Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats (original) (raw)
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Journal of Clinical Investigation, 2008
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.
Alveolar Epithelial A2B Adenosine Receptors in Pulmonary Protection during Acute Lung Injury
Journal of Immunology, 2015
Acute lung injury (ALI) is an acute inflammatory lung disease that causes morbidity and mortality in critically ill patients. However, there are many instances where ALI resolves spontaneously through endogenous pathways that help to control excessive lung inflammation. Previous studies have implicated the extracellular signaling molecule adenosine and signaling events through the A2B adenosine receptor in lung protection. In this context, we hypothesized that tissue-specific expression of the A2B adenosine receptor is responsible for the previously described attenuation of ALI. To address this hypothesis, we exposed mice with tissue-specific deletion of Adora2b to ALI, utilizing a two-hit model where intratracheal LPS treatment is followed by injurious mechanical ventilation. Interestingly, a head-to-head comparison of mice with deletion of Adora2b in the myeloid lineage (Adora2b loxP/loxP LysM Cre +), endothelial cells (Adora2b loxP/loxP VE-cadherin Cre +), or alveolar epithelial cells (Adora2b loxP/loxP SPC Cre +) revealed a selective increase in disease susceptibility in Adora2b loxP/loxP SPC Cre + mice. More detailed analysis of Adora2b loxP/loxP SPC Cre + mice confirmed elevated lung inflammation and attenuated alveolar fluid clearance. To directly deliver an A2B adenosine receptor-specific agonist to alveolar epithelial cells, we subsequently performed studies with inhaled BAY 60-6583. Indeed, aerosolized BAY 60-6583 treatment was associated with attenuated pulmonary edema, improved histologic lung injury, and dampened lung inflammation. Collectively, these findings suggest that alveolar epithelial A2B adenosine receptor signaling contributes to lung protection, and they implicate inhaled A2B adenosine receptor agonists in ALI treatment.
Adenosine A1 receptor activation attenuates lung ischemia–reperfusion injury
The Journal of Thoracic and Cardiovascular Surgery, 2013
Objectives: Ischemia-reperfusion injury contributes significantly to morbidity and mortality in lung transplant patients. Currently, no therapeutic agents are clinically available to prevent ischemia-reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury by binding to various adenosine receptors; however, the role of the adenosine A 1 receptor in ischemia-reperfusion injury and inflammation is not well understood. The present study tested the hypothesis that selective, exogenous activation of the A 1 receptor would be anti-inflammatory and attenuate lung ischemia-reperfusion injury.
Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury
The Journal of Thoracic and Cardiovascular Surgery, 2010
Objective: Adenosine and the activation of specific adenosine receptors are implicated in the attenuation of inflammation and organ ischemia-reperfusion injury. We hypothesized that activation of A 1 , A 2A , or A 3 adenosine receptors would provide protection against lung ischemia-reperfusion injury. Methods: With the use of an isolated, ventilated, blood-perfused rabbit lung model, lungs underwent 18 hours of cold ischemia followed by 2 hours of reperfusion. Lungs were administered vehicle, adenosine, or selective A 1 , A 2A , or A 3 receptor agonists (CCPA, ATL-313, or IB-MECA, respectively) alone or with their respective antagonists (DPCPX, ZM241385, or MRS1191) during reperfusion. Results: Compared with the vehicle-treated control group, treatment with A 1 , A 2A , or A 3 agonists significantly improved function (increased lung compliance and oxygenation and decreased pulmonary artery pressure), decreased neutrophil infiltration by myeloperoxidase activity, decreased edema, and reduced tumor necrosis factor-a production. Adenosine treatment was also protective, but not to the level of the agonists. When each agonist was paired with its respective antagonist, all protective effects were blocked. The A 2A agonist reduced pulmonary artery pressure and myeloperoxidase activity and increased oxygenation to a greater degree than the A 1 or A 3 agonists. Conclusion: Selective activation of A 1 , A 2A , or A 3 adenosine receptors provides significant protection against lung ischemia-reperfusion injury. The decreased elaboration of the potent proinflammatory cytokine tumor necrosis factor-a and decreased neutrophil sequestration likely contribute to the overall improvement in pulmonary function. These results provide evidence for the therapeutic potential of specific adenosine receptor agonists in lung transplant recipients.
Adenosine A2A Agonist Improves Lung Function During Ex Vivo Lung Perfusion
The Annals of Thoracic Surgery, 2011
Background. Ex vivo lung perfusion (EVLP) is a novel technique than can be used to assess and potentially repair marginal lungs that may otherwise be rejected for transplantation. Adenosine has been shown to protect against pulmonary ischemia-reperfusion (IR) injury through its A 2A receptor. We hypothesized that combining EVLP with adenosine A 2A receptor agonist treatment would enhance lung functional quality and increase donor lung use.
Attenuation of Pulmonary Ischemia-Reperfusion Injury by Adenosine A2B Receptor Antagonism
The Annals of thoracic surgery, 2016
Ischemia-reperfusion injury (IRI) is a major source of morbidity and mortality after lung transplantation. We previously demonstrated a proinflammatory role of adenosine A2B receptor (A2BR) in lung IR injury. The current study tests the hypothesis that A2BR antagonism is protective of ischemic lungs after in vivo reperfusion or ex vivo lung perfusion (EVLP). Mice underwent lung IR with or without administration of ATL802, a selective A2BR antagonist. A murine model of EVLP was also used to evaluate rehabilitation of donation after circulatory death (DCD) lungs. DCD lungs underwent ischemia, cold preservation, and EVLP with Steen solution with or without ATL802. A549 human type 2 alveolar epithelial cells were exposed to hypoxia-reoxygenation (HR) (3 hours/1 hour) with or without ATL802 treatment. Cytokines were measured in bronchoalveolar lavage (BAL) fluid and culture media by enzyme-linked immunoassay (ELISA). After IR, ATL802 treatment significantly improved lung function (increa...
Protection from pulmonary ischemia-reperfusion injury by adenosine A2A receptor activation
Respiratory Research, 2009
Background: Lung ischemia-reperfusion (IR) injury leads to significant morbidity and mortality which remains a major obstacle after lung transplantation. However, the role of various subset(s) of lung cell populations in the pathogenesis of lung IR injury and the mechanisms of cellular protection remain to be elucidated. In the present study, we investigated the effects of adenosine A 2A receptor (A 2A AR) activation on resident lung cells after IR injury using an isolated, bufferperfused murine lung model.
Adenosine A2A Activation Attenuates Nontransplantation Lung Reperfusion Injury
Journal of Surgical Research, 2008
Background. Lung reperfusion injury is a significant problem in cardiothoracic surgery. Previous studies have demonstrated that an adenosine A 2A agonist can attenuate lung reperfusion injury in a lung transplantation model. There has been little work, however, examining its effects in the setting of nontransplant ischemia reperfusion. Our hypothesis was that an A 2A agonist would attenuate lung reperfusion injury in a warm ischemia hilar clamping model.
Critical Care, 2006
Introduction Although activation of A 3 adenosine receptors attenuates reperfusion lung injury and associated apoptosis, the signaling pathway that mediates this protection remains unclear. Adenosine agonists activate mitogen-activated protein kinases, and these kinases have been implicated in ischemia/reperfusion injury; the purpose of this study was therefore to determine whether A 3 adenosine receptor stimulation with reperfusion modulates expression of the different mitogen-activated protein kinases. In addition, we compared the effect of the A 3 adenosine agonist IB-MECA with the newly synthesized, highly selective A 3 adenosine receptor agonist MRS3558 on injury in reperfused lung.