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Enhanced Airway Inflammation and Remodeling in Adenosine Deaminase-Deficient Mice Lacking the A_2B Adenosine Receptor¹

Yang Zhou^*, Amir Mohsenin^*, Eva Morschl^*, Hays W. J. Young^*, Jose G. Molina^*, Wenbin Ma, Chun-Xiao Sun^*, Hector Martinez-Valdez and Michael R. Blackburn^2,*

^* Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030; and Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

Adenosine is a signaling nucleoside that is generated in response to cellular injury and orchestrates the balance between tissue protection and the progression to pathological tissue remodeling. Adenosine deaminase (ADA)-deficient mice develop progressive airway inflammation and remodeling in association with adenosine elevations, suggesting that adenosine can promote features of chronic lung disease. Furthermore, pharmacological studies in ADA-deficient mice demonstrate that A_2BR antagonism can attenuate features of chronic lung disease, implicating this receptor in the progression of chronic lung disease. This study examines the contribution of A_2BR signaling in this model by generating ADA/A_2BR double-knockout mice. Our hypothesis was that genetic removal of the A_2BR from ADA-deficient mice would lead to diminished pulmonary inflammation and damage. Unexpectedly, ADA/A_2BR double-knockout mice exhibited enhanced pulmonary inflammation and airway destruction. Marked loss of pulmonary barrier function and excessive airway neutrophilia are thought to contribute to the enhanced tissue damage observed. These findings support an important protective role for A_2BR signaling during acute stages of lung disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI43572 and HL70952 to M.R.B. W.M. was supported by an Odyssey Program Fellowship and The Cockrell Foundation Award for Scientific Achievement at M. D. Anderson Cancer Center.

² Address correspondence and reprint requests to Dr. Michael R. Blackburn, Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX. E-mail address: michael.r.blackburn{at}uth.tmc.edu

³ Abbreviations used in this paper: ADA, adenosine deaminase; AR, adenosine receptor; PEG-ADA, polyethelene glycol-ADA; BAL, bronchial alveolar lavage; PAS, periodic acid-Schiff.

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