Therapeutic Anti-Inflammatory Effects of Myeloid Cell Adenosine Receptor A2a Stimulation in Lipopolysaccharide-Induced Lung Injury

Abstract

To determine the role of the adenosine receptor A2a in a murine model of LPS-induced lung injury, migration of polymorphonuclear leukocytes (PMNs) into the different compartments of the lung was determined by flow cytometry, microvascular permeability was assessed by the extravasation of Evans blue, and the release of chemotactic cytokines into the alveolar airspace was determined by ELISA. Measurements were performed in wild-type and A2a gene-deficient mice (A2a−/−). To differentiate the role of A2a on hemopoietic and nonhemopoietic cells, we created chimeric mice by transfer of bone marrow (BM) between wild-type and A2a−/− mice and used mice that lacked A2a expression selectively on myeloid cells (A2aflox/flox × LysM-cre). A specific A2a receptor agonist (ATL202) was used to evaluate its potential to reduce lung injury in vivo. In wild-type mice, therapeutic treatment with ATL202 reduced LPS-induced PMN recruitment, and release of cytokines. Pretreatment, but not posttreatment, also reduced Evans blue extravasation. In the BM chimeric mice lacking A2a on BM-derived cells, PMN migration into the alveolar space was increased by ∼50%. These findings were confirmed in A2aflox/flox × LysM-cre mice. ATL202 was only effective when A2a was present on BM-derived cells. A2a agonists may be effective at curbing inflammatory lung tissue damage.

Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats

“…In ischemia reperfusion models, the use of A 2A receptor agonists resulted in a decrease in macrophage activation and adhesion molecular expression on endothelial cells, blockage of endothelial-neutrophil interactions, and attenuation of vascular derangement (11,12,(17)(18)(19)(20)(21). The administration of the A 2A receptors agonist CGS-21680 has been shown to ameliorate lung injury in animal models of ischemia and reperfusion (12,17).…”

“…The A 2A R expressed on leukocytes and lung displays high affinity for adenosine (8). Several studies have shown that activation of A 2A receptor is protective against ischemia/reperfusion injury by decreasing the expression of endothelial adhesion molecules and the production of cytokines and reactive oxygen species (17)(18)(19)(20)(21). We thus hypothesized that a pharmacologic intervention with an A 2A R agonist protects the lung from injury in a two-hit model of HSR followed by mechanical ventilation.…”

Microarray Analysis of Gene Expression Profiles in Response to Treatment with Melatonin in Lipopolysaccharide Activated RAW 264.7 Cells

“…Each type of adenosine receptor exhibits a distinct pharmacological and physiological profile [14]. Adenosine receptors A2a and A2b have been recognized as important mediators in inflammatory models [15,16]. Additionally, Schingnitz et al [17] showed that LPS treatment induced Adora2b transcription and corresponding protein expression in in vivo and in vitro studies.…”

Adenosine Receptor A1 Regulates Polymorphonuclear Cell Trafficking and Microvascular Permeability in Lipopolysaccharide-Induced Lung Injury

“…Recent studies identified CD39 and CD73, both rate-limiting enzymes for the generation of extracellular adenosine, as critical mediators in pulmonary inflammation (16,17). In addition, activation of ARs A2a and A2b has been demonstrated to attenuate organ damage in LPS-and ventilator-induced lung injury (18,19).…”