serval:BIB_B3922CED6696
Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia.
10.1371/journal.pone.0173916
000399089000043
28323904
Francioli
C.
author
Wang
X.
author
Parapanov
R.
author
Abdelnour
E.
author
Lugrin
J.
author
Gronchi
F.
author
Perentes
J.
author
Eckert
P.
author
Ris
H.B.
author
Piquilloud
L.
author
Krueger
T.
co-last author
Liaudet
L.
author
article
2017
PloS one
1932-6203
1932-6203
journal
12
3
e0173916
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.
Animals
Antioxidants/administration & dosage
Bronchoalveolar Lavage Fluid/immunology
Cytokines/metabolism
Disease Models, Animal
Immunity, Innate/drug effects
In Vitro Techniques
Lung/immunology
Lung/physiopathology
Lung Injury/immunology
Lung Injury/physiopathology
Lung Injury/rehabilitation
Lung Transplantation/adverse effects
Lung Transplantation/methods
Male
NF-kappa B/antagonists & inhibitors
Perfusion
Pyrrolidines/administration & dosage
Rats
Rats, Sprague-Dawley
Reperfusion Injury/immunology
Reperfusion Injury/physiopathology
Reperfusion Injury/rehabilitation
Thiocarbamates/administration & dosage
Tissue Donors
Tissue and Organ Procurement
Transplantation Immunology
Warm Ischemia/adverse effects
eng
60_published
true
peer-reviewed
Publication types: Journal Article
Publication Status: epublish
University of Lausanne
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