Uncontrolled transmigration of polymorphonuclear leukocytes (PMNs) into the different compartments of the lungs (intravascular, interstitial, alveolar) is a critical event in the early stage of acute lung injury and acute respiratory distress syndrome. Adenosine receptor A2b is highly expressed in the inflamed lungs and has been suggested to mediate cell trafficking. In a murine model of LPS-induced lung inflammation, we investigated the role of A2b on migration of PMNs into the different compartments of the lung. In A2b−/− mice, LPS-induced accumulation of PMNs was significantly higher in the interstitium, but not in the alveolar space. In addition, pulmonary clearance of PMNs was delayed in A2b−/− mice. Using chimeric mice, we identified A2b on hematopoietic cells as crucial for PMN migration. A2b did not affect the release of relevant chemokines into the alveolar space. LPS-induced microvascular permeability was under the control of A2b on both hematopoietic and nonhematopoietic cells. Activation of A2b on endothelial cells also reduced formation of LPS-induced stress fibers, highlighting its role for endothelial integrity. A specific A2b agonist (BAY 60–6583) was effective in decreasing PMN migration into the lung interstitium and microvascular permeability. In addition, in vitro transmigration of human PMNs through a layer of human endothelial or epithelial cells was A2b dependent. Activation of A2b on human PMNs reduced oxidative burst activity. Together, our results demonstrate anti-inflammatory effects of A2b on two major characteristics of acute lung injury, with a distinct role of hematopoietic A2b for cell trafficking and endothelial A2b for microvascular permeability.
Signaling through the A2B Adenosine Receptor Dampens Endotoxin-Induced Acute Lung Injury
