title: A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice.
abstract: Although acute lung injury contributes significantly to critical illness, resolution often occurs spontaneously via activation of incompletely understood pathways. We recently found that mechanical ventilation of mice increases the level of pulmonary adenosine, and that mice deficient for extracellular adenosine generation show increased pulmonary edema and inflammation after ventilator-induced lung injury (VILI). Here, we profiled the response to VILI in mice with genetic deletions of each of the 4 adenosine receptors (ARs) and found that deletion of the A2BAR gene was specifically associated with reduced survival time and increased pulmonary albumin leakage after injury. In WT mice, treatment with an A2BAR-selective antagonist resulted in enhanced pulmonary inflammation, edema, and attenuated gas exchange, while an A2BAR agonist attenuated VILI. In bone marrow-chimeric A2BAR mice, although the pulmonary inflammatory response involved A2BAR signaling from bone marrow-derived cells, A2BARs located on the lung tissue attenuated VILI-induced albumin leakage and pulmonary edema. Furthermore, measurement of alveolar fluid clearance (AFC) demonstrated that A2BAR signaling enhanced amiloride-sensitive fluid transport and elevation of pulmonary cAMP levels following VILI, suggesting that A2BAR agonist treatment protects by drying out the lungs. Similar enhancement of pulmonary cAMP and AFC were also observed after beta-adrenergic stimulation, a pathway known to promote AFC. Taken together, these studies reveal a role for A2BAR signaling in attenuating VILI and implicate this receptor as a potential therapeutic target during acute lung injury.
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eckle
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Laucher
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D002678:Chimera / Q000378:metabolism; D015633:Extravascular Lung Water / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D055370:Lung Injury; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000235:genetics; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D012122:Ventilators, Mechanical / Q000009:adverse effects*; D014970:Xanthines / Q000494:pharmacology
chemical_list: C518874:1-propyl-8-(4-sulfophenyl)xanthine; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines; C518875:BAY 60-6583; D043704:Receptor, Adenosine A2B; D018047:Receptors, Purinergic P1; D014970:Xanthines
references.citation: Nat Rev Immunol. 2005 Sep;5(9):712-21
references.pmid: 16110315
references.citation: Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1469-73
references.pmid: 16299262
references.citation: Nature. 1997 Aug 14;388(6643):674-8
references.pmid: 9262401
references.citation: J Clin Invest. 2002 Dec;110(11):1603-5
references.pmid: 12464663
references.citation: Crit Care Med. 2003 May;31(5):1325-30
references.pmid: 12771598
references.citation: J Clin Invest. 2002 Oct;110(7):993-1002
references.pmid: 12370277
references.citation: J Exp Med. 2004 Dec 6;200(11):1395-405
references.pmid: 15583013
references.citation: Circ Res. 2004 Apr 30;94(8):1091-100
references.pmid: 15016730
references.citation: J Exp Med. 2000 Jul 17;192(2):159-70
references.pmid: 10899903
references.citation: Pulm Pharmacol Ther. 1999;12(2):111-4
references.pmid: 10373392
references.citation: J Clin Invest. 2006 Mar;116(3):695-702
references.pmid: 16485040
references.citation: Nat Cell Biol. 2005 Aug;7(8):758-65
references.pmid: 16056267
references.citation: Crit Care Med. 2004 Jul;32(7):1470-6
references.pmid: 15241090
references.citation: J Immunol. 2007 Jul 15;179(2):1254-63
references.pmid: 17617618
references.citation: Am Rev Respir Dis. 1993 Jul;148(1):91-7
references.pmid: 8317821
references.citation: FASEB J. 2006 Nov;20(13):2242-50
references.pmid: 17077301
references.citation: N Engl J Med. 2000 May 4;342(18):1334-49
references.pmid: 10793167
references.citation: J Exp Med. 2006 Nov 27;203(12):2639-48
references.pmid: 17088433
references.citation: Trends Immunol. 2004 Jan;25(1):33-9
references.pmid: 14698282
references.citation: Circulation. 2008 Jul 8;118(2):166-75
references.pmid: 18591435
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10212-7
references.pmid: 16009933
references.citation: Blood. 2004 Dec 15;104(13):3986-92
references.pmid: 15319286
references.citation: J Clin Invest. 1994 Aug;94(2):663-71
references.pmid: 8040320
references.citation: Circ Res. 2005 May 13;96(9):999-1005
references.pmid: 15802612
references.citation: Am J Physiol Cell Physiol. 2005 Apr;288(4):C881-90
references.pmid: 15761213
references.citation: J Immunol Methods. 1996 Oct 30;198(1):1-14
references.pmid: 8914592
references.citation: J Clin Invest. 2007 Mar;117(3):703-11
references.pmid: 17318263
references.citation: Chest. 2001 Mar;119(3):884-8
references.pmid: 11243972
references.citation: Annu Rev Physiol. 2006;68:543-61
references.pmid: 16460283
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4083-8
references.pmid: 17360481
references.citation: FASEB J. 2003 Oct;17(13):1800-11
references.pmid: 14519659
references.citation: Cell Death Differ. 2007 Jul;14(7):1315-23
references.pmid: 17396131
references.citation: Blood. 2008 Feb 15;111(4):2024-35
references.pmid: 18056839
references.citation: J Exp Med. 2003 Sep 1;198(5):783-96
references.pmid: 12939345
references.citation: Mol Pharmacol. 2005 May;67(5):1385-7
references.pmid: 15703375
references.citation: Eur Respir J. 2002 Dec;20(6):1393-8
references.pmid: 12503694
references.citation: Nature. 2001 Dec 20-27;414(6866):916-20
references.pmid: 11780065
references.citation: N Engl J Med. 2005 Oct 20;353(16):1685-93
references.pmid: 16236739
references.citation: PLoS Biol. 2005 Jun;3(6):e174
references.pmid: 15857155
references.citation: J Clin Invest. 2005 Jan;115(1):35-43
references.pmid: 15630442
references.citation: J Immunol. 2007 Jun 15;178(12):8127-37
references.pmid: 17548651
references.citation: J Pharmacol Toxicol Methods. 1998 Apr;39(3):169-78
references.pmid: 9741392
references.citation: PLoS Med. 2008 Jun 24;5(6):e137
references.pmid: 18578565
references.citation: FASEB J. 2002 Apr;16(6):583-5
references.pmid: 11919161
references.citation: Am J Respir Cell Mol Biol. 2005 Jan;32(1):52-8
references.pmid: 15388514
references.citation: Nat Med. 2007 Apr;13(4):406-8
references.pmid: 17415371
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9983-8
references.pmid: 11504952
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L464-75
references.pmid: 12716652
references.citation: Biochem Pharmacol. 2003 Jun 15;65(12):2081-90
references.pmid: 12787889
references.citation: J Immunol. 2005 Aug 1;175(3):1937-46
references.pmid: 16034138
references.citation: J Clin Invest. 2006 Jul;116(7):1913-23
references.pmid: 16823489
references.citation: Circulation. 2007 Mar 27;115(12):1581-90
references.pmid: 17353435
references.citation: Circulation. 2007 Oct 16;116(16):1784-94
references.pmid: 17909107
references.citation: J Biol Chem. 2000 Feb 11;275(6):4429-34
references.pmid: 10660615
references.citation: J Clin Invest. 2008 Apr;118(4):1491-501
references.pmid: 18340377
references.citation: Circulation. 2005 May 3;111(17):2190-7
references.pmid: 15851591
references.citation: Anesth Analg. 2003 Dec;97(6):1558-1565
references.pmid: 14633519
references.citation: J Exp Med. 2005 Dec 5;202(11):1493-505
references.pmid: 16330813
references.citation: J Appl Physiol (1985). 1986 Sep;61(3):1126-31
references.pmid: 3759752
references.citation: J Exp Med. 1998 Oct 19;188(8):1433-43
references.pmid: 9782120
references.citation: J Appl Physiol (1985). 1985 Mar;58(3):921-7
references.pmid: 3980393
references.citation: J Clin Invest. 2002 Dec;110(11):1703-16
references.pmid: 12464676
references.citation: Trends Cardiovasc Med. 2008 Apr;18(3):103-7
references.pmid: 18436149
references.citation: Annu Rev Immunol. 2004;22:657-82
references.pmid: 15032592
references.citation: Trends Pharmacol Sci. 2003 Feb;24(2):66-70
references.pmid: 12559769
references.citation: Pharmacol Rev. 1994 Jun;46(2):143-56
references.pmid: 7938164
references.citation: J Clin Invest. 2006 Aug;116(8):2173-2182
references.pmid: 16841096
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L769-L776
references.pmid: 16284214
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):792-6
references.pmid: 18184815