Abstract
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.
Highlights
Lung transplantation is the only definitive treatment available for end-stage lung diseases, this option remains critically limited by the shortage of available donor lungs [1]
A crucial step in triggering such response relies in the activation of the transcription factor nuclear factor kappaB (NF-κB), a master regulator of inflammation activated in response to the engagement of immune receptors belonging to the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily [10]
The main results of this study are that the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), administered during ex-vivo lung perfusion (EVLP) of rat lungs obtained after circulatory death and warm ischemia, significantly reduced lung inflammation, edema formation and physiological deterioration
Summary
Lung transplantation is the only definitive treatment available for end-stage lung diseases, this option remains critically limited by the shortage of available donor lungs [1]. EVLP has been proposed as a platform to deliver drugs ex vivo (concept of pharmacological reconditioning) [6], in order to improve the status of the donor lung and to reduce the risk of primary graft dysfunction (PGD), a severe form of lung ischemia and reperfusion injury (LIR) which may develop early after transplantation [7]. Ross et al reported that the selective NFκB inhibitor pyrrolidine dithiocarbamate (PDTC) reduced lung edema and improved lung function following lung transplantation in a porcine model [12] This observation raises the hypothesis that PDTC could be a potential candidate drug for the ex-vivo treatment of damaged, non standard lung grafts. We addressed this hypothesis by assessing the effects of PDTC administered during EVLP, in damaged rat lungs obtained after circulatory death and extended warm ischemic time
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
