The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats.
There is a significant unmet need for treatments of patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The primary mechanism that leads to resolution of alveolar and pulmonary edema is active vectorial Na(+) and Cl(-) transport across the alveolar epithelium. Several studies have suggested a role for adenosine receptors in regulating this fluid transport in the lung. Furthermore, these studies point to the A(2A) subtype of adenosine receptor (A(2A)R) as playing a role to enhance fluid transport, suggesting that activation of the A(2A)R may enhance alveolar fluid clearance (AFC). The current studies test the potential therapeutic value of the A(2A)R agonist GW328267C to accelerate resolution of alveolar edema and ALI/ARDS in rats. GW328267C, at concentrations of 10(-5) M to 10(-3) M, instilled into the airspaces, increased AFC in control animals. GW328267C did not increase AFC beyond that produced by maximal β-adrenergic stimulation. The effect of GW328267C was inhibited by amiloride but was not affected by cystic fibrosis transmembrane conductance regulator inhibition. The drug was tested in three models of ALI, HCl instillation 1 h, LPS instillation 16 h, and live Escherichia coli instillation 2 h before GW328267C instillation. After either type of injury, GW328267C (10(-4) M) decreased pulmonary edema formation and restored AFC, measured 1 h after GW328267C instillation. These findings show that GW328267C has beneficial effects in experimental models of ALI and may be a useful agent for treating patients with ALI or prophylactically to prevent ALI.
Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, Ohio 44272-0095, USA.
Hans G
HG
Folkesson
Stephanie R
SR
Kuzenko
David A
DA
Lipson
Michael A
MA
Matthay
Mark A
MA
Simmons
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D018893:Bronchoalveolar Lavage; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels / Q000378:metabolism; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D015151:Immunoblotting; D008297:Male; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011654:Pulmonary Edema / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D012143:Respiratory Physiological Phenomena; D026941:Sodium Channel Blockers / Q000494:pharmacology; D014230:Triazoles / Q000627:therapeutic use*
D062686:Epithelial Sodium Channel Blockers; D053503:Epithelial Sodium Channels; C545367:GW 328267; D043705:Receptor, Adenosine A2A; D026941:Sodium Channel Blockers; D014230:Triazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000584:Amiloride; D000241:Adenosine