Inhibition of Adenosine Kinase Attenuates Acute Lung Injury.
OBJECTIVE
Extracellular adenosine has tissue-protective potential in several conditions. Adenosine levels are regulated by a close interplay between nucleoside transporters and adenosine kinase. On the basis of the evidence of the role of adenosine kinase in regulating adenosine levels during hypoxia, we evaluated the effect of adenosine kinase on lung injury. Furthermore, we tested the influence of a pharmacologic approach to blocking adenosine kinase on the extent of lung injury.


METHODS
Prospective experimental animal study.


METHODS
University-based research laboratory.


METHODS
In vitro cell lines, wild-type and adenosine kinase+/- mice.


METHODS
We tested the expression of adenosine kinase during inflammatory stimulation in vitro and in a model of lipopolysaccharide inhalation in vivo. Studies using the adenosine kinase promoter were performed in vitro. Wild-type and adenosine kinase+/- mice were subjected to lipopolysaccharide inhalation. Pharmacologic inhibition of adenosine kinase was performed in vitro, and its effect on adenosine uptake was evaluated. The pharmacologic inhibition was also performed in vivo, and the effect on lung injury was assessed.


RESULTS
We observed the repression of adenosine kinase by proinflammatory cytokines and found a significant influence of nuclear factor kappa-light-chain-enhancer of activated B-cells on regulation of the adenosine kinase promoter. Mice with endogenous adenosine kinase repression (adenosine kinase+/-) showed reduced infiltration of leukocytes into the alveolar space, decreased total protein and myeloperoxidase levels, and lower cytokine levels in the alveolar lavage fluid. The inhibition of adenosine kinase by 5-iodotubercidin increased the extracellular adenosine levels in vitro, diminished the transmigration of neutrophils, and improved the epithelial barrier function. The inhibition of adenosine kinase in vivo showed protective properties, reducing the extent of pulmonary inflammation during lung injury.


CONCLUSIONS
Taken together, these data show that adenosine kinase is a valuable target for reducing the inflammatory changes associated with lung injury and should be pursued as a therapeutic option.
1Department of Anaesthesiology and Intensive Care Medicine, Tübingen University Hospital, Eberhard-Karls University Tübingen, Tübingen, Germany. 2Department of Neurology, Neurobiology Laboratories, Legacy Research Institutes, Portland, OR.
David
D
Köhler
Ariane
A
Streienberger
Julio C
JC
Morote-García
Tiago F
TF
Granja
Mariella
M
Schneider
Andreas
A
Straub
Detlev
D
Boison
Peter
P
Rosenberger
D055371:Acute Lung Injury / Q000188:drug therapy / Q000378:metabolism*; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000378:metabolism*; D051379:Mice; D011014:Pneumonia / Q000378:metabolism; D011446:Prospective Studies; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
D016207:Cytokines; D008070:Lipopolysaccharides; C034214:5-iodotubercidin; D000248:Adenosine Kinase; D014372:Tubercidin