu, Y., X. Hu, Y. Cao, Z. Zhang, and N. Zhang. 2015. Saikosaponin a inhibits lipopolysaccharide-oxidative stress and inflammation in human umbilical vein endothelial cells via preventing TLR4 translocation into lipid rafts. Free Radical Biology & Medicine 89: 777–785.CrossRefGoogle Scholar
  13. 13.
    He, D., H. Wang, L. Xu, X. Wang, K. Peng, L. Wang, P. Liu, and P. Qu. 2016. Saikosaponin-a attenuates oxidized LDL uptake and prompts cholesterol efflux in THP-1 cells. Journal of Cardiovascular Pharmacology 67: 510–518.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhao, H., S. Li, H. Zhang, G. Wang, G. Xu, and H. Zhang. 2015. Saikosaponin a protects against experimental sepsis via inhibition of NOD2-mediated NF-kappaB activation. Experimental and Therapeutic Medicine 10: 823–827.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Guan, S.P., W. Tee, D.S. Ng, T.K. Chan, H.Y. Peh, W.E. Ho, C. Cheng, J.C. Mak, and W.S. Wong. 2013. Andrographolide protects against cigarette smoke-induced oxidative lung injury via augmentation of Nrf2 activity. British Journal of Pharmacology 168: 1707–1718.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sin, D.D., N.R. Anthonisen, J.B. Soriano, and A.G. Agusti. 2006. Mortality in COPD: role of comorbidities. The European Respiratory Journal 28: 1245–1257.CrossRefPubMedGoogle Scholar
  17. 17.
    Peinado, V.I., J.A. Barbera, P. Abate, J. Ramirez, J. Roca, S. Santos, and R. Rodriguez-Roisin. 1999. Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 159: 1605–1611.CrossRefPubMedGoogle Scholar
  18. 18.
    Ito, K., S. Lim, G. Caramori, K.F. Chung, P.J. Barnes, and I.M. Adcock. 2001. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. The FASEB Journal 15: 1110–1112.CrossRefPubMedGoogle Scholar
  19. 19.
    Nie, Y.C., H. Wu, P.B. Li, Y.L. Luo, K. Long, L.M. Xie, J.G. Shen, and W.W. Su. 2012. Anti-inflammatory effects of naringin in chronic pulmonary neutrophilic inflammation in cigarette smoke-exposed rats. Journal of Medicinal Food 15: 894–900.CrossRefPubMedGoogle Scholar
  20. 20.
    Lawrence, T. 2009. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor Perspectives in Biology 1: a001651.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Pasparakis, M. 2009. Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nature Reviews. Immunology 9: 778–788.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang, J., C. Guo, Z. Wei, X. He, J. Kou, E. Zhou, Z. Yang, and Y. Fu. 2016. Morin suppresses inflammatory cytokine expression by downregulation of nuclear factor-kappaB and mitogen-activated protein kinase (MAPK) signaling pathways in lipopolysaccharide-stimulated primary bovine mammary epithelial cells. Journal of Dairy Science 99: 3016–3022.CrossRefPubMedGoogle Scholar
  23. 23.
    Wullaert, A., M.C. Bonnet, and M. Pasparakis. 2011. NF-kappaB in the regulation of epithelial homeostasis and inflammation. Cell Research 21: 146–158.CrossRefPubMedGoogle Scholar
  24. 24.
    Hasnis, E., M. Bar-Shai, Z. Burbea, and A.Z. Reznick. 2007. Cigarette smoke-induced NF-kappaB activation in human lymphocytes: the effect of low and high exposure to gas phase of cigarette smoke. Journal of Physiology and Pharmacology 58 (Suppl 5): 263–274.PubMedGoogle Scholar
  25. 25.
    Edwards, M.R., N.W. Bartlett, D. Clarke, M. Birrell, M. Belvisi, and S.L. Johnston. 2009. Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacology & Therapeutics 121: 1–13.CrossRefGoogle Scholar
  26. 26.
    Lu, C.N., Z.G. Yuan, X.L. Zhang, R. Yan, Y.Q. Zhao, M. Liao, and J.X. Chen. 2012. Saikosaponin a and its epimer saikosaponin d exhibit anti-inflammatory activity by suppressing activation of NF-kappaB signaling pathway. International Immunopharmacology 14: 121–126.CrossRefPubMedGoogle Scholar
  27. 27.
    Pinazo-Duran, M.D., V. Zanon-Moreno, J.J. Garcia-Medina, and R. Gallego-Pinazo. 2013. Evaluation of presumptive biomarkers of oxidative stress, immune response and apoptosis in primary open-angle glaucoma. Current Opinion in Pharmacology 13: 98–107.CrossRefPubMedGoogle Scholar
  28. 28.
    Rahman, I. 2008. Antioxidant therapeutic advances in COPD. Therapeutic Advances in Respiratory Disease 2: 351–374.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Pi, J., Q. Zhang, J. Fu, C.G. Woods, Y. Hou, B.E. Corkey, S. Collins, and M.E. Andersen. 2010. ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function. Toxicology and Applied Pharmacology 244: 77–83.CrossRefPubMedGoogle Scholar
  30. 30.
    Rangasamy, T., C.Y. Cho, R.K. Thimmulappa, L. Zhen, S.S. Srisuma, T.W. Kensler, M. Yamamoto, I. Petrache, R.M. Tuder, and S. Biswal. 2004. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. The Journal of Clinical Investigation 114: 1248–1259.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ru-jie Chen
    • 1
  • Xian-yang Guo
    • 1
  • Bi-huan Cheng
    • 1
  • Yu-qiang Gong
    • 1
  • Bin-yu Ying
    • 1
  • Meng-xiang Lin
    • 1
  1. 1.Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children’s HospitalWenzhou Medical UniversityWenzhouChina

Personalised recommendations