Attenuation of chronic pulmonary inflammation in A2B adenosine receptor knockout mice

Rinat Zaynagetdinov, Sergey Ryzhov, Anna E. Goldstein, Huiyong Yin, Sergey V. Novitskiy, Kasia Goleniewska, Vasiliy V. Polosukhin, Dawn C. Newcomb, Daphne Mitchell, Eva Morschl, Yang Zhou, Michael R. Blackburn, R. Stokes Peebles, Italo Biaggioni, Igor Feoktistov

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Abstract

Pharmacologic evidence suggests that activation of A2B adenosine receptors results in proinflammatory effects relevant to the progression of asthma, a chronic lung disease associated with elevated interstitial adenosine concentrations in the lung. This concept has been challenged by the finding that genetic removal of A2B receptors leads to exaggerated responses in models of acute inflammation. Therefore, the goal of our study was to determine the effects of A2B receptor gene ablation in the context of ovalbumin-induced chronic pulmonary inflammation. We found that repetitive airway allergen challenge induced a significant increase in adenosine levels in fluid recovered by bronchoalveolar lavage. Genetic ablation of A2B receptors significantly attenuated allergen-induced chronic pulmonary inflammation, as evidenced by a reduction in the number of bronchoalveolar lavage eosinophils and in peribronchial eosinophilic infiltration. The most striking difference in the pulmonary inflammation induced in A2B receptor knockout (A2BKO) and wildtype mice was the lack of allergen-induced IL-4 release in the airways of A2BKO animals, in line with a significant reduction in IL-4 protein and mRNA levels in lung tissue. In addition, attenuation of allergen-induced transforming growth factor-β release in airways of A2BKO mice correlated with reduced airway smooth muscle and goblet cell hyperplasia/hypertrophy. In conclusion, genetic removal of A2B adenosine receptors in mice leads to inhibition of allergen-induced chronic pulmonary inflammation and airway remodeling. These findings are in agreement with previous pharmacologic studies suggesting a deleterious role for A2B receptor signaling in chronic lung inflammation.

Original languageEnglish
Pages (from-to)564-571
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume42
Issue number5
DOIs
Publication statusPublished - May 1 2010

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Keywords

  • Adenosine
  • Asthma
  • IL-4
  • Pulmonary inflammation
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Zaynagetdinov, R., Ryzhov, S., Goldstein, A. E., Yin, H., Novitskiy, S. V., Goleniewska, K., Polosukhin, V. V., Newcomb, D. C., Mitchell, D., Morschl, E., Zhou, Y., Blackburn, M. R., Peebles, R. S., Biaggioni, I., & Feoktistov, I. (2010). Attenuation of chronic pulmonary inflammation in A2B adenosine receptor knockout mice. American journal of respiratory cell and molecular biology, 42(5), 564-571. https://doi.org/10.1165/rcmb.2008-0391OC