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Published online before print May 8, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070952

Accepted for publication March 11, 2008.

Article

Pharmacological Blockade of A2A Receptors Prevents Dermal Fibrosis in a Model of Elevated Tissue Adenosine

Patricia Fernández*, Sean Trzaska*, Tuere Wilder*, Luis Chiriboga{dagger}, Michael R. Blackburn{ddagger}, Bruce N. Cronstein*, and Edwin S.L. Chan*@

From the Department of Medicine,* Division of Clinical Pharmacology, New York University School of Medicine, New York, New York; Department of Pathology,{dagger} New York University School of Medicine, New York, New York; and Department of Biochemistry and Molecular Biology,{ddagger} University of Texas-Houston Medical School, Houston, Texas

@ To whom correspondence should be addressed. E-mail: chane01{at}nyu.edu.


  Abstract

Adenosine is a potent modulator of inflammation and tissue repair. We have recently reported that activation of adenosine A2A receptors promotes collagen synthesis by human dermal fibroblasts and that blockade or deletion of this receptor in mice protects against bleomycin-induced dermal fibrosis, a murine model of scleroderma. Adenosine deaminase (ADA) is the principal catabolic enzyme for adenosine in vivo, and its deficiency leads to the spontaneous development of pulmonary fibrosis in mice. The aim of this study was to characterize further the contributions of endogenous adenosine and adenosine A2A receptors to skin fibrosis. Taking advantage of genetically modified ADA-deficient mice, we herein report a direct fibrogenic effect of adenosine on the skin, in which increased collagen deposition is accompanied by increased levels of key mediators of fibrosis, including transforming growth factor {beta}1, connective tissue growth factor, and interleukin-13. Pharmacological treatment of ADA-deficient mice with the A2A receptor antagonist ZM-241385 prevented the development of dermal fibrosis in this model of elevated tissue adenosine, by reducing dermal collagen content and expression of profibrotic cytokines and growth factors. These data confirm a fibrogenic role for adenosine in the skin and reveal A2A receptor antagonists as novel therapeutic agents for the modulation of dermal fibrotic disorders.






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Copyright © 2008 by the American Society for Investigative Pathology.