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

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.

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.

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.

Targeting intragraft DPP IV enzymatic activity attenuated post-transplantation I/R injury and preserved early graft function after extended ischemia.