Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury.
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 (A2a(flox/flox) x 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 approximately 50%. These findings were confirmed in A2a(flox/flox) x 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.
Reutershan
Jörg
J
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Cagnina
Rebecca E
RE
Chang
Daniel
D
Linden
Joel
J
Ley
Klaus
K
D000818:Animals; D002199:Capillary Permeability; D018925:Chemokines / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018183:Transplantation Chimera
D018925:Chemokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A