Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia.
Damaged lung grafts obtained after circulatory death (DCD lungs) and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP). Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB) is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6) or in presence of PDTC (2.5g/L, PDTC group, N = 6). Static pulmonary compliance (SPC), peak airway pressure (PAWP), pulmonary vascular resistance (PVR), and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema), and the concentration of LDH (cell damage), proteins (permeability edema) and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL), and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation.
Service of Thoracic Surgery, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Cyril
C
Francioli
Service of Thoracic Surgery, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Xingyu
X
Wang
Service of Thoracic Surgery, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.|Service of Adult Intensive Care Medicine, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Roumen
R
Parapanov
Service of Thoracic Surgery, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Etienne
E
Abdelnour
Service of Adult Intensive Care Medicine, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Jérôme
J
Lugrin
Service of Anesthesiology, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Fabrizio
F
Gronchi
Service of Thoracic Surgery, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Jean
J
Perentes
Service of Adult Intensive Care Medicine, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Philippe
P
Eckert
Service of Thoracic Surgery, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Hans-Beat
HB
Ris
Service of Adult Intensive Care Medicine, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Lise
L
Piquilloud
Service of Thoracic Surgery, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Thorsten
T
Krueger
Service of Adult Intensive Care Medicine, University Hospital Medical Center and Faculty of Biology and Medicine, Lausanne, Switzerland.
Lucas
http://orcid.org/0000-0003-2670-4930
L
Liaudet
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007113:Immunity, Innate / Q000187:drug effects; D066298:In Vitro Techniques; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D055370:Lung Injury / Q000276:immunology / Q000503:physiopathology / Q000534:rehabilitation*; D016040:Lung Transplantation / Q000009:adverse effects / Q000379:methods*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010477:Perfusion; D011759:Pyrrolidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000276:immunology / Q000503:physiopathology / Q000534:rehabilitation*; D013859:Thiocarbamates / Q000008:administration & dosage*; D014019:Tissue Donors; D009927:Tissue and Organ Procurement; D014181:Transplantation Immunology; D052096:Warm Ischemia / Q000009:adverse effects
D000975:Antioxidants; D016207:Cytokines; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid