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Background: Reperfusion injury continues to significantly affect patients undergoing lung transplantation. Isolated lung models have demonstrated that adenosine A 2A receptor activation preserves function while decreasing inflammation. We hypothesized that adenosine A 2A receptor activation by ATL-146e during the initial reperfusion period preserves pulmonary function and attenuates inflammation in a porcine model of lung transplantation., Methods: Mature pig lungs preserved with Viaspan (Barr Laboratories, Pomona, NY) underwent 6 hours of cold ischemia before transplantation and 4 hours of reperfusion. Animals were treated with (ATL group, n = 7) and without (IR group, n = 7) ATL-146e (0.05 microg kg -1 . min -1 ATL-146e administered intravenously for 3 hours). With occlusion of the opposite pulmonary artery, the animal was maintained for the final 30 minutes on the allograft alone. Recipient lung physiology was monitored before tissue evaluation of pulmonary edema (wet-to-dry weight ratio), myeloperoxidase assay, and tissue tumor necrosis factor alpha by means of enzyme-linked immunosorbent assay., Results: When the ATL group was compared with the IR group, the ATL group had better partial pressure of carbon dioxide (43.8 +/- 4.1 vs 68.9 +/- 6.3 mm Hg, P < .01) and partial pressure of oxygen (272.3 +/- 132.7 vs 100.1 +/- 21.4 mm Hg, P < .01). ATL-146e-treated animals exhibited lower pulmonary artery pressures (33.6 +/- 2.1 vs 47.9 +/- 3.5 mm Hg, P < .01) and mean airway pressures (16.25 +/- 0.08 vs 16.64 +/- 0.15 mm Hg, P = .04). ATL-146e-treated lungs had lower wet-to-dry ratios (5.9 +/- 0.39 vs 7.3 +/- 0.38, P < .02), lower myeloperoxidase levels (2.9 x 10 -5 +/- 1.2 x 10 -5 vs 1.3 x 10 -4 +/- 4.0 x 10 -5 DeltaOD mg -1 . min -1 , P = .03), and a trend toward decreased lung tumor necrosis factor alpha levels (57 +/- 12 vs 96 +/- 15 pg/mL, P = .06). The ATL group demonstrated significantly less inflammation on histology., Conclusion: Adenosine A 2A activation during early reperfusion attenuated lung inflammation and preserved pulmonary function in this model of lung transplantation. ATL-146e and similar compounds could play a significant role in improving outcomes of pulmonary transplantation.

Objective: A central role of macrophages in initiating lung ischemia-reperfusion injury is emerging. Tumor necrosis factor-alpha is a proinflammatory cytokine secreted mainly by macrophages under various conditions. We hypothesized that tumor necrosis factor-alpha from resident lung cells is a key initiating factor in pulmonary ischemia-reperfusion injury., Methods: We used an isolated, buffer-perfused lung system to explore the role of tumor necrosis factor-alpha production by resident lung cells in pulmonary ischemia-reperfusion injury. Lungs from wild-type mice and tumor necrosis factor-alpha-deficient mice were subjected to 60 minutes of ischemia followed by 60 minutes of reperfusion. Histologic injury scores and measurements of lung compliance, airway resistance, mean pulmonary artery pressure, vascular reactivity, and wet lung weight index were obtained and compared using repeated-measures analysis of variance., Results: Lungs from tumor necrosis factor-alpha-deficient mice showed significantly less injury in all physiologic parameters throughout the entire 60 minutes of reperfusion compared with lungs from wild-type mice (P <.001). The most notable effects were observed in pulmonary artery pressure and airway resistance. Vascular reactivity (acute vasoconstrictive episodes per 60 minutes) was also blunted in the lungs from tumor necrosis factor-alpha-deficient mice compared with the lungs from wild-type mice (5.8 responses/hour vs 1.2 responses). Histologic injury scores and wet lung weight index were significantly reduced in lungs from tumor necrosis factor-alpha-deficient mice., Conclusions: By using the advantages of a nonblood-perfused system, we have focused our investigation on resident lung cells. Our results demonstrate that resident cell-produced tumor necrosis factor-alpha is a key initiating factor in acute lung ischemia-reperfusion injury.

Background: Coronary artery bypass is an acceptable therapy in patients with ischemic cardiomyopathy. However, it has been demonstrated that patients with increased left ventricular volume have a worse outcome than patients with normal ventricular volume. Our hypothesis was that ventricular restoration plus coronary artery bypass provides improved outcome compared with coronary artery bypass alone in ischemic cardiomyopathy with ventricular enlargement., Methods: A retrospective analysis was performed of patients with ischemic cardiomyopathy (ejection fraction <30%) who underwent operation between 1998 and 2002. Patients with enlarged ventricles (end-diastolic dimension > or =6.0 cm) who underwent either coronary artery bypass alone or coronary artery bypass with ventricular restoration were compared. Preoperative and postoperative ejection fraction, morbidity, mortality, and freedom from heart failure (hospitalization secondary to heart failure) were assessed., Results: Ninety-five patients were included in the study. Thirty-nine patients had coronary artery bypass alone, whereas 56 patients had ventricular restoration with coronary artery bypass. Both groups demonstrated an improved postoperative ejection fraction; however, the improvement was significantly greater in the ventricular restoration plus coronary artery bypass group (P <.01). There were no hospital deaths in either group; however, late mortality was higher in the coronary artery bypass group. Freedom from heart failure was achieved in all but 2 of the ventricular restoration plus coronary artery bypass patients (2/56, or 3.6%) versus 7 in the coronary artery bypass group (7/39, or 18%). The combined outcomes of freedom from failure and late mortality were significantly improved in the ventricular restoration plus coronary artery bypass group (P <.05)., Conclusions: Ventricular restoration affords significant improvement in ejection fraction compared with coronary artery bypass alone, without added mortality. Most importantly, left ventricular restoration reduces late morbidity and mortality compared with coronary artery bypass alone in patients with large ventricles.