Intragraft DPP IV Inhibition Attenuates Post-transplant Pulmonary Ischemia/Reperfusion Injury After Extended Ischemia

Zhai, Wei; Cardell, Markus; De Meester, Ingrid; Augustyns, Koen; Hillinger, Sven; Inci, Ilhan; Arni, Stephan; Jungraithmayr, Wolfgang; Scharpé, Simon; Weder, Walter; Korom, Stephan

doi:10.1016/j.healun.2006.11.601

« Previous Next »The Journal of Heart and Lung Transplantation
Volume 26, Issue 2 , Pages 174-180, February 2007

Intragraft DPP IV Inhibition Attenuates Post-transplant Pulmonary Ischemia/Reperfusion Injury After Extended Ischemia

Wei Zhai, MD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Huazhong, China
Markus Cardell, MD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Ingrid De Meester, PhD
- Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
Koen Augustyns, PhD
- Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
Sven Hillinger, MD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Ilhan Inci, MD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Stephan Arni, PhD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Wolfgang Jungraithmayr, MD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Simon Scharpé, PhD
- Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
Walter Weder, MD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Stephan Korom, MD
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
- Reprint requests: Stephan Korom, MD, Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. Telephone: +41-1-255-8802. Fax: +41-1-255-8805.

Received 21 June 2006; received in revised form 9 October 2006; accepted 21 November 2006.

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°C and then transplanted and reperfused for 2 hours. Group II grafts were perfused with and stored in Perfadex + 25 μmol/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.