title: Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury.
abstract: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) affect 200,000 people a year in the USA. Pulmonary vascular and specifically endothelial cell (EC) barrier compromise is a hallmark of these diseases. We have recently shown that extracellular adenosine enhances human pulmonary (EC) barrier via activation of adenosine receptors (ARs) in cell cultures. On the basis of these data, we hypothesized that activation of ARs might exert barrier-protective effects in a model of ALI/ARDS in mice. To test this hypothesis, we examined the effects of pre- and posttreatment of adenosine and 5'-N-ethylcarboxamidoadenosine (NECA), a nonselective stable AR agonist, on LPS-induced lung injury. Mice were given vehicle or LPS intratracheally followed by adenosine, NECA, or vehicle instilled via the internal jugular vein. Postexperiment cell counts, Evans Blue Dye albumin (EBDA) extravasation, levels of proteins, and inflammatory cytokines were analyzed. Harvested lungs were used for histology and myeloperoxidase studies. Mice challenged with LPS alone demonstrated an inflammatory response typical of ALI. Cell counts, EBDA extravasation, as well as levels of proteins and inflammatory cytokines were decreased in adenosine-treated mice. Histology displayed reduced infiltration of neutrophils. NECA had a similar effect on LPS-induced vascular barrier compromise. Importantly, posttreatment with adenosine or NECA recovers lung vascular barrier and reduces inflammation induced by LPS challenge. Furthermore, adenosine significantly attenuated protein degradation of A2A and A3 receptors induced by LPS. Collectively, our results demonstrate that activation of ARs protects and restores vascular barrier functions and reduces inflammation in LPS-induced ALI.
authors.affiliation: Assistant Prof. of Medicine, Div. of Pulmonary and Critical Care Medicine, Georgia Regents Univ., Rm. BBR-5513, 1120 15th St., Augusta, GA 30912. JGONZALES@gru.edu.
authors.forename: Joyce N
authors.initials: JN
authors.lastname: Gonzales
authors.forename: Boris
authors.initials: B
authors.lastname: Gorshkov
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Varn
authors.forename: Marina A
authors.initials: MA
authors.lastname: Zemskova
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Zemskov
authors.forename: Supriya
authors.initials: S
authors.lastname: Sridhar
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Verin
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D004727:Endothelium / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D058906:Purinergic P1 Receptor Agonists / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D014409:Tumor Necrosis Factor-alpha; D019830:Adenosine-5'-(N-ethylcarboxamide); D000241:Adenosine
keywords: acute lung injury; adenosine; lipopolysaccharide; pulmonary edema; receptors