A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice.
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.
Eckle
Tobias
T
Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Grenz
Almut
A
Laucher
Stefanie
S
Eltzschig
Holger K
HK
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
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
Nat Rev Immunol. 2005 Sep;5(9):712-21
16110315
Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1469-73
16299262
Nature. 1997 Aug 14;388(6643):674-8
9262401
J Clin Invest. 2002 Dec;110(11):1603-5
12464663
Crit Care Med. 2003 May;31(5):1325-30
12771598
J Clin Invest. 2002 Oct;110(7):993-1002
12370277
J Exp Med. 2004 Dec 6;200(11):1395-405
15583013
Circ Res. 2004 Apr 30;94(8):1091-100
15016730
J Exp Med. 2000 Jul 17;192(2):159-70
10899903
Pulm Pharmacol Ther. 1999;12(2):111-4
10373392
J Clin Invest. 2006 Mar;116(3):695-702
16485040
Nat Cell Biol. 2005 Aug;7(8):758-65
16056267
Crit Care Med. 2004 Jul;32(7):1470-6
15241090
J Immunol. 2007 Jul 15;179(2):1254-63
17617618
Am Rev Respir Dis. 1993 Jul;148(1):91-7
8317821
FASEB J. 2006 Nov;20(13):2242-50
17077301
N Engl J Med. 2000 May 4;342(18):1334-49
10793167
J Exp Med. 2006 Nov 27;203(12):2639-48
17088433
Trends Immunol. 2004 Jan;25(1):33-9
14698282
Circulation. 2008 Jul 8;118(2):166-75
18591435
Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10212-7
16009933
Blood. 2004 Dec 15;104(13):3986-92
15319286
J Clin Invest. 1994 Aug;94(2):663-71
8040320
Circ Res. 2005 May 13;96(9):999-1005
15802612
Am J Physiol Cell Physiol. 2005 Apr;288(4):C881-90
15761213
J Immunol Methods. 1996 Oct 30;198(1):1-14
8914592
J Clin Invest. 2007 Mar;117(3):703-11
17318263
Chest. 2001 Mar;119(3):884-8
11243972
Annu Rev Physiol. 2006;68:543-61
16460283
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4083-8
17360481
FASEB J. 2003 Oct;17(13):1800-11
14519659
Cell Death Differ. 2007 Jul;14(7):1315-23
17396131
Blood. 2008 Feb 15;111(4):2024-35
18056839
J Exp Med. 2003 Sep 1;198(5):783-96
12939345
Mol Pharmacol. 2005 May;67(5):1385-7
15703375
Eur Respir J. 2002 Dec;20(6):1393-8
12503694
Nature. 2001 Dec 20-27;414(6866):916-20
11780065
N Engl J Med. 2005 Oct 20;353(16):1685-93
16236739
PLoS Biol. 2005 Jun;3(6):e174
15857155
J Clin Invest. 2005 Jan;115(1):35-43
15630442
J Immunol. 2007 Jun 15;178(12):8127-37
17548651
J Pharmacol Toxicol Methods. 1998 Apr;39(3):169-78
9741392
PLoS Med. 2008 Jun 24;5(6):e137
18578565
FASEB J. 2002 Apr;16(6):583-5
11919161
Am J Respir Cell Mol Biol. 2005 Jan;32(1):52-8
15388514
Nat Med. 2007 Apr;13(4):406-8
17415371
Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9983-8
11504952
Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L464-75
12716652
Biochem Pharmacol. 2003 Jun 15;65(12):2081-90
12787889
J Immunol. 2005 Aug 1;175(3):1937-46
16034138
J Clin Invest. 2006 Jul;116(7):1913-23
16823489
Circulation. 2007 Mar 27;115(12):1581-90
17353435
Circulation. 2007 Oct 16;116(16):1784-94
17909107
J Biol Chem. 2000 Feb 11;275(6):4429-34
10660615
J Clin Invest. 2008 Apr;118(4):1491-501
18340377
Circulation. 2005 May 3;111(17):2190-7
15851591
Anesth Analg. 2003 Dec;97(6):1558-1565
14633519
J Exp Med. 2005 Dec 5;202(11):1493-505
16330813
J Appl Physiol (1985). 1986 Sep;61(3):1126-31
3759752
J Exp Med. 1998 Oct 19;188(8):1433-43
9782120
J Appl Physiol (1985). 1985 Mar;58(3):921-7
3980393
J Clin Invest. 2002 Dec;110(11):1703-16
12464676
Trends Cardiovasc Med. 2008 Apr;18(3):103-7
18436149
Annu Rev Immunol. 2004;22:657-82
15032592
Trends Pharmacol Sci. 2003 Feb;24(2):66-70
12559769
Pharmacol Rev. 1994 Jun;46(2):143-56
7938164
J Clin Invest. 2006 Aug;116(8):2173-2182
16841096
Am J Physiol Lung Cell Mol Physiol. 2006 Apr;290(4):L769-L776
16284214
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):792-6
18184815