Postmortem and ex vivo carbon monoxide ventilation reduces injury in rat lungs transplanted from non–heart-beating donors

Abstract

Objective: We sought to determine whether ventilation of lungs after death in non-heart-beating donors with carbon monoxide during warm ischemia and ex vivo lung perfusion and after transplant would reduce ischemia-reperfusion injury and improve lung function. Methods: One hour after death, Sprague-Dawley rats were ventilated for another hour with 60% oxygen (control group) or 500 ppm carbon monoxide in 60% oxygen (CO-vent group; n¼6/group). Then, lungs were flushed with 20 mL cold Perfadex, stored cold for 1 hour, then warmed to 37 C in an ex vivo lung perfusion circuit perfused with Steen solution. At 37 C, lungs were ventilated for 15 minutes with alveolar gas with or without 500 ppm carbon monoxide, then perfusion-cooled to 20 C, flushed with cold Perfadex and stored cold for 2 hours. The left lung was transplanted using a modified cuff technique. Recipients were ventilated with 60% oxygen with or without carbon monoxide. One hour after transplant, we measured blood gases from the left pulmonary vein and aorta, and wet-to-dry ratio of both lungs. The RNA and protein extracted from graft lungs underwent real-time polymerase chain reaction and Western blotting, and measurement of cyclic guanosine monophosphate by enzyme-linked immunosorbent assay. Results: Carbon monoxide ventilation begun 1 hour after death reduced wet/dry ratio after ex vivo lung perfusion. After transplantation, the carbon monoxide-ventilation group had better oxygenation; higher levels of tissue cyclic guanosine monophosphate, heme oxidase-1 expression, and p38 phosphorylation; reduced c-Jun N-terminal kinase phosphorylation; and reduced expression of interleukin-6 and interleukin-1b messenger RNA. Conclusions: Administration of carbon monoxide to the deceased donor and non-heart-beating donor lungs reduces ischemia-reperfusion injury in rat lungs transplanted from non-heart-beating donors. Therapy to the deceased donor via the airway may improve post-transplant lung function.

Organ preservation: from the past to the future

“…A series of therapeutic strategies have been studied using EVLP for lung repair. For example, different drugs were delivered through perfusate to mitigate IRI [113][114][115] , therapeutic gases (NO, CO, H 2 ) were inhaled during EVLP to reduce inflammatory response and lung edema [116][117][118] , mesenchymal stem cells were used to treat lung injury induced by endotoxins and infection [119] , and IL-10 gene therapy was developed to prevent IRI [120,121] . When the types of injury are clear, injury-specific treatments can be used during EVLP.…”

Lung Transplantation With Donation After Circulatory Determination of Death Donors and the Impact of Ex Vivo Lung Perfusion

“…Firstly, the refinement of donor selection was illustrated by the study of Sanchez et al, which showed that, despite similar clinical characteristics and alveolocapillary barrier properties after the period of cardiac arrest and warm ischemia, donor lungs that did not receive prearrest heparinization had significantly worse physiological performance on EVLP compared to lungs from donors that received pre-arrest heparin (32). Secondly, the normothermic and metabolically active environment restored by EVLP provides an ideal platform for therapeutic manipulation of the DCDD organ (33)(34)(35)(36). EVLP-treated lungs showed better posttransplant lung function and less microthrombi formation compared to no-EVLP lungs in a DCDD experimental study (37).…”

Ex Vivo Perfusion With Adenosine A2A Receptor Agonist Enhances Rehabilitation of Murine Donor Lungs After Circulatory Death

“…EVLP has been utilized as an effective strategy for the assessment of marginal, high-risk donor lungs and has also demonstrated potential for expansion of the limited donor organ pool through the rehabilitation of DCD lungs (11-14). While current advancements in EVLP-mediated rehabilitation merit optimism concerning the future utilization of DCD lungs, two principle benefits to this approach that have not been adequately explored are the delivery of therapeutic, anti-inflammatory agents to the injured lung and the identification of molecular markers that may serve as predictors of PGD after transplantation.…”