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.
Zhai
Wei
W
Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
Jungraithmayr
Wolfgang
W
De Meester
Ingrid
I
Inci
Ilhan
I
Augustyns
Koen
K
Arni
Stephan
S
Hillinger
Sven
S
Scharpé
Simon
S
Weder
Walter
W
Korom
Stephan
S
D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005500:Follow-Up Studies; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006493:Heparin / Q000627:therapeutic use; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008550:Melatonin / Q000627:therapeutic use; D010477:Perfusion; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000503:physiopathology*; D016019:Survival Analysis; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014185:Transplantation, Isogeneic / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000276:immunology*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D014660:Vasoactive Intestinal Peptide; D006493:Heparin; D009195:Peroxidase; D018819:Dipeptidyl Peptidase 4; D008550:Melatonin