Journal of Clinical Immunology

, Volume 32, Issue 6, pp 1292–1304 | Cite as

Grape Seed Proanthocyanidin Extract Attenuates Allergic Inflammation in Murine Models of Asthma

  • Taehoon Lee
  • Hyouk-Soo Kwon
  • Bo-Ram Bang
  • Yoon Su Lee
  • Mi-Young Park
  • Keun-Ai Moon
  • Tae-Bum Kim
  • Ki-Young Lee
  • Hee-Bom Moon
  • You Sook ChoEmail author
Original Research



Antioxidants have been suggested to alleviate the pathophysiological features of asthma, and grape seed proanthocyanidin extract (GSPE) has been reported to have powerful antioxidant activity.


This study was performed to determine whether GSPE has a therapeutic effect on allergic airway inflammation in both acute and chronic murine model of asthma.


Acute asthma model was generated by intraperitoneal sensitization of ovalbumin (OVA) with alum followed by aerosolized OVA challenges, whereas chronic asthma model was induced by repeated intranasal challenges of OVA with fungal protease twice a week for 8 weeks. GSPE was administered by either intraperitoneal injection or oral gavage before OVA challenges. Airway hyperresponsiveness (AHR) was measured, and airway inflammation was evaluated by bronchoalveolar lavage (BAL) fluid analysis and histopathological examination of lung tissue. Lung tissue levels of various cytokines, chemokines, and growth factors were analyzed by quantitative polymerase chain reaction and ELISA. Glutathione assay was done to measure oxidative burden in lung tissue.


Compared to untreated asthmatic mice, mice treated with GSPE showed significantly reduced AHR, decreased inflammatory cells in the BAL fluid, reduced lung inflammation, and decreased IL-4, IL-5, IL-13, and eotaxin-1 expression in both acute and chronic asthma models. Moreover, airway subepithelial fibrosis was reduced in the lung tissue of GSPE-treated chronic asthmatic mice compared to untreated asthmatic mice. Reduced to oxidized glutathione (GSH/GSSG) ratio was increased after GSPE treatment in acute asthmatic lung tissue.


GSPE effectively suppressed inflammation in both acute and chronic mouse models of asthma, suggesting a potential role of GSPE as a therapeutic agent for asthma.


Proanthocyanidins grape seed extract asthma antioxidants airway remodeling 



This work was supported by a grant (No. 20090086092) from the National Research Foundation of Korea (NRF) to Y.S.C. and a grant (No.2012-302) from Asan Life and Science Institute to Y.S.C.


  1. 1.
    Bateman and Boulet, Global strategy for asthma management and prevention (2010 update), 2010.
  2. 2.
    Expert Panel Report 3 (EPR-3). Guidelines for the diagnosis and management of asthma-summary report 2007. J Allergy Clin Immunol. 2007;120(5 Suppl):S94–138.Google Scholar
  3. 3.
    Barnes PJ. Reactive oxygen species and airway inflammation. Free Radic Biol Med. 1990;9(3):235–43.PubMedCrossRefGoogle Scholar
  4. 4.
    Bowler RP, Crapo JD. Oxidative stress in airways: is there a role for extracellular superoxide dismutase? Am J Respir Crit Care Med. 2002;166(12 Pt 2):S38–43.PubMedCrossRefGoogle Scholar
  5. 5.
    Henderson WR, et al. A small molecule inhibitor of redox-regulated NF-kappa B and activator protein-1 transcription blocks allergic airway inflammation in a mouse asthma model. J Immunol. 2002;169(9):5294–9.PubMedGoogle Scholar
  6. 6.
    Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol. 2003;36(1):95–109.PubMedCrossRefGoogle Scholar
  7. 7.
    Rahman I, Yang SR, Biswas SK. Current concepts of redox signaling in the lungs. Antioxid Redox Signal. 2006;8(3–4):681–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Fitzpatrick AM, et al. Airway glutathione homeostasis is altered in children with severe asthma: evidence for oxidant stress. J Allergy Clin Immunol. 2009;123(1):146–152.e8.PubMedCrossRefGoogle Scholar
  9. 9.
    Fitzpatrick AM, et al. Levels of nitric oxide oxidation products are increased in the epithelial lining fluid of children with persistent asthma. J Allergy Clin Immunol. 2009;124(5):990–6.e1–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Comhair SA, et al. Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma. Am J Respir Crit Care Med. 2005;172(3):306–13.PubMedCrossRefGoogle Scholar
  11. 11.
    Lasmar L, et al. Adherence rate to inhaled corticosteroids and their impact on asthma control. Allergy. 2009;64(5):784–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Rachelefsky G. Inhaled corticosteroids and asthma control in children: assessing impairment and risk. Pediatrics. 2009;123(1):353–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Riedl MA, Nel AE. Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol. 2008;8(1):49–56.PubMedCrossRefGoogle Scholar
  14. 14.
    Shaheen SO, et al. Randomised, double blind, placebo-controlled trial of selenium supplementation in adult asthma. Thorax. 2007;62(6):483–90.PubMedCrossRefGoogle Scholar
  15. 15.
    Garcia V, et al. Dietary intake of flavonoids and asthma in adults. Eur Respir J. 2005;26(3):449–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Ram FS, Rowe BH, Kaur B. Vitamin C supplementation for asthma. Cochrane Database Syst Rev. 2004;3:CD000993.PubMedGoogle Scholar
  17. 17.
    Pearson PJ, et al. Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial. Thorax. 2004;59(8):652–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Fogarty A, et al. Oral magnesium and vitamin C supplements in asthma: a parallel group randomized placebo-controlled trial. Clin Exp Allergy. 2003;33(10):1355–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Ariga T. The antioxidative function, preventive action on disease and utilization of proanthocyanidins. Biofactors. 2004;21(1–4):197–201.PubMedCrossRefGoogle Scholar
  20. 20.
    Li BY, et al. Back-regulation of six oxidative stress proteins with grape seed proanthocyanidin extracts in rat diabetic nephropathy. J Cell Biochem. 2008;104(2):668–79.PubMedCrossRefGoogle Scholar
  21. 21.
    Guler A, et al. Proanthocyanidin prevents myocardial ischemic injury in adult rats. Med Sci Monit. 2011;17(11):BR326-331.PubMedGoogle Scholar
  22. 22.
    Ulusoy S, et al. Anti-apoptotic and anti-oxidant effects of grape seed proanthocyanidin extract in preventing cyclosporine A-induced nephropathy. Nephrol (Carlton). 2012;17(4):372–9.CrossRefGoogle Scholar
  23. 23.
    Mantena SK, Baliga MS, Katiyar SK. Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells. Carcinogenesis. 2006;27(8):1682–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Han Y. Synergic effect of grape seed extract with amphotericin B against disseminated candidiasis due to Candida albicans. Phytomedicine. 2007;14(11):733–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Cho ML, et al. Grape seed proanthocyanidin extract (GSPE) attenuates collagen-induced arthritis. Immunol Lett. 2009;124(2):102–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Henriet JP. Veno-lymphatic insufficiency. 4,729 patients undergoing hormonal and procyanidol oligomer therapy. Phlebologie. 1993;46(2):313–25.PubMedGoogle Scholar
  27. 27.
    Bagchi D, et al. Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology. 2000;148(2–3):187–97.PubMedCrossRefGoogle Scholar
  28. 28.
    Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52(4):673–751.PubMedGoogle Scholar
  29. 29.
    Xia EQ, et al. Biological activities of polyphenols from grapes. Int J Mol Sci. 2010;11(2):622–46.PubMedCrossRefGoogle Scholar
  30. 30.
    Nassiri-Asl M, Hosseinzadeh H. Review of the pharmacological effects of Vitis vinifera (Grape) and its bioactive compounds. Phytother Res. 2009;23(9):1197–204.PubMedCrossRefGoogle Scholar
  31. 31.
    Zhou DY, et al. Grape seed proanthocyanidin extract attenuates airway inflammation and hyperresponsiveness in a murine model of asthma by downregulating inducible nitric oxide synthase. Planta Med. 2011;77(14):1575–81.PubMedCrossRefGoogle Scholar
  32. 32.
    Kheradmand F, et al. A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease. J Immunol. 2002;169(10):5904–11.PubMedGoogle Scholar
  33. 33.
    Barrett EG, et al. Cigarette smoke-induced airway hyperresponsiveness is not dependent on elevated immunoglobulin and eosinophilic inflammation in a mouse model of allergic airway disease. Am J Respir Crit Care Med. 2002;165(10):1410–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;11(7):577–84.PubMedCrossRefGoogle Scholar
  35. 35.
    D’Amato G, et al. Urban air pollution and climate change as environmental risk factors of respiratory allergy: an update. J Investig Allergol Clin Immunol. 2010;20(2):95–102. quiz following 102.PubMedGoogle Scholar
  36. 36.
    D’Amato G, et al. Outdoor air pollution, climatic changes and allergic bronchial asthma. Eur Respir J. 2002;20(3):763–76.PubMedCrossRefGoogle Scholar
  37. 37.
    Fogarty A, et al. Dietary vitamin E, IgE concentrations, and atopy. Lancet. 2000;356(9241):1573–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Grievink L, et al. Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study. Thorax. 1998;53(3):166–71.PubMedCrossRefGoogle Scholar
  39. 39.
    Wood LG, et al. Lipid peroxidation as determined by plasma isoprostanes is related to disease severity in mild asthma. Lipids. 2000;35(9):967–74.PubMedCrossRefGoogle Scholar
  40. 40.
    Rahman I, et al. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med. 1996;154(4 Pt 1):1055–60.PubMedGoogle Scholar
  41. 41.
    Vachier I, et al. Increased oxygen species generation in blood monocytes of asthmatic patients. Am Rev Respir Dis. 1992;146(5 Pt 1):1161–6.PubMedGoogle Scholar
  42. 42.
    Chanez P, et al. Generation of oxygen free radicals from blood eosinophils from asthma patients after stimulation with PAF or phorbol ester. Eur Respir J. 1990;3(9):1002–7.PubMedGoogle Scholar
  43. 43.
    Kelly FJ, et al. Altered lung antioxidant status in patients with mild asthma. Lancet. 1999;354(9177):482–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Kharitonov SA, et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994;343(8890):133–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Nadeem A, et al. Increased oxidative stress and altered levels of antioxidants in asthma. J Allergy Clin Immunol. 2003;111(1):72–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Kongerud J, et al. Ascorbic acid is decreased in induced sputum of mild asthmatics. Inhal Toxicol. 2003;15(2):101–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Hasselmark L, et al. Lowered platelet glutathione peroxidase activity in patients with intrinsic asthma. Allergy. 1990;45(7):523–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Pearson DJ, et al. Selenium status in relation to reduced glutathione peroxidase activity in aspirin-sensitive asthma. Clin Exp Allergy. 1991;21(2):203–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Smith LJ, et al. Reduced superoxide dismutase in lung cells of patients with asthma. Free Radic Biol Med. 1997;22(7):1301–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Picado C, et al. Dietary micronutrients/antioxidants and their relationship with bronchial asthma severity. Allergy. 2001;56(1):43–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Ercan H, et al. Oxidative stress and genetic and epidemiologic determinants of oxidant injury in childhood asthma. J Allergy Clin Immunol. 2006;118(5):1097–104.PubMedCrossRefGoogle Scholar
  52. 52.
    Rusznak C, Devalia JL, Davies RJ. The impact of pollution on allergic disease. Allergy. 1994;49(18 Suppl):21–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J. 2000;16(3):534–54.PubMedCrossRefGoogle Scholar
  54. 54.
    Meister A. Glutathione metabolism and its selective modification. J Biol Chem. 1988;263(33):17205–8.PubMedGoogle Scholar
  55. 55.
    Yang G, et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine. 2004;28(6):224–32.PubMedCrossRefGoogle Scholar
  56. 56.
    Cang CX, Luan B. Expression of basic fibroblast growth factor and nuclear factor-kappaB and the effect of budesonide on their expression in rats with asthma. Zhongguo Dang Dai Er Ke Za Zhi. 2009;11(5):393–6.PubMedGoogle Scholar
  57. 57.
    Lewis CC, et al. Airway fibroblasts exhibit a synthetic phenotype in severe asthma. J Allergy Clin Immunol. 2005;115(3):534–40.PubMedCrossRefGoogle Scholar
  58. 58.
    Puddicombe SM, et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 2000;14(10):1362–74.PubMedCrossRefGoogle Scholar
  59. 59.
    Vignola AM, et al. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med. 1997;156(2 Pt 1):591–9.PubMedGoogle Scholar
  60. 60.
    Kabuyama Y, et al. Involvement of selenoprotein P in the regulation of redox balance and myofibroblast viability in idiopathic pulmonary fibrosis. Genes Cells. 2007;12(11):1235–44.PubMedCrossRefGoogle Scholar
  61. 61.
    Hackett TL. Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. Curr Opin Allergy Clin Immunol. 2012;12(1):53–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee T, et al. Smoking, longer disease duration and absence of rhinosinusitis are related to fixed airway obstruction in Koreans with severe asthma: findings from the COREA study. Respir Res. 2011;12:1.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Taehoon Lee
    • 1
  • Hyouk-Soo Kwon
    • 1
  • Bo-Ram Bang
    • 2
  • Yoon Su Lee
    • 1
  • Mi-Young Park
    • 2
  • Keun-Ai Moon
    • 2
  • Tae-Bum Kim
    • 1
  • Ki-Young Lee
    • 3
  • Hee-Bom Moon
    • 1
  • You Sook Cho
    • 1
    Email author
  1. 1.Department of Allergy and Clinical Immunology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  2. 2.Asan Institute for Life ScienceSeoulKorea
  3. 3.Department of Molecular Cell BiologySungkyunkwan University School of MedicineSuwonKorea

Personalised recommendations