Document Detail


Macrophage A2A adenosinergic receptor modulates oxygen-induced augmentation of murine lung injury.
MedLine Citation:
PMID:  23349051     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality. Exacerbating factors increasing the risk of ARDS remain unknown. Supplemental oxygen is often necessary in both mild and severe lung disease. The potential effects of supplemental oxygen may include augmentation of lung inflammation by inhibiting anti-inflammatory pathways in alveolar macrophages. We sought to determine oxygen-derived effects on the anti-inflammatory A2A adenosinergic (ADORA2A) receptor in macrophages, and the role of the ADORA2A receptor in lung injury. Wild-type (WT) and ADORA2A(-/-) mice received intratracheal lipopolysaccharide (IT LPS), followed 12 hours later by continuous exposure to 21% oxygen (control mice) or 60% oxygen for 1 to 3 days. We measured the phenotypic endpoints of lung injury and the alveolar macrophage inflammatory state. We tested an ADORA2A-specific agonist, CGS-21680 hydrochloride, in LPS plus oxygen-exposed WT and ADORA2A(-/-) mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A(-/-) mice exposed to IT LPS and 60% oxygen demonstrated significantly more histologic lung injury, alveolar neutrophils, and protein. Macrophages from ADORA2A(-/-) mice exposed to LPS plus oxygen expressed higher concentrations of proinflammatory cytokines and cosignaling molecules. CGS-21680 prevented the oxygen-induced augmentation of lung injury after LPS only in WT mice. Chimera experiments demonstrated that the transfer of WT but not ADORA2A(-/-) bone marrow cells into irradiated ADORA2A(-/-) mice reduced lung injury after LPS plus oxygen, demonstrating myeloid ADORA2A protection. ADORA2A is protective against lung injury after LPS and oxygen. Oxygen after LPS increases macrophage activation to augment lung injury by inhibiting the ADORA2A pathway.
Authors:
Neil R Aggarwal; Franco R D'Alessio; Yoshiki Eto; Eric Chau; Claudia Avalos; Adam T Waickman; Brian T Garibaldi; Jason R Mock; Daniel C Files; Venkataramana Sidhaye; Vsevolod Y Polotsky; Jonathan Powell; Maureen Horton; Landon S King
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  48     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-02     Completed Date:  2013-06-25     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  635-46     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acute Lung Injury / chemically induced,  immunology,  metabolism*
Adenosine / analogs & derivatives,  pharmacology
Adenosine A2 Receptor Agonists / pharmacology
Animals
Bronchoalveolar Lavage Fluid
Cells, Cultured
Chemokines / secretion
Gene Knockout Techniques
Inflammation Mediators / physiology
Lipopolysaccharides / pharmacology
Lung / drug effects,  immunology,  pathology
Macrophages, Alveolar / drug effects,  immunology,  metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxygen / toxicity*
Oxygen Inhalation Therapy
Phenethylamines / pharmacology
Receptor, Adenosine A2A / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
K99HL103973/HL/NHLBI NIH HHS; P30 AR053503/AR/NIAMS NIH HHS; P50-HL084945/HL/NHLBI NIH HHS; R01-HL80105/HL/NHLBI NIH HHS; R01HL089346/HL/NHLBI NIH HHS; T32 AI007247/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Adenosine A2 Receptor Agonists; 0/Chemokines; 0/Inflammation Mediators; 0/Lipopolysaccharides; 0/Phenethylamines; 0/Receptor, Adenosine A2A; 120225-54-9/2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; K72T3FS567/Adenosine; S88TT14065/Oxygen
Comments/Corrections

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