Inflammation Research

, Volume 61, Issue 7, pp 749–758 | Cite as

Short-term roxithromycin treatment attenuates airway inflammation via MAPK/NF-κB activation in a mouse model of allergic asthma

  • Xinxin Ci
  • Xiao Chu
  • Xue Xu
  • Hongyu Li
  • Xuming Deng
Original Research Paper



We investigated whether roxithromycin reduces ovalbumin-specific allergic asthma symptoms in mice, and we further investigated the inhibitory mechanism of roxithromycin in ovalbumin-specific allergic asthma.


Mice were divided into five groups (n = 10 for each): control group, roxithromycin-treated groups (5, 20 and 40 mg/kg) and ovalbumin-challenged group. We measured the recruitment of inflammatory cells into the bronchoalveolar lavage fluid (BALF) or the lung tissues by Kwik-Diff and hematoxylin and eosin (H&E) staining, goblet cell hyperplasia by alcian blue–periodic acid–Schiff (AB-PAS) staining, airway hyperresponsiveness (AHR) by whole-body plethysmograph chamber, cytokine and immunoglobulin E (IgE) levels by ELISA, and the activation of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-κB) in the lung tissues by Western blotting.


Treatment with roxithromycin resulted in fewer inflammatory cells in the BALF and peribronchial areas, and decreased AHR, goblet cell hyperplasia, IgE levels and inflammatory cytokines, as well as MAP kinases and NF-κB activation, which are increased in lung tissues of mice with ovalbumin-induced allergic asthma.


Our data suggest that oral administration of roxithromycin suppresses ovalbumin-induced airway inflammation and AHR by regulating the inflammatory cytokines via MAP kinases/NF-κB pathway in inflammatory cells. Based on these results, we suggest that roxithromycin may be used as a therapeutic agent for allergy-induced asthma.


Asthma Airway inflammation AHR NF-κB MAPKs 



This work was supported by the National Science and Technology Supporting Plan of China (No. 2006BAD31B03-4).


  1. 1.
    Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma––United States, 1980–1999. MMWR Surveillance summaries: Morbidity and mortality weekly report. Surveillance summaries CDC. 2002; 51:1–13.Google Scholar
  2. 2.
    Robertson CF, Roberts MF, Kappers JH. Asthma prevalence in Melbourne schoolchildren: have we reached the peak? Med J Aust. 2004;180:273–6.PubMedGoogle Scholar
  3. 3.
    Verlato G, Corsico A, Villani S, Cerveri I, Migliore E, Accordini S, et al. Is the prevalence of adult asthma and allergic rhinitis still increasing? Results of an Italian study. J Allergy Clin Immunol. 2003;111:1232–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Robinson D, Hamid Q, Bentley A, Ying S, Kay AB, Durham SR. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol. 1993;92:313–24.PubMedCrossRefGoogle Scholar
  5. 5.
    Renz H, Smith HR, Henson JE, Ray BS, Irvin CG, Gelfand EW. Aerosolized antigen exposure without adjuvant causes increased IgE production and increased airway responsiveness in the mouse. J Allergy Clin Immunol. 1992;89:1127–38.PubMedCrossRefGoogle Scholar
  6. 6.
    Vojdani A, Erde J. Regulatory T cells, a potent immunoregulatory target for CAM researchers: modulating tumor immunity, autoimmunity and alloreactive immunity (III). Evid Based Compl Altern. 2006;3:309–16.CrossRefGoogle Scholar
  7. 7.
    Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001;344:350–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Barnes PJ. Corticosteroids, IgE, and atopy. J Clin Invest. 2001;107:265–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Resp Crit Care. 1998;158:1585–92.Google Scholar
  10. 10.
    Epstein ME, Amodio-Groton M, Sadick NS. Antimicrobial agents for the dermatologist. I. Beta-lactam antibiotics and related compounds. J Am Acad Dermatol. 1997;37:149–65. (quiz 166–8).PubMedCrossRefGoogle Scholar
  11. 11.
    Ivetic Tkalcevic V, Bosnjak B, Hrvacic B, Bosnar M, Marjanovic N, Ferencic Z, et al. Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice. Eur J Pharmacol. 2006;539:131–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Leiva M, Ruiz-Bravo A, Jimenez-Valera M. Effects of telithromycin in in vitro and in vivo models of lipopolysaccharide-induced airway inflammation. Chest. 2008;134:20–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Beigelman A, Gunsten S, Mikols CL, Vidavsky I, Cannon CL, Brody SL, et al. Azithromycin attenuates airway inflammation in a noninfectious mouse model of allergic asthma. Chest. 2009;136:498–506.PubMedCrossRefGoogle Scholar
  14. 14.
    Hrvacic B, Bosnjak B, Bosnar M, Ferencic Z, Glojnaric I, Erakovic Haber V. Clarithromycin suppresses airway hyperresponsiveness and inflammation in mouse models of asthma. Eur J Pharmacol. 2009;616:236–43.PubMedCrossRefGoogle Scholar
  15. 15.
    Noma T, Hayashi M, Yoshizawa I, Aoki K, Shikishima Y, Kawano Y. A comparative investigation of the restorative effects of roxithromycin on neutrophil activities. Int Immunopharmacol. 1998;20:615–24.CrossRefGoogle Scholar
  16. 16.
    Kusano S, Kadota J, Kohno S, Iida K, Kawakami K, Morikawa T, et al. Effect of roxithromycin on peripheral neutrophil adhesion molecules in patients with chronic lower respiratory tract disease. Respiration. 1995;62:217–22.PubMedCrossRefGoogle Scholar
  17. 17.
    Sakito O, Kadota J, Kohno S, Abe K, Shirai R, Hara K. Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration. 1996;63:42–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Nakamura H, Fujishima S, Inoue T, Ohkubo Y, Soejima K, Waki Y, et al. Clinical and immunoregulatory effects of roxithromycin therapy for chronic respiratory tract infection. Eur Respir J. 1999;13:1371–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Kimura N, Nishioka K, Nishizaki K, Ogawa T, Naitou Y, Masuda Y. Clinical effect of low-dose, long-term roxithromycin chemotherapy in patients with chronic sinusitis. Acta Med Okayama. 1997;51:33–7.PubMedGoogle Scholar
  20. 20.
    Wakita H, Tokura Y, Furukawa F, Takigawa M. The macrolide antibiotic, roxithromycin suppresses IFN-gamma-mediated immunological functions of cultured normal human keratinocytes. Biol Pharm Bull. 1996;19:224–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Shimizu T, Kato M, Mochizuki H, Tokuyama K, Morikawa A, Kuroume T. Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma. Chest. 1994;106:458–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Konno S, Asano K, Kurokawa M, Ikeda K, Okamoto K, Adachi M. Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo. Int Arch Allergy Immunol. 1994;105:308–16.PubMedCrossRefGoogle Scholar
  23. 23.
    Blease K. Targeting kinases in asthma. Expert Opin Invest Drug. 2005;14:1213–20.CrossRefGoogle Scholar
  24. 24.
    Gosens R, Schaafsma D, Nelemans SA, Halayko AJ. Rho-kinase as a drug target for the treatment of airway hyperresponsiveness in asthma. Mini Rev Med Chem. 2006;6:339–48.PubMedCrossRefGoogle Scholar
  25. 25.
    Hall DJ, Cui J, Bates ME, Stout BA, Koenderman L, Coffer PJ, et al. Transduction of a dominant-negative H-Ras into human eosinophils attenuates extracellular signal-regulated kinase activation and interleukin-5-mediated cell viability. Blood. 2001;98:2014–21.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang CC, Lin WN, Lee CW, Lin CC, Luo SF, Wang JS, et al. Involvement of p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB in IL-1beta-induced VCAM-1 expression in human tracheal smooth muscle cells. Am J Physiol Lung C. 2005;288:L227–37.CrossRefGoogle Scholar
  27. 27.
    Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-kappa B in pulmonary diseases. Chest. 2000;117:1482–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhou LF, Zhu Y, Cui XF, Xie WP, Hu AH, Yin KS. Arsenic trioxide, a potent inhibitor of NF-kappaB, abrogates allergen-induced airway hyperresponsiveness and inflammation. Respir Res. 2006;7:146.PubMedCrossRefGoogle Scholar
  29. 29.
    McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol. 2004;172:2903–8.PubMedGoogle Scholar
  30. 30.
    Edwan JH, Perry G, Talmadge JE, Agrawal DK. Flt-3 ligand reverses late allergic response and airway hyper-responsiveness in a mouse model of allergic inflammation. J Immunol. 2004;172:5016–23.PubMedGoogle Scholar
  31. 31.
    Cheng C, Ho WE, Goh FY, Guan SP, Kong LR, Lai WQ, et al. Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PLoS One. 2011;6:e20932.PubMedCrossRefGoogle Scholar
  32. 32.
    Bao Z, Lim S, Liao W, Lin Y, Thiemermann C, Leung BP, et al. Glycogen synthase kinase-3beta inhibition attenuates asthma in mice. Am J Respir Crit Care. 2007;176:431–8.CrossRefGoogle Scholar
  33. 33.
    Marjanovic N, Bosnar M, Michielin F, Wille DR, Anic-Milic T, Culic O, et al. Macrolide antibiotics broadly and distinctively inhibit cytokine and chemokine production by COPD sputum cells in vitro. Pharmacol Res. 2011;63:389–97.PubMedCrossRefGoogle Scholar
  34. 34.
    Karakawa M, Komine M, Tamaki K, Ohtsuki M. Roxithromycin downregulates production of CTACK/CCL27 and MIP-3alpha/CCL20 from epidermal keratinocytes. Arch Dermatol Res. 2010;302:763–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Biotechnology. 1979;24:145–9.Google Scholar
  36. 36.
    Kawazu K, Kurokawa M, Asano K, Mita A, Adachi M. Suppressive activity of a macrolide antibiotic, roxithromycin on co-stimulatory molecule expression on mouse splenocytes in vivo. Mediat Inflamm. 2000;9:39–43.CrossRefGoogle Scholar
  37. 37.
    Lee YN, Tuckerman J, Nechushtan H, Schutz G, Razin E, Angel P. c-Fos as a regulator of degranulation and cytokine production in FcepsilonRI-activated mast cells. J Immunol. 2004;173:2571–7.PubMedGoogle Scholar
  38. 38.
    Inoue H, Kato R, Fukuyama S, Nonami A, Taniguchi K, Matsumoto K, et al. Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. J Exp Med. 2005;201:73–82.PubMedCrossRefGoogle Scholar
  39. 39.
    Sutherland CL, Heath AW, Pelech SL, Young PR, Gold MR. Differential activation of the ERK, JNK, and p38 mitogen-activated protein kinases by CD40 and the B cell antigen receptor. J Immunol. 1996;157:3381–90.PubMedGoogle Scholar
  40. 40.
    Maneechotesuwan K, Xin Y, Ito K, Jazrawi E, Lee KY, Usmani OS, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol. 2007;178:2491–8.PubMedGoogle Scholar
  41. 41.
    Kim DY, Park JW, Jeoung D, Ro JY. Celastrol suppresses allergen-induced airway inflammation in a mouse allergic asthma model. Eur J Pharmacol. 2009;612:98–105.PubMedCrossRefGoogle Scholar
  42. 42.
    Marok R, Winyard PG, Coumbe A, Kus ML, Gaffney K, Blades S, et al. Activation of the transcription factor nuclear factor-kappaB in human inflamed synovial tissue. Arthritis Rheum. 1996;39:583–91.PubMedCrossRefGoogle Scholar
  43. 43.
    Labro MT. Macrolide antibiotics: current and future uses. Expert Opin Pharmacother. 2004;5:541–50.PubMedCrossRefGoogle Scholar
  44. 44.
    Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin Immunol. 2006;117:1233–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Desaki M, Takizawa H, Ohtoshi T, Kasama T, Kobayashi K, Sunazuka T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267:124–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Shinkai M, Lopez-Boado YS, Rubin BK. Clarithromycin has an immunomodulatory effect on ERK-mediated inflammation induced by Pseudomonas aeruginosa flagellin. J Antimicrob Chemother. 2007;59:1096–101.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Xinxin Ci
    • 1
  • Xiao Chu
    • 1
  • Xue Xu
    • 1
  • Hongyu Li
    • 1
  • Xuming Deng
    • 1
  1. 1.Key Laboratory of Zoonosis Research, Institute of Zoonosis, College of Animal Science and Veterinary Medicine, Ministry of EducationJilin UniversityChangchunPeople’s Republic of China

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