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Am J Physiol Lung Cell Mol Physiol 290: L579-L587, 2006. First published October 28, 2005; doi:10.1152/ajplung.00258.2005
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Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations

Janci L. Chunn,1,2 Amir Mohsenin,1,2 Hays W. J. Young,1,2 Chun G. Lee,3 Jack A. Elias,3 Rodney E. Kellems,1,2 and Michael R. Blackburn1,2

1Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston; 2Graduate School of Biomedical Sciences, Houston, Texas; and 3Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

Submitted 15 June 2005 ; accepted in final form 18 October 2005

Adenosine, a signaling nucleoside, exhibits tissue-protective and tissue-destructive effects. Adenosine levels in tissues are controlled in part by the enzyme adenosine deaminase (ADA). ADA-deficient mice accumulate adenosine levels in multiple tissues, including the lung, where adenosine contributes to the development of pulmonary inflammation and chronic airway remodeling. The present 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 mo and die from apparent respiratory distress. Detailed investigations of the lung histopathology of partially ADA-deficient mice revealed progressive pulmonary fibrosis marked by an increase in the number of pulmonary myofibroblasts and an increase in collagen deposition. In addition, in regions of the distal airways that did not exhibit fibrosis, an increase in the number of large foamy macrophages and a substantial enlargement of the alveolar air spaces suggest emphysemic changes. Furthermore, important proinflammatory and profibrotic signaling pathways, including IL-13 and transforming growth factor-beta1, 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 of lung adenosine concentrations and alterations in lung adenosine receptor levels, supporting the hypothesis that elevation of endogenous adenosine is a proinflammatory and profibrotic signal in this model.

adenosine receptor; cytokine; chemokine


Address for reprint requests and other correspondence: M. R. Blackburn, Dept. of Biochemistry and Molecular Biology, Univ. of Texas-Houston Medical School, 6431 Fannin, Houston, TX 77030 (e-mail: michael.r.blackburn{at}uth.tmc.edu)




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