Alveolar Epithelial A2B Adenosine Receptors in Pulmonary Protection during Acute Lung Injury.

Abstract

Acute lung injury (ALI) is an acute inflammatory lung disease that causes morbidity and mortality in critically ill patients. However, there are many instances where ALI resolves spontaneously through endogenous pathways that help to control excessive lung inflammation. Previous studies have implicated the extracellular signaling molecule adenosine and signaling events through the A2B adenosine receptor in lung protection. In this context, we hypothesized that tissue-specific expression of the A2B adenosine receptor is responsible for the previously described attenuation of ALI. To address this hypothesis, we exposed mice with tissue-specific deletion of Adora2b to ALI, utilizing a two-hit model where intratracheal LPS treatment is followed by injurious mechanical ventilation. Interestingly, a head-to-head comparison of mice with deletion of Adora2b in the myeloid lineage (Adora2b(loxP/loxP) LysM Cre(+)), endothelial cells (Adora2b(loxP/loxP) VE-cadherin Cre(+)), or alveolar epithelial cells (Adora2b(loxP/loxP) SPC Cre(+)) revealed a selective increase in disease susceptibility in Adora2b(loxP/loxP) SPC Cre(+) mice. More detailed analysis of Adora2b(loxP/loxP) SPC Cre(+) mice confirmed elevated lung inflammation and attenuated alveolar fluid clearance. To directly deliver an A2B adenosine receptor-specific agonist to alveolar epithelial cells, we subsequently performed studies with inhaled BAY 60-6583. Indeed, aerosolized BAY 60-6583 treatment was associated with attenuated pulmonary edema, improved histologic lung injury, and dampened lung inflammation. Collectively, these findings suggest that alveolar epithelial A2B adenosine receptor signaling contributes to lung protection, and they implicate inhaled A2B adenosine receptor agonists in ALI treatment.

• Authors: Sandra Hoegl, Kelley S Brodsky, Michael R Blackburn, Harry Karmouty-Quintana, Bernhard Zwissler, Holger K Eltzschig
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 4 Pg. 1815-24 (Aug 15 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26188061 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Adenosine A2 Receptor Agonists
• Receptor, Adenosine A2B

Topics

• Acute Lung Injury (drug therapy, genetics, metabolism, pathology)
• Adenosine A2 Receptor Agonists (administration & dosage)
• Administration, Inhalation
• Alveolar Epithelial Cells (metabolism)
• Animals
• Disease Models, Animal
• Gene Deletion
• Genetic Predisposition to Disease
• Humans
• Macrophages, Alveolar (metabolism)
• Mice
• Mice, Knockout
• Neutrophils (metabolism)
• Organ Specificity (genetics)
• Receptor, Adenosine A2B (genetics, metabolism)
• Severity of Illness Index