Skip to main content

Pine bark extract (Pycnogenol®) suppresses cigarette smoke-induced fibrotic response via transforming growth factor-β1/Smad family member 2/3 signaling

Abstract

Chronic obstructive pulmonary diseases (COPD) is an important disease featured as intense inflammation, protease imbalance, and air flow limitation and mainly induced by cigarette smoke (CS). In present study, we explored the effects of Pycnogenol® (PYC, pine bark extract) on pulmonary fibrosis caused by CS+lipopolysaccharide (LPS) exposure. Mice were treated with LPS intranasally on day 12 and 26, followed by CS exposure for 1 h/day (8 cigarettes per day) for 4 weeks. One hour before CS exposure, 10 and 20 mg/kg of PYC were administered by oral gavage for 4 weeks. PYC effectively reduced the number of inflammatory cells and proinflammatory mediators caused by CS+LPS exposure in bronchoalveolar lavage fluid. PYC inhibited the collagen deposition on lung tissue caused by CS+LPS exposure, as evidenced by Masson’s trichrome stain. Furthermore, transforming growth factor-β1 (TGF-β1) expression and Smad family member 2/3 (Smad 2/3) phosphorylation were effectively suppressed by PYC treatment. PYC markedly reduced the collagen deposition caused by CS+LPS exposure, which was closely involved in TGF-β1/Smad 2/3 signaling, which is associated with pulmonary fibrotic change. These findings suggest that treatment with PYC could be a therapeutic strategy for controlling COPD progression.

References

  1. 1.

    Churg A, Tai H, Coulthard T, Wang R, Wright JL. Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall. Am J Respir Crit Care Med 2006; 174(12): 1327–1334.

    CAS  Article  Google Scholar 

  2. 2.

    Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med 2001; 164: S28–S38.

    CAS  Article  Google Scholar 

  3. 3.

    Milara J, Peiró T, Serrano A, Cortijo J. Epithelial to mesenchymal transition is increased in patients with COPD and induced by cigarette smoke. Thorax 2013; 68(5): 410–420.

    Article  Google Scholar 

  4. 4.

    Dhainaut JF, Charpentier J, Chiche JD. Transforming growth factor-beta: a mediator of cell regulation in acute respiratory distress syndrome. Crit Care Med 2003; 31(4): S258–S264.

    CAS  Article  Google Scholar 

  5. 5.

    Xu F, Liu C, Zhou D, Zhang L. TGF-â/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J Histochem Cytochem 2016; 64(3): 157–167.

    CAS  Article  Google Scholar 

  6. 6.

    Brandsma CA, Timens W, Jonker MR, Rutgers B, Noordhoek JA, Postma DS. Differential effects of fluticasone on extracellular matrix production by airway and parenchymal fibroblasts in severe COPD. Am J Physiol Lung Cell Mol Physiol 2013; 305(8): L582–L589.

    CAS  Article  Google Scholar 

  7. 7.

    Farid M, Kanaji N, Nakanishi M, Gunji Y, Michalski J, Iwasawa S, Ikari J, Wang X, Basma H, Nelson AJ, Liu X, Rennard SI. Smad3 mediates cigarette smoke extract (CSE) induction of VEGF release by human fetal lung fibroblasts. Toxicol Lett 2013; 220(2): 126–134.

    CAS  Article  Google Scholar 

  8. 8.

    Ko JW, Lee IC, Park SH, Moon C, Kang SS, Kim SH, Kim JC. Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats. Lab Anim Res 2014; 30(4): 174–180.

    Article  Google Scholar 

  9. 9.

    Matsumori A, Higuchi H, Shimada M. French maritime pine bark extract inhibits viral replication and prevents development of viral myocarditis. J Card Fail 2007; 13(9): 785–791.

    Article  Google Scholar 

  10. 10.

    Mei L, Mochizuki M, Hasegawa N. Hepatoprotective effects of pycnogenol in a rat model of non-alcoholic steatohepatitis. Phytother Res 2012; 26(10): 1572–1574.

    CAS  PubMed  Google Scholar 

  11. 11.

    Cho HS, Lee MH, Lee JW, No KO, Park SK, Lee HS, Kang S, Cho W G, Park HJ, Oh KW, Hong JT. Anti-wrinkling effects of the mixture of vitamin C, vitamin E, pycnogenol and evening primrose oil, and molecular mechanisms on hairless mouse skin caused by chronic ultraviolet B irradiation. Photodermatol Photoimmunol Photomed 2007; 23(5): 155–162.

    CAS  Article  Google Scholar 

  12. 12.

    Shin NR, Ryu HW, Ko JW, Park JW, Kwon OK, Oh SR, Kim JC, Shin IS, Ahn KS. A standardized bark extract of Pinus pinaster Aiton (Pycnogenol®) attenuated chronic obstructive pulmonary disease via Erk-sp1 signaling pathway. J Ethnopharmacol 2016; 194: 412–420.

    Article  Google Scholar 

  13. 13.

    Tashkin D P. Roflumilast: the new orally active, selective phophodiesterase-4 inhibitor, for the treatment of COPD. Expert Opin Pharmacother 2014; 15(1): 85–96.

    CAS  Article  Google Scholar 

  14. 14.

    Shin IS, Shin NR, Park JW, Jeon CM, Hong JM, Kwon OK, Kim JS, Lee IC, Kim JC, Oh SR, Ahn KS. Melatonin attenuates neutrophil inflammation and mucus secretion in cigarette smoke-induced chronic obstructive pulmonary diseases via the suppression of Erk-Sp1 signaling. J Pineal Res 2015; 58(1): 50–60.

    CAS  Article  Google Scholar 

  15. 15.

    Takizawa H, Tanaka M, Takami K, Ohtoshi T, Ito K, Satoh M, Okada Y, Yamasawa F, Nakahara K, Umeda A. Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 2001; 163(6): 1476–1483.

    CAS  Article  Google Scholar 

  16. 16.

    Eltom S, Belvisi MG, Stevenson CS, Maher SA, Dubuis E, Fitzgerald KA, Birrell MA. Role of the inflammasome-caspase1/ 11-IL-1/18 axis in cigarette smoke driven airway inflammation: an insight into the pathogenesis of COPD. PLoS One 2014; 9(11): e112829.

    Article  Google Scholar 

  17. 17.

    Barnes PJ. Alveolar macrophages as orchestrators of COPD. COPD 2004; 1(1): 59–70.

    Article  Google Scholar 

  18. 18.

    Ryu HW, Song HH, Shin IS, Cho BO, Jeong SH, Kim DY, Ahn KS, Oh SR. Suffruticosol A isolated from paeonia lactiflora seedcases attecuates airway inflammation in mice induced by cigarette smoke and LPS exposure. J Funct Foods 2015; 17: 774–784.

    CAS  Article  Google Scholar 

  19. 19.

    Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS. Tissue renewal and repair: regeneration, healing, and fibrosis. Pathologic basis of disease 2005; 7: 87–118.

    Google Scholar 

  20. 20.

    Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol 2008; 214(2): 199–210.

    CAS  Article  Google Scholar 

  21. 21.

    Peng YJ, Lee CH, Wang CC, Salter DM, Lee HS. Pycnogenol attenuates the inflammatory and nitrosative stress on joint inflammation induced by urate crystals. Free Radic Biol Med 2012; 52(4): 765–774.

    CAS  Article  Google Scholar 

  22. 22.

    Khan MM, Kempuraj D, Thangavel R, Zaheer A. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol. Neurochem Int 2013; 62(4): 379–388.

    CAS  Article  Google Scholar 

  23. 23.

    Shin IS, Shin NR, Jeon CM, Hong JM, Kwon OK, Kim JC, Oh SR, Hahn KW, Ahn KS. Inhibitory effects of Pycnogenol® (French maritime pine bark extract) on airway inflammation in ovalbumin-induced allergic asthma. Food Chem Toxicol 2013; 62: 681–686.

    CAS  Article  Google Scholar 

  24. 24.

    Xia YF, Zhang JH, Xu ZF, Deng XM. Pycnogenol, a compound isolated from the bark of pinus maritime mill, attenuates ventilator-induced lung injury through inhibiting NF-κB-mediated inflammatory response. Int J Clin Exp Med 2015; 8(2): 1824–1833.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Barkauskas CE, Noble PW. Cellular mechanisms of tissue fibrosis. 7. New insights into the cellular mechanisms of pulmonary fibrosis. Am J Physiol Cell Physiol 2014; 306(11): C987–C996.

    CAS  PubMed  Google Scholar 

  26. 26.

    Gao W, Li L, Wang Y, Zhang S, Adcock IM, Barnes PJ, Huang M, Yao X. Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease? Respirology 2015; 20(5): 722–729.

    Article  Google Scholar 

  27. 27.

    Spurzem JR, Rennard SI. Pathogenesis of COPD. Semin Respir Crit Care Med 2005; 26(2): 142–153.

    Article  Google Scholar 

  28. 28.

    Zhang H, Liu H, Borok Z, Davies KJ, Ursini F, Forman HJ. Cigarette smoke extract stimulates epithelial-mesenchymal transition through Src activation. Free Radic Biol Med 2012; 52(8): 1437–1442.

    CAS  Article  Google Scholar 

  29. 29.

    Vietti G, Lison D, van den Brule S. Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP). Part Fibre Toxicol 2016; 13(1): 11.

    Article  Google Scholar 

  30. 30.

    Zandvoort A, Postma DS, Jonker MR, Noordhoek JA, Vos JT, van der Geld YM, Timens W. Altered expression of the Smad signalling pathway: implications for COPD pathogenesis. Eur Respir J 2006; 28(3): 533–541.

    CAS  Article  Google Scholar 

  31. 31.

    Adcock IM, Caramori G, Barnes PJ. Chronic obstructive pulmonary disease and lung cancer: new molecular insights. Respiration 2011; 81(4): 265–284.

    CAS  Article  Google Scholar 

  32. 32.

    Mahmood MQ, Reid D, Ward C, Muller HK, Knight DA, Sohal SS, Walters EH. Transforming growth factor (TGF) β1 and Smad signalling pathways: A likely key to EMT-associated COPD pathogenesis. Respirology 2017; 22(1): 133–140.

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (grant number: NRF-2016RICIB2008818).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to In-Sik Shin or Dong-Ho Shin.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ko, JW., Shin, NR., Park, SH. et al. Pine bark extract (Pycnogenol®) suppresses cigarette smoke-induced fibrotic response via transforming growth factor-β1/Smad family member 2/3 signaling. Lab Anim Res 33, 76–83 (2017). https://doi.org/10.5625/lar.2017.33.2.76

Download citation

Keywords

  • Pycnogenol
  • chronic obstructive pulmonary disease
  • cigarette smoke
  • collagen deposition
  • transforming growth factor-β1/Smad family member 2/3