The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats.

Title

The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats.

Creator

Folkesson Hans G; Kuzenko Stephanie R; Lipson David A; Matthay Michael A; Simmons Mark A

Publisher

American journal of physiology. Lung cellular and molecular physiology

Date

2012
2012-08

Description

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 beta-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.

Subject

Acute Lung Injury/*drug therapy/metabolism/pathology; Adenosine A2A/*chemistry; Adenosine/*analogs & derivatives/therapeutic use; Amiloride/pharmacology; Animals; Biological Transport; Bronchoalveolar Lavage; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism; Endotoxemia/*drug therapy/metabolism/microbiology; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels/metabolism; Escherichia coli; Escherichia coli Infections/drug therapy/metabolism/microbiology; Immunoblotting; Male; Pneumonia/*drug therapy/metabolism/microbiology; Pulmonary Alveoli/cytology/*drug effects/metabolism; Pulmonary Edema/*drug therapy/metabolism/pathology; Rats; Receptor; Respiratory Physiological Phenomena; Sodium Channel Blockers/pharmacology; Sprague-Dawley; Triazoles/*therapeutic use

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

L259–271

Issue

3

Volume

303

Citation

Folkesson Hans G; Kuzenko Stephanie R; Lipson David A; Matthay Michael A; Simmons Mark A, “The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats.,” NEOMED Bibliography Database, accessed April 14, 2021, https://neomed.omeka.net/items/show/4633.

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