Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

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



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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Bateman and Boulet, Global strategy for asthma management and prevention (2010 update), www.ginaasthma.com. 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.

  3. 3.

    Barnes PJ. Reactive oxygen species and airway inflammation. Free Radic Biol Med. 1990;9(3):235–43.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  11. 11.

    Lasmar L, et al. Adherence rate to inhaled corticosteroids and their impact on asthma control. Allergy. 2009;64(5):784–9.

  12. 12.

    Rachelefsky G. Inhaled corticosteroids and asthma control in children: assessing impairment and risk. Pediatrics. 2009;123(1):353–66.

  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.

  14. 14.

    Shaheen SO, et al. Randomised, double blind, placebo-controlled trial of selenium supplementation in adult asthma. Thorax. 2007;62(6):483–90.

  15. 15.

    Garcia V, et al. Dietary intake of flavonoids and asthma in adults. Eur Respir J. 2005;26(3):449–52.

  16. 16.

    Ram FS, Rowe BH, Kaur B. Vitamin C supplementation for asthma. Cochrane Database Syst Rev. 2004;3:CD000993.

  17. 17.

    Pearson PJ, et al. Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial. Thorax. 2004;59(8):652–6.

  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.

  19. 19.

    Ariga T. The antioxidative function, preventive action on disease and utilization of proanthocyanidins. Biofactors. 2004;21(1–4):197–201.

  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.

  21. 21.

    Guler A, et al. Proanthocyanidin prevents myocardial ischemic injury in adult rats. Med Sci Monit. 2011;17(11):BR326-331.

  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.

  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.

  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.

  25. 25.

    Cho ML, et al. Grape seed proanthocyanidin extract (GSPE) attenuates collagen-induced arthritis. Immunol Lett. 2009;124(2):102–10.

  26. 26.

    Henriet JP. Veno-lymphatic insufficiency. 4,729 patients undergoing hormonal and procyanidol oligomer therapy. Phlebologie. 1993;46(2):313–25.

  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.

  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.

  29. 29.

    Xia EQ, et al. Biological activities of polyphenols from grapes. Int J Mol Sci. 2010;11(2):622–46.

  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.

  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.

  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.

  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.

  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.

  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.

  36. 36.

    D’Amato G, et al. Outdoor air pollution, climatic changes and allergic bronchial asthma. Eur Respir J. 2002;20(3):763–76.

  37. 37.

    Fogarty A, et al. Dietary vitamin E, IgE concentrations, and atopy. Lancet. 2000;356(9241):1573–4.

  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.

  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.

  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.

  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.

  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.

  43. 43.

    Kelly FJ, et al. Altered lung antioxidant status in patients with mild asthma. Lancet. 1999;354(9177):482–3.

  44. 44.

    Kharitonov SA, et al. Increased nitric oxide in exhaled air of asthmatic patients. Lancet. 1994;343(8890):133–5.

  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.

  46. 46.

    Kongerud J, et al. Ascorbic acid is decreased in induced sputum of mild asthmatics. Inhal Toxicol. 2003;15(2):101–9.

  47. 47.

    Hasselmark L, et al. Lowered platelet glutathione peroxidase activity in patients with intrinsic asthma. Allergy. 1990;45(7):523–7.

  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.

  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.

  50. 50.

    Picado C, et al. Dietary micronutrients/antioxidants and their relationship with bronchial asthma severity. Allergy. 2001;56(1):43–9.

  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.

  52. 52.

    Rusznak C, Devalia JL, Davies RJ. The impact of pollution on allergic disease. Allergy. 1994;49(18 Suppl):21–7.

  53. 53.

    Rahman I, MacNee W. Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J. 2000;16(3):534–54.

  54. 54.

    Meister A. Glutathione metabolism and its selective modification. J Biol Chem. 1988;263(33):17205–8.

  55. 55.

    Yang G, et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling. Cytokine. 2004;28(6):224–32.

  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.

  57. 57.

    Lewis CC, et al. Airway fibroblasts exhibit a synthetic phenotype in severe asthma. J Allergy Clin Immunol. 2005;115(3):534–40.

  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.

  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.

  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.

  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.

  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.

Download references


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.

Author information

Correspondence to You Sook Cho.

Additional information

Taehoon Lee and Hyouk-Soo Kwon equally contributed to this article.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lee, T., Kwon, H., Bang, B. et al. Grape Seed Proanthocyanidin Extract Attenuates Allergic Inflammation in Murine Models of Asthma. J Clin Immunol 32, 1292–1304 (2012). https://doi.org/10.1007/s10875-012-9742-8

Download citation


  • Proanthocyanidins
  • grape seed extract
  • asthma
  • antioxidants
  • airway remodeling