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1 Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, Medical School, Houston, TX, USA
* To whom correspondence should be addressed. E-mail: michael.r.blackburn{at}uth.tmc.edu.
Adenosine is a signaling nucleoside that exhibits both tissue protective and tissue destructive effects. The levels of adenosine in tissues are controlled in part by the enzyme adenosine deaminase (ADA). Mice deficient in this enzyme accumulate adenosine levels in multiple tissues including the lung where adenosine contributes to the development of pulmonary inflammation and chronic airway remodeling. The current study describes the development of pulmonary fibrosis in mice that have been genetically engineered to possess partial ADA enzyme activity and thus accumulate adenosine over a prolonged period of time. These partially ADA-deficient mice live for up to 5 months and die from apparent respiratory distress. Detailed investigations of the lung histopathology revealed that partially ADA-deficient mice exhibit progressive pulmonary fibrosis marked by an increase in pulmonary myofibroblasts and increased collagen deposition. In addition, regions of the distal airways that did not exhibit fibrosis contained increased numbers of large foamy macrophages, and there was substantial enlargement of the alveolar air spaces suggesting emphysemic changes. Furthermore, important pro-inflammatory and pro-fibrotic signaling pathways, including IL-13 and TGF-
1 were activated. Increases in tissue fibrosis were also seen in the liver and kidneys of these mice. These changes occurred in association with pronounced elevations in lung adenosine concentrations and alterations in lung adenosine receptor levels supporting the hypothesis that elevations in endogenous adenosine functions as a pro-inflammatory and pro-fibrotic signal in this model.
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