Primary Graft Dysfunction in Lung Transplantation: The Role of CD26/Dipeptidylpeptidase IV and Vasoactive Intestinal Peptide

BACKGROUND: Enzymatic activity inhibition of CD26/dipeptidylpeptidase IV (CD26/DPP IV) attenuated short-term post-Tx (transplantation) ischemia-reperfusion injury after 18-hr-ischemia. Here, we investigated the effect of intragraft CD26/DPP IV catalytic inhibition on primary graft dysfunction during 7 day post-Tx, following extended ischemia. METHODS: A syngeneic rat (LEW [Lewis abstract]) orthotopic lung Tx model was used, grafts exposed to 18 hr cold ischemia before Tx. Controls were flushed and preserved in Perfadex, and harvested after 1 day (CON1) or 7 day (CON7) post-Tx. Investigational groups IN1, IN3, and IN7 grafts were perfused with and stored in Perfadex + inhibitor (AB192) and harvested at 1, 3, and 7 days post-Tx, respectively. Blood gas analysis, peak airway pressure (PAwP), wet/dry weight ratio, myeloperoxidase thiobarbituric acid reactive substances (TBARS), and staining for vasoactive intestinal peptide (VIP) were analyzed. RESULTS: IN1 versus CON1 showed preserved histology, increased pO2 (P<0.01), lowered PAwP (P<0.01), less edema (P<0.05) and decreased TBARS (P<0.05). Survival was better for IN7 versus CON7 (P<0.01). The course of AB192-perfused grafts from 1 to 7 days displayed improved values for pO2 (P<0.01), PAwP (P<0.01), edema (P<0.05), TBARS (P<0.05), and myeloperoxidase (P<0.05). Compared with controls, VIP was preserved during 18 hr ischemia in alveolar macrophages (P=0.0001) and respiratory epithelial cells (P=0.001). CONCLUSIONS: Perfusion with an inhibitor of CD26/DPP IV enzymatic activity significantly reduced the incidence and severity of pulmonary primary graft dysfunction and enabled recovery after extended ischemia. This is the first report that CD26/DPPIV inhibitor treatment increases local pulmonary VIP levels, which correlate with preserved ventilatory function and pulmonary structural integrity.