Activation of A1, A2A, or A3 adenosine receptors attenuates lung ischemia-reperfusion injury

Abstract

Objective Adenosine and the activation of specific adenosine receptors are implicated in the attenuation of inflammation and organ ischemia-reperfusion (IR) injury. We hypothesized that activation of A1, A2A, or A3 adenosine receptors would provide protection against lung IR injury. Methods Using an isolated, ventilated, blood-perfused rabbit lung model, lungs underwent 18 hours cold ischemia followed by 2 hours reperfusion. Lungs were administered either vehicle, adenosine, or selective A1, A2A, or A3 receptor agonists (CCPA, ATL-313, or IB-MECA, respectively) alone or with their respective antagonists (DPCPX, ZM241385, or MRS1191) during reperfusion. Results Compared to the vehicle-treated control group, treatment with A1, A2A, or A3 agonists significantly improved function (increased lung compliance and oxygenation and decreased pulmonary artery pressure), decreased neutrophil infiltration by myeloperoxidase activity, decreased edema, and reduced TNF-α 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 A2A agonist reduced pulmonary artery pressure and myeloperoxidase activity and increased oxygenation to a greater degree than the A1 or A3 agonists. Conclusions Selective activation of A1, A2A, or A3 adenosine receptors provides significant protection against lung IR injury. The decreased elaboration of the potent proinflammatory cytokine, TNF-α, 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.

Heart injury following intestinal ischemia reperfusion in rats is attenuated by association of ischemic preconditioning and adenosine

“…The cellular protection promoted by adenosine seems to be due to the activation of different subtypes of G proteins coupled receptors and its relationship of those with ATP dependent mitochondrial potassium channels, protein kinase C and mitogen activated protein kinase 15,16 . This idea is strengthened by the known effect of adenosine preconditioning, mediated by A 1 AR receptors, before organ ischemia, and this process has been described by the tolerance to injury arising from myocardial ischemia, in the early and late stages 13,14 .…”

“…In this way, drugs and cellular protector strategies to prevent or to attenuate systemic organ dysfunction must be investigated. Many types of strategies has been studied [5][6][7][8][9][10][11] , such as exogenous Adenosine treatment [12][13][14][15][16] and ischemic preconditioning [17][18][19][20][21] .…”

Adenosine A1 Receptor Activation Attenuates Lung Ischemia-Reperfusion Injury

“…There is evidence for an anti-inflammatory role for A 1 R in lung 5 , liver 15 , kidney 16 , heart 17 , intestine 18 and skeletal muscle. 19 However, other studies have suggested that A 1 R antagonism has beneficial effects in lung and heart IR models.…”

“…10 However, more recent studies, including our own, suggest that A 1 R activation has protective effects in several models of inflammatory lung injury. 5,11,12 Using A 1 R knockout mice and a specific pharmacological A 1 R agonist, the present study tests the hypothesis that specific A 1 R activation is anti-inflammatory and provides significant protection from lung IR injury.…”

Pulmonary Transplantation and Ischemia-Reperfusion Injury

“…Protective effects of adenosine receptor signaling classically occur through second messenger p a t h w a y s s u c h a s t h e c A M P / P K A o r p h o s pholipase C pathways. Most studies have provided evidence that A 1 R, A 2A R and A 3 R may primarily be involved in anti-inflammatory actions whereas the A 2B R may have more pro-inflammatory actions in the lung (Anvari, et al, 2010;Ellman, et al, 2008;Gazoni, et al, 2010;Reece, et al, 2005Reece, et al, , 2008Rivo, et al, 2004;Sharma, et al, 2009Sharma, et al, , 2010Sun, et al, 2006). However, the role of the A 2B R in IR injury remains less understood.…”