Intragraft DPP IV inhibition attenuates post-transplant pulmonary ischemia/reperfusion injury after extended ischemia.

摘要

BACKGROUND: CD26/DPP IV is a T-cell-membrane protein that cleaves dipeptides from extracellular peptides. Inhibition of its enzymatic activity using Pro-Pro-diphenylphosphonate derivatives has been shown to abrogate acute and accelerated rejection in models of cardiac and pulmonary allotransplantation. Here we investigated the effects of enzymatic DPP IV inhibition on ischemia/reperfusion (I/R) injury after extended ischemia before pulmonary transplantation. METHODS: A syngeneic rat orthotopic left-lung transplantation model was used. Group I donor lungs (controls) were flushed and preserved in Perfadex for 18 hours at 4 degrees C and then transplanted and reperfused for 2 hours. Group II grafts were perfused with and stored in Perfadex + 25 micromol/liter AB192 [bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate]. Group III lungs were perfused with Perfadex + AB192, and stored in Perfadex. After 2-hour reperfusion, oxygenation, peak airway pressure (PawP), graft wet/dry (W/D) weight ratio, myeloperoxidase activity, thiobarbituric acid-reactive substances, graft specific DPP IV enzymatic activities and histomorphology were analyzed. RESULTS: AB192 perfusion significantly reduced DPP IV intragraft enzymatic activity in Groups II and III. Compared with controls, transplants from Groups II and III showed significantly improved oxygenation capacity, PawP and W/D weight ratio, with lower intragraft lipid peroxidation; and preserved histologic structure. CONCLUSIONS: Targeting intragraft DPP IV enzymatic activity attenuated post-transplantation I/R injury and preserved early graft function after extended ischemia.