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Phosphodiesterases Inhibition by Bacilli Calmette-Guérin Contributes to Decrease Asthma in Allergic Rats

Abstract

Phosphodiesterases  (PDE)  hydrolyse intracellular cAMP  and  cGMP  to  inactive  5’ monophosphates. Decreased level of cAMP is involved in the pathogenesis of asthma. We and others have shown that phosphodiesterases were upregulated in the lung of allergic rats, and Bacilli Calmette-Guérin (BCG) induced the production of cAMP in vitro. However, it is unclear how BCG’s effect asthma and whether it is related to PDEs.
In  this  study,  BCG  was  intraperitoneally  injected  into  male  Sprague-Dawley rats sensitized and later the rats were challenged with ovabumin/pertusis. The inflammation in lungs was measured. Airway hyperresponsiveness was determined using MedLab software after intravenous methacholine challenge. Furthermore,  cAMP level and adenylate cyclase activity in lungs were analyzed by ELISA, phosphodiesterases activities were analyzed by HPLC, while PDEs mRNA levels in lungs was analyzed by reverse transcription-polymerase chain  reaction.  Administration  of  BCG  significantly attenuated  allergen-induced  lung inflammatory response  and  hyper  responsiveness  as  compared  with  vehicle treatment. Furthermore,  the  levels of  cAMP in lungs were significantly increased in  BCG-treated allergic rats. Interestingly, administration of BCG decreased the activity of cAMP-PDE, but not adenylyl cyclase (AC), activity in lungs of animals. Furthermore, pretreatment with BCG significantly decreased the mRNA levels of PDE4A, 4C, 5 and 8, which were induced in lungs of allergic rats.
BCG  administration  attenuated  airway inflammatory  response  and  bronchial  hyper responsiveness in rats, which are the most important symptoms in asthma. The decreased PDEs  mRNA  and  inhibited cAMP-PDE  activities by BCG  contribute,  at least in part, prevention of allergen-induced airway inflammation and asthma in rats.

  1. Thomas MS, Parolia A, Kundabala M, Vikram M.Asthma and oral health. Aust Dent J 2010; 55(2):128-33.
  2. Fromer L. Managing asthma: an evidence-based approach to optimizing inhaled corticosteroid treatment. South Med J 2010; 103(10):1038-44.
  3. Dozor AJ. The role of oxidative stress in the pathogenesis and treatment of asthma. Ann N Y Acad Sci 2010;1203:133-7.
  4. Fanta CH. Asthma. N Engl J Med 2009; 360(10):1002-14.
  5. Kim SR, Rhee YK. Overlap Between Asthma and COPD: Where the Two Diseases Converge. Allergy Asthma Immunol Res 2010; 2(4):209-14.
  6. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT,Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006; 354(19):1985-97.
  7. Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006;354(19):1998-2005.
  8. Essayan DM. Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 2001; 108(5):671-80.
  9. Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 2010; 35(2):91-100.
  10. Grandoch M, Roscioni SS, Schmidt M. The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. Br J Pharmacol 2010; 159(2):265-84.
  11. Parker CW, Smith JW. Alterations in cyclic adenosine monophosphate metabolism in human bronchial asthma. I. Leukocyte responsiveness to -adrenergic agents. J Clin Invest 1973; 52(1):48-59.
  12. Brown WM. Treating COPD with PDE 4 inhibitors. Int J Chron Obstruct Pulmon Dis 2007; 2(4):517-33.
  13. Anderson GP. Current issues with beta2-adrenoceptor agonists: pharmacology and molecular and cellular mechanisms. Clin Rev Allergy Immunol 2006; 31(2-3):119-30.
  14. Halpin DM. ABCD of the phosphodiesterase family: interaction and differential activity in COPD. Int J Chron Obstruct Pulmon Dis 2008; 3(4):543-61.
  15. Takeuchi M, Tatsumi Y, Kitaichi K, Baba K, Suzuki R, Shibata E, et al. Selective phosphodiesterase type 4 inhibitors reduce the prolonged survival of eosinophils stimulated by granulocyte-macrophage colony- stimulating factor. Biol Pharm Bull 2002; 25(2):184-7.
  16. Wang K, Shen HH, Huang HQ, Chen JC, Chen Z.Acetamide-45 inhibited hyperresponsiveness and airway inflammation in mice partly depending on phosphodiesterase activity suppression. Acta Pharmacol Sin 2008; 29(10):1195-201.
  17. Yamaki K, Alam AH, Hossain MA, Taneda S, Yanagisawa R, Takano H, et al. Effect of rolipram, a phosphodiesterase IV inhibitor, on allergic footpad swelling using various adjuvants in mice. Scand J Immunol 2005; 62(4):378-84.
  18. Rousseau MC, Parent ME, St-Pierre Y. Potential health effects from non-specific stimulation of the immune function in early age: the example of BCG vaccination. Pediatr Allergy Immunol 2008; 19(5):438-48.
  19. El-Zein M, Parent ME, Benedetti A, Rousseau MC. Does BCG vaccination protect against the development of childhood asthma? A systematic review and meta- analysis of epidemiological studies. Int J Epidemiol 2010;39(2):469-86.
  20. Miyake Y, Arakawa M, Tanaka K, Sasaki S, Ohya Y.Tuberculin reactivity and allergic disorders in schoolchildren, Okinawa, Japan. Clin Exp Allergy 2008;38(3):486-92.
  21. Ramsey CD, Celedon JC. The hygiene hypothesis and asthma. Curr Opin Pulm Med 2005; 11(1):14-20.
  22. Alyasin S, Katibeh P, Asadi S. The relationship between tuberculin response, BCG vaccine scar and asthma. Iran J Allergy Asthma Immunol 2009; 8(4):205-10.
  23. Martignon G, Oryszczyn MP, Annesi-Maesano I. Does childhood immunization against infectious diseases protect from the development of atopic disease? Pediatr Allergy Immunol 2005; 16(3):193-200.
  24. Soysal A, Bahceciler N, Barlan I, Bakir M. Lack of an inverse association between tuberculosis infection and atopy: by T-cell-based immune assay (RD1-ELISpot). Pediatr Allergy Immunol 2008; 19(8):709-15.
  25. Shen HH, Zhang GS, Wang PL. Mycobacterium bovis- Bacillus Calmette-Guerin and asthma. Chin Med J (Engl)2005; 118(11):942-7.
  26. Han ER, Choi IS, Eom SH, Kim HJ. Preventive effects of mycobacteria and their culture supernatants against asthma development in BALB/c mice. Allergy Asthma Immunol Res; 2010; 2(1):34-40.
  27. Li J, Luo DF, Li SY, Sun BQ, Zhong NS. Efficacy of intramuscular BCG polysaccharide nucleotide on mild to moderate bronchial asthma accompanied with allergic rhinitis: a randomized, double blind, placebo-controlled study. Chin Med J (Engl) 2005; 118(19):1595-603.
  28. Sartono E, Lisse IM, Terveer EM, van de Sande PJ, Whittle H, Fisker AB, et al. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment. PLoS One 2010; 5(5):10328.
  29. Zhang GS, Shen HH. [The preventive effect of bacillus Calmette-Guerin vaccination in early life on airway inflammation and mucus production in a murine model of asthma]. Zhonghua Jie He He Hu Xi Za Zhi 2005;28(1):17-21.
  30. Koh YI, Choi IS, Kim WY, Lee HC, Lee J. Effects of BCG infection on Schultz-Dale reaction, allergen-specific IgE levels, and Th2 immune response in sensitized rats. Korean J Intern Med 2001; 16(3):180-6.
  31. Yang X, Wang S, Fan Y, Zhu L. Systemic mycobacterial infection inhibits antigen-specific immunoglobulin E production, bronchial mucus production and eosinophilic inflammation induced by allergen. Immunology 1999;98(3):329-37.
  32. Choi IS, Lin XH, Koh YA, Koh YI, Lee HC. Strain- dependent suppressive effects of BCG vaccination on asthmatic reactions in BALB/c mice. Ann Allergy Asthma Immunol 2005; 95(6):571-8.
  33. Li R, Liu EM, Yang XQ, Wang LJ. [Combined effects of neonatal Bacillus Calmette-Guerin vaccination and respiratory syncytial infection on experimental asthma in mice]. Zhonghua Er Ke Za Zhi 2006; 44(6):420-4.
  34. Li C, Xu Y, Zhang Z, Yang D, Liu X, Xiong W. An experimental study of the effect of bacille calmette-guerin vaccine on the production of a rat asthmatic model and its relation with gamma delta T cells. Zhonghua Jie He He Hu Xi Za Zhi 2002; 25(3):162-5.
  35. Lagranderie M, Abolhassani M, Vanoirbeek JA, Lima C, Balazuc AM, Vargaftig BB, et al. Mycobacterium bovis bacillus Calmette-Guerin killed by extended freeze- drying targets plasmacytoid dendritic cells to regulate lung inflammation. J Immunol; 2010; 184(2):1062-70.
  36. Zhang Y, Mahendran R, Yap LL, Esuvaranathan K, Khoo HE. The signalling pathway for BCG-induced interleukin-6 production in human bladder cancer cells. Biochem Pharmacol 2002; 63(2):273-82.
  37. Tang HF, Chen JQ, Xie QM, Zheng XY, Zhu YL, Adcock I, et al. The role of PDE4 in pulmonary inflammation and goblet cell hyperplasia in allergic rats. Biochim Biophys Acta 2006; 1762(5):525-32.
  38. Tang HF, Song YH, Chen JC, Chen JQ, Wang P.Upregulation of phosphodiesterase-4 in the lung of allergic rats. Am J Respir Crit Care Med 2005;171(8):823-8.
  39. Koh YI, Choi IS, Park SC, Kang KW. BCG infection during pre-sensitization or even post-sensitization inhibits airway sensitivity in an animal model of allergic asthma. J Korean Med Sci 2000; 15(3):265-72.
  40. Sergienko DV, Boklag SP. [Bronchial asthma: characteristics of modern diagnostics]. Lik Sprava 2010; (1-2):31-9.
  41. Xie QM, Chen JQ, Shen WH, Yang QH, Bian RL. Effects of cyclosporin A by aerosol on airway hyperresponsiveness and inflammation in guinea pigs. Acta Pharmacol Sin 2002; 23(3):243-7.
  42. Leon D, Albasanz JL, Ruiz MA, Martin M. Chronic caffeine or theophylline intake during pregnancy inhibits A1 receptor function in the rat brain. Neuroscience 2005;131(2):481-9.
  43. Kostic MM, Erdogan S, Rena G, Borchert G, Hoch B, Bartel S, et al. Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxo- prostacyclin-preconditioned rat heart. J Mol Cell Cardiol 1997; 29(11):3135-46.
  44. Naro F, Sette C, Vicini E, De Arcangelis V, Grange M, Conti M, et al. Involvement of type 4 cAMP- phosphodiesterase in the myogenic differentiation of L6 cells. Mol Biol Cell 1999; 10(12):4355-67.
  45. Phillips PG, Long L, Wilkins MR, Morrell NW. cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 2005;288(1):L103-15.
  46. Witwicka H, Kobialka M, Siednienko J, Mitkiewicz M, Gorczyca WA. Expression and activity of cGMP- dependent phosphodiesterases is up-regulated by lipopolysaccharide (LPS) in rat peritoneal macrophages. Biochim Biophys Acta 2007; 1773(2):209-18.
  47. Parker CW, Huber MG, Baumann ML. Alterations incyclic AMP metabolism in human bronchial asthma. 3. Leukocyte and lymphocyte responses to steroids. J Clin Invest 1973; 52(6):1342-8.
  48. Lehmann S, Ott H. Glucocorticoid hypersensitivity as a rare but potentially fatal side effect of paediatric asthma treatment: a case report. J Med Case Reports 2008; 2:186.
  49. Harrison TW, Oborne J, Newton S, Tattersfield AE.Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004; 363(9405):271-5.
  50. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003; 168(11):1308-11.
  51. Erb KJ, Holloway JW, Sobeck A, Moll H, Le Gros G.Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia. J Exp Med 1998; 187(4):561-9.
  52. Major T, Wohlleben G, Reibetanz B, Erb KJ. Application of heat killed Mycobacterium bovis-BCG into the lung inhibits the development of allergen-induced Th2 responses. Vaccine 2002; 20(11-12):1532-40.
  53. Nahori MA, Lagranderie M, Lefort J, Thouron F, Joseph D, Winter N, et al. Effects of Mycobacterium bovis BCG on the development of allergic inflammation and bronchial hyperresponsiveness in hyper-IgE BP2 mice vaccinated as newborns. Vaccine 2001; 19(11-12):1484-95.
  54. Shen H, Huang H, Wang J, Ye S, Li W, Wang K, et al.Neonatal vaccination with Bacillus Calmette-Guerin elicits long-term protection in mouse-allergic responses. Allergy 2008; 63(5):555-63.
  55. Fan Chung K. Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol 2006; 533(1-3):110-7.
  56. Moon HG, Kim YS, Choi JP, Choi DS, Yoon CM, Jeon SG, et al. Aspirin attenuates the anti-inflammatory effects of theophylline via inhibition of cAMP production in mice with non-eosinophilic asthma. Exp Mol Med 2010;42(1):47-60.
  57. Kaur M, Holden NS, Wilson SM, Sukkar MB, Chung KF, Barnes PJ, et al. Effect of beta2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A. Am J Physiol Lung Cell Mol Physiol 2008;295(3):L505-14.
  58. Deng YM, Xie QM, Tang HF, Sun JG, Deng JF, Chen JQ, et al. Effects of ciclamilast, a new PDE 4 PDE4 inhibitor, on airway hyperresponsiveness, PDE4D expression and airway inflammation in a murine model of asthma. Eur J Pharmacol 2006; 547(1-3):125-35.
  59. Sun JG, Deng YM, Wu X, Tang HF, Deng JF, Chen JQ, et al. Inhibition of phosphodiesterase activity, airway inflammation and hyperresponsiveness by PDE4 inhibitor and glucocorticoid in a murine model of allergic asthma. Life Sci 2006; 79(22):2077-85.
  60. Fabbri LM, Beghe B, Yasothan U, Kirkpatrick P.Roflumilast. Nat Rev Drug Discov 2010; 9(10):761-2.
  61. Spina D. PDE4 inhibitors: current status. Br J Pharmacol 2008; 155(3):308-15.
  62. Wang H, Peng MS, Chen Y, Geng J, Robinson H, Houslay MD, et al. Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J 2007; 408(2):193-201.
  63. Woyda K, Koebrich S, Reiss I, Rudloff S, Pullamsetti SS, Ruhlmann A, et al. Inhibition of phosphodiesterase 4 enhances lung alveolarisation in neonatal mice exposed to hyperoxia. Eur Respir J 2009; 33(4):861-70.
  64. Jeong HC, Lee SY, Lee EJ, Jung KH, Kang EH, Kim JH,et al. Proteomic analysis of peripheral T-lymphocytes in patients with asthma. Chest 2007; 132(2):489-96.
  65. Al Qadi-Nassar B, Bichon-Laurent F, Portet K, Tramini P, Arnoux B, Michel A. Effects of L-arginine and phosphodiesterase-5 inhibitor, sildenafil, on inflammation and airway responsiveness of sensitized BP2 mice. Fundam Clin Pharmacol 2007; 21(6):611-20.
  66. Dong H, Osmanova V, Epstein PM, Brocke S.Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes. Biochem Biophys Res Commun 2006; 345(2):713-9.
  67. Toward TJ, Smith N, Broadley KJ. Effect of phosphodiesterase-5 inhibitor, sildenafil (Viagra), in animal models of airways disease. Am J Respir Crit Care Med 2004; 169(2):227-34.

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SectionArticles
Keywords
Adenylyl Cyclase Asthma Bacillus Calmette-Guérin cAMP Phosphodiesterase
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1.
Wang Y, Jiang Y, Tang H, Wang X, Zhao C, Chen J. Phosphodiesterases Inhibition by Bacilli Calmette-Guérin Contributes to Decrease Asthma in Allergic Rats. Iran J Allergy Asthma Immunol. 1;10(3):207-220.