BACKGROUND Raising intracellular cyclic adenosine monophosphate levels protects lungs from ischemia-reperfusion injury. We hypothesized that the phosphodiesterase inhibitor theophylline would protect lungs during storage. METHODS Rat lungs were perfused with modified bicarbonate buffer mixed with rat blood (4:1 vol/vol) (37 degrees C) and ventilated (80 breaths/min). After 20 minutes of perfusion during which vascular resistance and airway compliance were measured, lungs were flushed with and then immersed in bicarbonate buffer (4 degrees C) alone or containing theophylline (30 to 1,000 micromol/L). After 6 hours of storage, lung function was reassessed during 40 minutes of reperfusion. RESULTS Lungs stored in the presence of theophylline had improved lung function on reperfusion. After 40 minutes of reperfusion, pulmonary compliance was 0.008+/-0.004 mL/cm H2O, 0.022+/-0.010, 0.037+/-0.007, 0.044+/-0.006, and 0.073+/-0.003 mL/cm H2O, and vascular resistance was 3.84+/-0.40 cm H2O x min x mL(-1), 3.64+/-0.78, 2.12+/-0.35, 2.22+/-0.25, and 1.90+/-0.38 cm H2O x min x mL(-1) in lungs stored in the presence of 0, 30, 100, 300, or 1,000 micromol/L theophylline, respectively. Similar improvements were obtained for wet to dry weight ratio and gas exchange. CONCLUSIONS Theophylline merits investigation as a potentially beneficial addition to solutions for the flushing and storage of human lungs for transplantation.