Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations.
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.
Chunn
Janci L
JL
Dept. of Biochemistry and Molecular Biology, Univ. of Texas-Houston Medical School, 6431 Fannin, Houston, TX 77030, USA.
Mohsenin
Amir
A
Young
Hays W J
HW
Lee
Chun G
CG
Elias
Jack A
JA
Kellems
Rodney E
RE
Blackburn
Michael R
MR
D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D018793:Interleukin-13 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000209:etiology*; D012137:Respiratory System / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D018793:Interleukin-13; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D000243:Adenosine Deaminase; D000241:Adenosine