A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice
Tobias Eckle, … , Stefanie Laucher, Holger K. Eltzschig
Tobias Eckle, … , Stefanie Laucher, Holger K. Eltzschig
Published September 11, 2008
Citation Information: J Clin Invest. 2008;118(10):3301-3315. https://doi.org/10.1172/JCI34203.
View: Text | PDF
Research Article Pulmonology

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 β-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

Tobias Eckle, Almut Grenz, Stefanie Laucher, Holger K. Eltzschig

×

Figure 11

Influence of β2-adrenergic and/or A2BAR signaling on AFC during VILI.

Options: View larger image (or click on image) Download as PowerPoint
Influence of β2-adrenergic and/or A2BAR signaling on AFC during VILI. (A...
(A) Epinephrine plasma levels in A2BAR–/– and A2BAR+/+ mice that were mechanically ventilated in a pressure-controlled setting at 45 mbar over 180 minutes. (B) Basal cAMP levels in lung tissue from A2BAR+/+ mice that were treated with zinterol and/or BAY 60-6583. (C and D) To determine β2-adrenergic and A2BAR signaling effects on pulmonary fluid transport, A2BAR–/– and A2BAR+/+ mice were mechanically ventilated in a pressure-controlled setting at 45 mbar for 0 to 180 minutes. AFC was measured by instilling 300 μl of iso-osmolar 0.9% NaCl solution with 5% BSA. Mechanical ventilation was continued for 30 minutes, and AFC was measured in the presence or absence of the nonselective β-adrenergic receptor antagonist propranolol (intratracheal instillation of 10–4 M propranolol combined with 3 mg/kg i.p.) with or without BAY 60-6583 (10–3 M to the instilled fluid) or in the presence or absence of the β-adrenergic agonist zinterol (intratracheal, 10–7 M). *P < 0.01 compared with no propranolol (C) or zinterol (D), by ANOVA with Bonferroni post-hoc test. n = 8. In subsets of experiments, either propranolol or zinterol were added together with BAY 60-6583 10–3 M to the instilled fluid. §P < 0.01 compared with propranolol alone (C) or zinterol alone (D), by ANOVA with Bonferroni post-hoc test. n = 8.