Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Abstract

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 antiinflammatory 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 ADORA2A2/2 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 2/2 mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A2/2 mice exposed to IT LPS and 60% oxygen demonstrated significantly more histologic lung injury, alveolar neutrophils, and protein. Macrophages from ADORA2A 2/2 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 2/2 bone marrow cells into irradiated ADORA2A2/2 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.

Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection

“…This excessive collateral tissue damage was originally shown to be due to overactive neutrophils [28]. Similar effects on inflamed lungs were observed by others who implicated macrophages [32] and pulmonary invariant natural killer T (iNKT) cells in the effects of hyperoxia [33]. …”

“…The expectation is that in contrast to myeloid cells and due to their localized mechanism of lethal hit delivery [34], tumor-reactive T cells de-inhibited by 60% oxygen will still be selective for tumor-antigens. Thus, the tumor-reactive T cells will likely cause much less collateral damage when de-inhibited by oxygen compared to myeloid cells during episodes of acute inflammation [28][32][33]. …”

Immunological Priming Requires Regulatory T Cells and IL-10–Producing Macrophages To Accelerate Resolution from Severe Lung Inflammation

“…To further characterize differences between primed and non-primed macrophages, we assessed cytokine production among F4-80 + CD11c + or F4-80 + CD11b + alveolar macrophage subsets. We and others have determined that macrophage CD11b to be an acceptable marker of recruited or exudative macrophages (16, 52, 53). In contrast, CD11c expression among macrophages generally designates resident alveolar macrophages (54), but recruited macrophages also express CD11c at later time points with resolution of inflammation (53).…”

Diverse macrophage populations mediate acute lung inflammation and resolution

“…Macrophage-derived MMPs 1, 3, 8, and 12 cleave CXC chemokines (MIP-2) and CC chemokines (CCL2, 3,7,8,9, and 12) to mitigate neutrophil and exudate macrophage recruitment in various lung injury models (37,118,119,139,153).…”