Abstract 18004: Adenosine and ATPγS Protect Against Bacterial Pneumonia-Induced Acute Lung Injury

Introduction: Acute lung injury (ALI) is characterized by acute lung inflammation, increased vascular permeability, and high mortality. Sepsis associated with pneumonia from gram-negative Escherichia coli ( E. coli ) is a leading cause of ALI. Lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria, disrupts the alveolar-capillary membrane barrier and increases pulmonary vascular leak. We have previously shown that the administration of the extracellular purines, adenosine and ATP, attenuated and reversed LPS-induced endothelial barrier disruption and lung injury in mice through cortical cytoskeleton strengthening and myosin phosphatase-mediated decreases in endothelial contractile responses. Hypothesis: In this study, we explored the hypothesis that treatment with these extracellular purines, adenosine or a non-hydrolyzable ATP analog, adenosine 5’-(γ-thio)-triphosphate (ATPγS), can limit lung injury associated with E. coli -induced pneumonia. Methods: Mice received either adenosine, ATPγS (final calculated plasma concentrations for both are 100 μM), or saline intravenously through the right internal jugular vein 15 minutes prior to intratracheal inoculation with live E. coli (strain ATCC 25922, 1x10 5 bacteria in 30 μl suspension). After 24 hours, lung injury was assessed by measuring leukocyte infiltration and protein levels in the bronchoalveolar lavage fluid. In addition, lung function was evaluated by measuring pressure-volume curves and oxygen saturation, while harvested lungs were used for histology. Results: We found that intravenous injections of either adenosine or ATPγS attenuated the E. coli mediated increase in inflammatory cell infiltration and protein extravasation into the bronchoalveolar lavage fluid. Furthermore, adenosine prevented weight loss, lowered the increased heart rate, and improved lung function in E. coli exposed mice. Finally, treatment with adenosine or ATPγS increased oxygen saturation and reduced the histopathological signs of lung injury in mice exposed to E. coli . Conclusion: Our study demonstrates that adenosine or ATPγS mitigates E. coli -induced pneumonia and may be used as an adjuvant therapy to treat patients with ALI.