Activated Protein C in Ischemia-Reperfusion Injury After Experimental Lung Transplantation

BACKGROUND: Ischemia-reperfusion injury remains the major cause of early morbidity and mortality after lung transplantation. Activated protein C (APC) has been demonstrated to attenuate various acute inflammation-related injuries in the lung and other organs. METHODS: The effect of exogenous APC in lung transplantation was examined using a rat orthotopic lung transplantation model of ischemia-reperfusion injury with 24 hours of cold ischemia. APC was administered to the donor airway before cold pulmonary artery flush, or intravenously to the recipient before reperfusion. RESULTS: The levels of APC in the lung tissue were significantly higher in the intra-airway group compared with the intravenous group and the saline control group (p < 0.01). Transplanted lung oxygenation was significantly better in the intra-airway APC group at 2 hours after reperfusion compared with controls (Pao(2), mean +/- SD mm Hg: intra-airway APC, 350.9 +/- 85.5; intravenous APC, 241.1 +/- 59.3; control, 200.2 +/- 37.3; p < 0.05). No difference was detected in proinflammatory cytokines or thrombin-anti-thrombin complexes in the lung tissue. Histologic examination of the lung injury score or alveolar fibrin deposition did not demonstrate significant differences among groups. CONCLUSION: Exogenous APC administered to the donor airway attenuates ischemia-reperfusion injury after lung transplantation. This novel administration route sustains high levels of APC in the lung tissue, which should avoid frequent administration and potential systemic side effects of bleeding. Further investigation is necessary to determine the mechanism of the beneficial effect of APC in this setting.