Lung injury: Promoting fluid clearance

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Adenosine 2B receptor (A2BAR) signaling elevates pulmonary cAMP levels and can attenuate acute lung injury that develops in response to pneumonia, acid aspiration, major trauma and prolonged mechanical ventilation.

Acute lung injury can develop during the course of clinical conditions such as pneumonia, acid aspiration, major trauma and prolonged mechanical ventilation, and although many episodes resolve spontaneously, it can lead to critical illness. Little is known about how to prevent the interstitial and intra-alveolar oedema that is characteristic of the condition, but now Eltzschig and colleagues have shown that adenosine 2B receptor (A2BAR) signalling can attenuate acute lung injury, suggesting that A2BAR agonists might have therapeutic benefit.


CORBIS

Building on previous studies, which demonstrated an elevation in pulmonary adenosine levels during mechanical ventilation, the authors studied the role of different adenosine receptor subtypes in a mouse model of ventilation-induced lung injury (VILI). In A2bar^-/- mice (but not in mice lacking other adenosine receptor subtypes) VILI was enhanced, survival time was shortened and albumin leakage into the bronchoalveolar fluid was increased. Furthermore, A2bar^-/- mice with VILI showed increased pulmonary inflammation and injury.

In lung tissue from ventilated wild-type mice, there was up-regulation of A2BAR mRNA and protein levels, highlighting that there might be increased A2BAR signalling in VILI. Indeed, pulmonary cyclic AMP levels and protein kinase A activity was increased with mechanical ventilation, suggesting that A2BAR signalling effects result in elevated pulmonary cAMP levels — which has a protective role in VILI — and attenuation of acute liver injury. The authors next generated A2BAR bone marrow–chimeric mice to study the contribution of pulmonary versus myeloid A2BARs to lung injury during VILI. These studies showed that during VILI pulmonary A2BARs are crucial for attenuating increases in pulmonary oedema, and that both myeloid and pulmonary A2BAR signalling attenuate lung inflammation.

The authors then studied the effects of A2BAR antagonist (PSB1115) and agonist (BAY 60-6583) treatment on VILI. A2BAR antagonist treatment was associated with attenuated survival time, enhanced pulmonary albumin leakage and lung inflammation. By contrast, agonist treatment improved survival, which was accompanied by improved albumin leakage and gas exchange, and an attenuation of pulmonary inflammation. Similar results were also observed in a mouse model of endotoxin-induced acute lung injury. Further studies to investigate the role of A2BAR signalling in promoting alveolar fluid clearance during VILI demonstrated that A2BAR signalling enhanced sodium-channel-dependent fluid transport in the lung epithelium, and that A2BAR activation protected against lung injury by drying out the lungs.

Although there are not yet any A2BAR agonists in clinical use or in trials, this study suggests that A2BAR could be a promising therapeutic target in acute lung injury.

Charlotte Harrison

References

Eckle, T. et al. A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J. Clin. Invest. 118, 3301–3315 (2008) | Article | PubMed |