Inhibition of Adenosine Kinase Attenuates Acute Lung Injury*

Abstract

Objective Extracellular adenosine has tissue protective potential in several conditions. Adenosine levels are regulated by a close interplay between nucleoside transporters and adenosine kinase (ADK). Based on evidence of the role of ADK in regulating adenosine levels during hypoxia, we evaluated the effect of ADK on lung injury. Furthermore, we tested the influence of a pharmacological approach to blocking ADK on the extent of lung injury. Design Prospective experimental animal study. Setting University based research laboratory. Subjects In vitro cell lines, wildtype (Wt) and ADK+/− mice. Methods We tested the expression of ADK during inflammatory stimulation in vitro and in a model of lipopolysaccharide (LPS) inhalation in vivo. Studies using the ADK promoter were performed in vitro. Wt and ADK+/− mice were subjected to LPS inhalation. Pharmacological inhibition of ADK was performed in vitro, and its effect on adenosine uptake was evaluated. The pharmacological inhibition was also performed in vivo, and the effect on lung injury was assessed. Measurements and Results We observed the repression of ADK by pro-inflammatory cytokines and found a significant influence of NF-κB on regulation of the ADK promoter. Mice with endogenous ADK repression (ADK+/−) 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 ADK by 5-iodotubercidine increased the extracellular adenosine levels in vitro, diminished the transmigration of neutrophils and improved the epithelial barrier function. The inhibition of ADK in vivo showed protective properties, reducing the extent of pulmonary inflammation during lung injury. Conclusions Taken together, these data show that ADK is a valuable target for reducing the inflammatory changes associated with lung injury and should be pursued as a therapeutic option.

Purinergic Signalling: Therapeutic Developments

“…Protective effects of A 3 R activation in attenuating reperfusion lung injury has also been reported. Inhibition of adenosine kinase attenuates acute lung injury ( Köhler et al, 2016 ). Inhaled A 2B R agonists have been recommended for the treatment of acute lung injury ( Hoegl et al, 2015 ).…”

Therapeutic potential of adenosine kinase inhibition—Revisited

“…It is also noteworthy that the two drug discovery programs that generated these novel AK inhibitors were independently disbanded shortly after the discovery of these initial toxicology findings. Over the next decade and a half, further research on the development of AK inhibitors was largely absent until recently when new pharmacological and medicinal chemistry studies of AK inhibitors have been reported …”

Stage-Specific Effects of Hypoxia on Interstitial Lung Disease

“…Adenosine triggers high-affinity A 2A adenosine receptors on activated immune cells resulting in enhanced intracellular cAMP levels to suppress these immune cells. Few studies also show that hypoxia inhibits adenosine kinase, an enzyme responsible for re-phosphorylation of adenosine to AMP, to maximize the anti-inflammatory effect [60].…”