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

Am J Pathol. 2008 Jun;172(6):1675-82. doi: 10.2353/ajpath.2008.070952. Epub 2008 May 8.

Abstract

Adenosine is a potent modulator of inflammation and tissue repair. We have recently reported that activation of adenosine A(2A) 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 A(2A) 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 beta1, connective tissue growth factor, and interleukin-13. Pharmacological treatment of ADA-deficient mice with the A(2A) 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 A(2A) receptor antagonists as novel therapeutic agents for the modulation of dermal fibrotic disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / metabolism*
  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Collagen / metabolism
  • Fibrosis
  • Interleukin-13 / metabolism
  • Mice
  • Receptor, Adenosine A2A / physiology
  • Skin / drug effects*
  • Skin / metabolism
  • Skin / pathology
  • Transforming Growth Factor beta1 / metabolism
  • Triazines / pharmacology
  • Triazoles / pharmacology

Substances

  • Adenosine A2 Receptor Antagonists
  • Interleukin-13
  • Receptor, Adenosine A2A
  • Transforming Growth Factor beta1
  • Triazines
  • Triazoles
  • ZM 241385
  • Collagen
  • Adenosine