Hypoxia and Extracellular Adenosine A_2AR Function in the Same Anti-Inflammatory, Lung Tissue-Protecting Pathway

<div><p>(A) Effects of breathing hypoxic (10%) oxygen on arterial blood oxygen tension (left graph) and plasma adenosine concentration (right graph) in healthy wild-type mice. As a control, data are also shown for healthy mice breathing 21% and 100% oxygen.</p> <p>(B) No survival of <i>A_2AR</i> gene-deficient mice was observed in acute hypoxic lung injury. Wild-type and <i>A_2AR</i> gene-deficient mice were injected IT with LPS and exposed to hypoxia (10%). While the majority of wild-type mice survived, all of the <i>A_2AR</i> gene-deficient mice died, indicating that expression of A_2AR is required for survival of hypoxic lung inflammation; this experiment mimics the clinical situation in which lung inflammation increases to such severity that hypoxia occurs.</p> <p>(C) Significantly higher levels of pulmonary and systemic inflammatory cytokine production in hypoxic A_2AR-deficient mice. Observations of survival were supported by significantly higher BAL and serum (Se) levels of inflammatory cytokines in hypoxic A_2AR-deficient mice compared to hypoxic wild-type mice. Cytokines were determined 2 h after IT LPS injection, because A_2AR-deficient mice started to die soon after LPS administration and thus could not be used in comparative studies with wild-type control mice. The early mortality of A_2AR-deficient mice also did not allow the comparative determination of effects of hypoxia on other late markers of inflammation such as PMN accumulation, lung vascular permeability, and pulmonary gas exchange, which in wild-type mice need about 48 h to develop after IT endotoxin injection.</p> <p>(D) Degree of inflammation is independent from level of oxygen in A_2AR-deficient mice but not in wild-type mice. While BAL fluid TNF-α concentration determined 2 h after IT LPS injection was significantly suppressed in hypoxic wild-type mice compared to animals breathing 100% oxygen, hypoxia had no effect on TNF-α BAL concentrations in <i>A_2AR</i> gene-deficient mice, demonstrating that suppression of TNF-α formation by hypoxia is mediated through A_2AR signaling.</p>