Pulmonary Pharmacology

Acetamide-45 inhibited hyperresponsiveness and airway inflammation in mice partly depending on phosphodiesterase activity suppression

Abstract

Aim:

Asthma is characterized as a chronic inflammatory disorder of the airways. Phosphodiesterases (PDE), which hydrolyze cAMP, are considered to play important roles in asthma. We previously reported that acetamide-45 could inhibit cAMP-PDE activity, and histamine- and methacholine-induced contractions of isolated guinea pig trachea. The purpose of this study is to determine whether this agent could suppress allergic-induced airway hyperresponsiveness (AHR) and airway inflammation in allergic mice.

Methods:

A mouse model for asthma was used to investigate acetamide-45 on the airway lesions compared with glucocorticoids. The study was conducted on mice sensitized and challenged with ovalbumin and the whole body plethsmography was carried out to assess AHR. The bronchoalveolar lavage (BAL) histopathology was examined.

Results:

We found that acetamide-45 significantly inhibited the enhanced hyperresponsiveness and eosinophil recruitment in airways with elimination of cAMP-PDE activity in lung tissue. Elevated IL-4 and IL-5 in bronchoalveolar lavage fluid (BALF) in asthmatic mice were markedly decreased.

Conclusion:

Our results indicate that the agent has a potential role in inflammatory disease.

References

  1. 1

    Busse WW, Lemanske RF . Asthma. N Engl J Med 2001; 344: 350–62.

    CAS  Article  Google Scholar 

  2. 2

    Wills-Karp M . Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol 1999; 17: 255–81.

    CAS  Article  Google Scholar 

  3. 3

    Ray A, Cohn L . Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J Clin Invest 1999; 104: 985–93.

    CAS  Article  Google Scholar 

  4. 4

    Adamko D, Odemuyiwa SO, Moqbel R . The eosinophil as a therapeutic target in asthma: beginning of the end, or end of the beginning? Curr Opin Pharmacol 2003; 3: 227–32.

    CAS  Article  Google Scholar 

  5. 5

    Logan MR, Odemuyiwa SO, Moqbel R . Understanding exocytosis in immune and inflammatory cells: the molecular basis of mediator secretion. J Allergy Clin Immunol 2003; 111: 923–32.

    CAS  Article  Google Scholar 

  6. 6

    Larche M, Robinson DS, Kay AB . The role of T lymphocytes in the pathogenesis of asthma. J Allergy Clin Immunol 2003; 111: 450–63.

    CAS  Article  Google Scholar 

  7. 7

    Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: central mediator of allergic asthma. Science 1998; 282: 2258–61.

    CAS  Article  Google Scholar 

  8. 8

    Sanz MJ, Cortijo J, Morcillo EJ . PDE4 inhibitors as new anti-inflammatory drugs: effects on cell trafficking and cell adhesion molecules expression. Pharmacol Ther 2005; 106: 269–97.

    CAS  Article  Google Scholar 

  9. 9

    Torphy TJ . Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998; 157: 351–70.

    CAS  Article  Google Scholar 

  10. 10

    Fan Chung K . Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol 2006; 533: 110–7.

    Article  Google Scholar 

  11. 11

    Lipworth BJ . Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005; 365: 167–75.

    CAS  Article  Google Scholar 

  12. 12

    Menciu C, Duflos M, Fouchard F, Le Baut G, Emig P, Achterrath U, et al. New N-(pyridin-4-yl)-(indol-3-yl) acetamides and propana-mides as antiallergic agents. J Med Chem 1999; 42: 638–48.

    CAS  Article  Google Scholar 

  13. 13

    Lu YB, Chen Z, Wu M . Acetamide-45 inhibits histamine- and methacholine-induced contraction of isolated guinea pig trachea. Acta Pharmacol Sin 2002; 23: 152–6.

    PubMed  Google Scholar 

  14. 14

    Wang K, Chen JQ, Chen Z, Chen JC . Inhibition of human phosphodiesterase 4A expressed in yeast cell GL62 by theophylline, rolipram, and acetamide-45. Acta Pharmacol Sin 2002; 23: 1013–7.

    CAS  PubMed  Google Scholar 

  15. 15

    Wang K, Shen HH, Chen Z, Chen JC . Inhibitory effect of acetamide-45 on airway inflammation and phosphodiesterase 4 in allergic rats. Acta Pharmacol Sin 2005; 26: 1492–96.

    CAS  Article  Google Scholar 

  16. 16

    Duan W, Chan JH, Wong CH, Leung BP, Wong WS . Anti-inflammatory effects of mitogen-activated protein kinase inhibitor U0126 in an asthma mouse model. J Immunol 2004; 172: 7053–9.

    CAS  Article  Google Scholar 

  17. 17

    Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG . Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med 1996; 183: 195–201.

    CAS  Article  Google Scholar 

  18. 18

    Kanehiro A, Ikemura T, Makela MJ, Lahn M, Joetham A, Dakhama A, et al. Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge. Am J Respir Crit Care Med 2001; 163: 173–84.

    CAS  Article  Google Scholar 

  19. 19

    Foissier L, Lonchampt M, Coge F, Canet E . In vitro down-regulation of antigen-induced IL-5 gene expression and protein production by cAMP-specific phosphodiesterase type 4 inhibitor. J Pharmacol Exp Ther 1996; 278: 1484–90.

    CAS  PubMed  Google Scholar 

  20. 20

    Aoki M, Fukunaga M, Kitagawa M, Hayashi K, Morokata T, Ishikawa G, et al. Effect of a novel anti-inflammatory compound, YM976, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets. J Pharmacol Exp Ther 2000; 295: 1149–55.

    CAS  PubMed  Google Scholar 

  21. 21

    Barnes PJ, Adcock IM . NF-kB: a pivotal role in asthma and a new target for therapy. Trends Pharmacol Sci 1997; 18: 46–51.

    CAS  Article  Google Scholar 

  22. 22

    Bielekova B, Lincoln A, McFarland H, Martin R . Therapeutic potential of phosphodiesterase-4 and -3 inhibitors in Th1-mediated autoimmune diseases. J Immunol 2000; 164: 1117–24.

    CAS  Article  Google Scholar 

  23. 23

    Dinter H, Tse J, Halks-Miller M, Asarnow D, Onuffer J, Faulds D, et al. The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents. J Neuroimmunol 2000; 108: 136–46.

    CAS  Article  Google Scholar 

  24. 24

    Van Wauwe J, Aerts F, Walter H, de Boer M . Cytokine production by phytohemagglutinin-stimulated human blood cells: effects of corticosteroids, T cell immunosuppressants and phosphodiesterase IV inhibitors. Inflamm Res 1995; 44: 400–5.

    CAS  Article  Google Scholar 

  25. 25

    Kanda N, Watanabe S . Regulatory roles of adenylate cyclase and cyclic nucleotide phosphodiesterases 1 and 4 in interleukin-13 production by activated human T cells. Biochem Pharmacol 2001; 2: 495–507.

    Article  Google Scholar 

  26. 26

    Kumar RK, Herbert C, Thomas PS, Wollin L, Beume R, Yang M, et al. Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma. J Pharmacol Exp Ther 2003; 307: 349–55.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hua-hao Shen.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, K., Shen, Hh., Huang, Hq. et al. Acetamide-45 inhibited hyperresponsiveness and airway inflammation in mice partly depending on phosphodiesterase activity suppression. Acta Pharmacol Sin 29, 1195–1201 (2008). https://doi.org/10.1111/j.1745-7254.2008.00846.x

Download citation

Keywords

  • acetamide-45
  • 3′,5′-cyclic-nucleotide-phospho-diesterase
  • asthma
  • hyperresponsiveness
  • lung

Search