Abstract 339: Oxygen Blunts A2aR to Augment Lung Injury
Introduction: Mechanisms leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain incompletely understood, yet the severity of illness and societal disease burden necessitate continued investigation. On-going lung inflammation and injury may occur due to inhibition of anti-inflammatory pathways in alveolar macrophages. With tissue injury, released adenosine preferentially activates the adenosine 2A receptor (A2aR), a pathway which has been implicated in mediating anti-inflammatory effects and tissue protection; however, modifiers of this pathway in macrophages are not well-described. In a murine model, we have observed that moderate levels of oxygen after intratracheal LPS increase and sustain macrophage inflammation. We hypothesize that moderate oxygen inhibits the A2aR pathway in macrophages to augment inflammation and lung injury.
Methods: Murine model consists of intratracheal (IT) delivery of LPS, followed 12 hours later by 60% oxygen or 21% oxygen (RA) via sealed chamber.
Results: Wild-type mice exposed to IT LPS (0.375 [[Unsupported Character - Symbol Font ]]g/g mouse) followed by 60% oxygen had significantly more lung injury at days 2-4 in comparison to mice exposed to LPS or 60% oxygen alone, with increased alveolar cell influx, histologic injury, and epithelial barrier permeability. 60% oxygen after LPS significantly reduced lung A2aR mRNA and alveolar cell intracellular cyclic AMP (IC cAMP), located directly downstream of A2aR. Reduction in IC cAMP also occurred in isolated macrophages exposed to both LPS and oxygen when compared to LPS alone; this reduction was reversed using a specific A2aR agonist, CGS 21680. Adding oxygen or ZM241385 (A2aR antagonist) to LPS-exposed macrophages increased secretion of pro-inflammatory cytokines TNF-[[Unsupported Character - Symbol Font ]] and MIP-2, and expression of co-stimulatory molecules CD86 and CD40. Murine delivery of CGS 21680 (125ug/dose/mouse) every 24 hours starting concurrently with oxygen exposure reduced lung injury in LPS and oxygen-exposed mice.
Conclusion: After LPS exposure, 60% oxygen acts to decrease activation of the A2aR pathway in macrophages which may directly exacerbate lung injury.
- © 2012 by American Heart Association, Inc.