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

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-alpha 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-alpha 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.

Additive protection against lung ischemia-reperfusion injury by adenosine A2A receptor activation before procurement and during reperfusion.

OBJECTIVE: Adenosine A2A receptor activation during reperfusion improves lung ischemia-reperfusion injury. In this study we sought to determine whether pretreatment of rabbits with a potent and selective adenosine A2A receptor agonist, ATL-313, before transplantation or whether adding ATL-313 to the preservation solution results in equivalent or additional protection compared with ATL-313 added during reperfusion. METHODS: An isolated, ventilated, ex vivo blood-perfused rabbit lung model was used. All groups underwent 2 hours of reperfusion after 18 hours of cold ischemia (4 degrees C). ATL-313 was administered 1 hour before ischemia intravenously, with the preservation solution, and/or during reperfusion. RESULTS: Both pretreatment of donor animals with ATL-313 or adding ATL-313 just during reperfusion improved pulmonary function, but significantly greater improvement was observed when pretreatment and treatment during reperfusion were combined (all P < .05). Myeloperoxidase levels, bronchoalveolar lavage tumor necrosis factor alpha levels, and pulmonary edema were all maximally decreased in the combined treatment group. The administration of an equimolar amount of the potent and highly selective adenosine 2A receptor antagonist, ZM 241385, along with ATL-313, resulted in the loss of protection conferred by ATL-313. CONCLUSIONS: Adenosine A2A receptor activation with ATL-313 results in the greatest protection against lung ischemia-reperfusion injury when given before ischemia and during reperfusion. Improved pulmonary function observed with adenosine A2A receptor activation was correlated with decreased bronchoalveolar lavage tumor necrosis factor alpha and decreased lung myeloperoxidase. The loss of protection observed with the concurrent administration of the adenosine A2A receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A2A receptor activation.

Pulmonary macrophage inhibition and inhaled nitric oxide attenuate lung ischemia-reperfusion injury.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is postulated to occur biphasically. Donor pulmonary macrophages mediate early injury, and neutrophil-dependent injury predominates in the later phase of LIRI. We hypothesized that the biphasic response to LIRI would be attenuated by the administration of gadolinium, a known pulmonary macrophage inhibitor, and inhaled nitric oxide (NO), a pulmonary vasodilator that also interferes with neutrophil chemotaxis. METHODS: Using our isolated, ventilated, blood-perfused rabbit lung model, study groups (n = 10 per group) underwent two hours of reperfusion after 18 hours of cold ischemia (4 degrees C). Lungs received gadolinium alone, or inhaled NO in the presence or absence of macrophage inhibition with gadolinium. RESULTS: Compared with control animals, pulmonary macrophage inhibition with the concurrent administration of inhaled NO increased lung compliance (p < 0.01) and oxygenation (p = 0.03), while also decreasing pulmonary artery pressure (p < 0.01), myeloperoxidase content by 63% (p < 0.01), wet to dry ratios by 23% (p < 0.01), and lung tissue (p < 0.01) and bronchoalveolar lavage tumor necrosis factor-alpha (TNF-alpha) protein levels (p < 0.01). CONCLUSIONS: The severity of LIRI was most significantly reduced by the inhibition of pulmonary macrophages and the concomitant use of inhaled NO. Pulmonary macrophages, likely through the elaboration of proinflammatory cytokines such as TNF-alpha, not only cause early injury themselves but also prime cells such as neutrophils to injure lungs in the later stages of LIRI. The LIRI was effectively blunted by the reduction of macrophage-dependent injury by gadolinium while inhaled NO also attenuated injury by reducing pulmonary hypertension and minimizing neutrophil sequestration.