Inhibition of CD26/DPP IV attenuates ischemia/reperfusion injury in orthotopic mouse lung transplants: the pivotal role of vasoactive intestinal peptide.
The T cell activation Ag CD26/dipeptidylpeptidase IV (DPP IV) combines co-stimulatory and enzymatic properties. Catalytically, it functions as an exopeptidase, modulating biological activity of key chemokines and peptides. Here we investigated the effect of organ-specific inhibition of DPP IV catalytic activity on ischemia/reperfusion injury after extended ischemia in the mouse model of orthotopic single lung transplantation. C57BL/6 mice were syngeneically, transplanted, grafts were perfused and stored in Perfadex with (treated) or without (control) a DPP IV enzymatic activity inhibitor (AB192). Transplantation was performed after 18h cold ischemia time; following 2-h reperfusion, grafts were analyzed for oxygenation, thiobarbituric acid-reactive substances, histomorphology, and immunohistochemistry was performed for leukocyte Ag 6, myeloperoxidase, hemoxygenase 1, vasoactive intestinal protein (VIP), and real-time PCR for VIP. Treatment with the DPP IV inhibitor AB192 resulted in significant improvement of gas exchange, less lipid oxidation, preservation of parenchymal ultrastructure, reduced neutrophil infiltration, reduced myeloperoxidase expression, increased hemoxygenase 1 expression, pronounced expression of VIP in alveolar macrophages and increased mRNA expression of VIP. Inhibition of intragraft DPP IV catalytic activity with AB192 strikingly ameliorates ischemia/reperfusion injury after extended ischemia. Furthermore, preservation of endogenous intragraft VIP levels correlate with maintaining lung function and structural integrity.
Jungraithmayr
Wolfgang
W
Division of Thoracic Surgery, University Hospital of Zurich, Raemistr 100, 8091 Zurich, Switzerland. wolfgang.jungraithmayr@usz.ch
De Meester
Ingrid
I
Matheeussen
Veerle
V
Inci
Ilhan
I
Augustyns
Koen
K
Scharpé
Simon
S
Weder
Walter
W
Korom
Stephan
S
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000502:physiology; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014184:Transplantation, Homologous / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000276:immunology*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D063065:Organophosphonates; D017392:Thiobarbituric Acid Reactive Substances; C118220:bis(4-acetamidophenyl) 1-prolylpyrrolidine-2-phosphonate; D014660:Vasoactive Intestinal Peptide; D011392:Proline; D051547:Heme Oxygenase-1; D018819:Dipeptidyl Peptidase 4