Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality. Exacerbating factors increasing the risk of ARDS remain unknown. Supplemental
oxygen is often necessary in both mild and severe
lung disease. The potential effects of supplemental
oxygen may include augmentation of
lung inflammation by inhibiting anti-inflammatory pathways in alveolar macrophages. We sought to determine
oxygen-derived effects on the anti-inflammatory A2A adenosinergic (ADORA2A) receptor in macrophages, and the role of the ADORA2A receptor in
lung injury. Wild-type (WT) and ADORA2A(-/-) mice received intratracheal
lipopolysaccharide (IT LPS), followed 12 hours later by continuous exposure to 21%
oxygen (control mice) or 60%
oxygen for 1 to 3 days. We measured the phenotypic endpoints of
lung injury and the alveolar macrophage inflammatory state. We tested an ADORA2A-specific agonist, CGS-21680 hydrochloride, in LPS plus
oxygen-exposed WT and ADORA2A(-/-) mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A(-/-) mice exposed to IT LPS and 60%
oxygen demonstrated significantly more histologic
lung injury, alveolar neutrophils, and
protein. Macrophages from ADORA2A(-/-) mice exposed to LPS plus
oxygen expressed higher concentrations of proinflammatory
cytokines and cosignaling molecules. CGS-21680 prevented the
oxygen-induced augmentation of
lung injury after LPS only in WT mice. Chimera experiments demonstrated that the transfer of WT but not ADORA2A(-/-) bone marrow cells into irradiated ADORA2A(-/-) mice reduced
lung injury after LPS plus
oxygen, demonstrating myeloid ADORA2A protection. ADORA2A is protective against
lung injury after LPS and
oxygen.
Oxygen after LPS increases macrophage activation to augment
lung injury by inhibiting the ADORA2A pathway.