scholarly journals A method for translational rat ex vivo lung perfusion experimentation

2020 ◽  
Vol 319 (1) ◽  
pp. L61-L70
Author(s):  
Akihiro Ohsumi ◽  
Takashi Kanou ◽  
Aadil Ali ◽  
Zehong Guan ◽  
David M. Hwang ◽  
...  
Keyword(s):  
Lung Function ◽  
Ex Vivo ◽  
Left Lung ◽  
Lung Compliance ◽  
Lung Perfusion ◽  
Arterial Oxygen ◽  
Large Animal ◽  
Ex Vivo Lung Perfusion ◽  
Ischemic Time ◽  
Cold Ischemic Time

The application of ex vivo lung perfusion (EVLP) has significantly increased the successful clinical use of marginal donor lungs. While large animal EVLP models exist to test new strategies to improve organ repair, there is currently no rat EVLP model capable of maintaining long-term lung viability. Here, we describe a new rat EVLP model that addresses this need, while enabling the study of lung injury due to cold ischemic time (CIT). The technique involves perfusing and ventilating male Lewis rat donor lungs for 4 h before transplanting the left lung into a recipient rat and then evaluating lung function 2 h after reperfusion. To test injury within this model, lungs were divided into groups and exposed to different CITs (i.e., 20 min, 6 h, 12 h, 18 h and 24 h). Experiments involving the 24-h-CIT group were prematurely terminated due to the development of severe edema. For the other groups, no differences in the ratio of arterial oxygen partial pressure to fractional inspired oxygen ([Formula: see text]/[Formula: see text]) were observed during EVLP; however, lung compliance decreased over time in the 18-h group ( P = 0.012) and the [Formula: see text]/[Formula: see text] of the blood from the left pulmonary vein 2 h after transplantation was lower compared with 20-min-CIT group ( P = 0.0062). This new model maintained stable lung function during 4-h EVLP and after transplantation when exposed to up to 12 h of CIT.

scholarly journals Flow-controlled ventilation during EVLP improves oxygenation and preserves alveolar recruitment

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Sofie Ordies ◽  
Michaela Orlitova ◽  
Tobias Heigl ◽  
Annelore Sacreas ◽  
Anke Van Herck ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Regional Distribution ◽  
Left Lung ◽  
Dry Weight ◽  
Lung Compliance ◽  
Alveolar Recruitment ◽  
Large Animal ◽  
Ex Vivo Lung Perfusion ◽  
Controlled Ventilation ◽  
Porcine Lungs

Abstract Background Ex vivo lung perfusion (EVLP) is a widespread accepted platform for preservation and evaluation of donor lungs prior to lung transplantation (LTx). Standard lungs are ventilated using volume-controlled ventilation (VCV). We investigated the effects of flow-controlled ventilation (FCV) in a large animal EVLP model. Fourteen porcine lungs were mounted on EVLP after a warm ischemic interval of 2 h and randomized in two groups (n = 7/group). In VCV, 7 grafts were conventionally ventilated and in FCV, 7 grafts were ventilated by flow-controlled ventilation. EVLP physiologic parameters (compliance, pulmonary vascular resistance and oxygenation) were recorded hourly. After 6 h of EVLP, broncho-alveolar lavage (BAL) was performed and biopsies for wet-to-dry weight (W/D) ratio and histology were taken. The left lung was inflated, frozen in liquid nitrogen vapors and scanned with computed tomography (CT) to assess regional distribution of Hounsfield units (HU). Results All lungs endured 6 h of EVLP. Oxygenation was better in FCV compared to VCV (p = 0.01) and the decrease in lung compliance was less in FCV (p = 0.03). W/D ratio, pathology and BAL samples did not differ between both groups (p = 0.16, p = 0.55 and p = 0.62). Overall, CT densities tended to be less pronounced in FCV (p = 0.05). Distribution of CT densities revealed a higher proportion of well-aerated lung parts in FCV compared to VCV (p = 0.01). Conclusions FCV in pulmonary grafts mounted on EVLP is feasible and leads to improved oxygenation and alveolar recruitment. This ventilation strategy might prolong EVLP over time, with less risk for volutrauma and atelectrauma.

scholarly journals Nicotinamide Adenine Dinucleotide (NAD+) improves lung function in rat lung ex-vivo lung perfusion model

2021 ◽  
Vol 108 (Supplement_4) ◽  
Author(s):  
J P Ehrsam ◽  
S Arni ◽  
J Chen ◽  
H Rodriguez Cetina Biefer ◽  
I Opitz ◽  
...  
Keyword(s):  
Lung Function ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Male Rats ◽  
Interleukin 12 ◽  
Large Animal ◽  
Ex Vivo Lung Perfusion ◽  
Long Term Outcome ◽  
Anti Inflammatory ◽  
The Impact

Abstract Objective Ischemia-reperfusion injury compromises short- and long-term outcome after lung transplantation. The scarce existing data on the natural co-enzyme NAD+ suggest an antagonistic effect on hypoxia induced vasoconstriction, removal capacity on reactive oxygen species, and anti-inflammatory effects. We therefore investigated the impact of NAD+ on ischemic rat lungs during ex-vivo lung perfusion (EVLP). Methods Lungs were retrieved from 12 outbred Sprague Dawley male rats and exposed to 14 hours of cold ischemic storage. All lungs were then perfused in a rat EVLP system for 4 hours. Lung grafts were injected after 1, 2 and 3 hours with 2000 uM NAD + (N = 6) or placebo (N = 6) in the perfusate in proximity of the pulmonary artery. EVLP physiology and biochemistry were monitored. Results During the 4 hours of EVLP, the lung function increased significantly in the NAD+ group when compared to the placebo group. We monitored a higher vascular flow (p = 0.018), a lower mean pulmonary pressure (p = 0.007) and increased oxygenation capacity (p = 0.003). Lung compliance and weight were comparable. Tissue inflammation measured by myeloperoxidase was significantly lower in the NAD+ group (p = 0.015). In the perfusate, we observed in the NAD+ group significantly lower levels of pro-inflammatory interleukin-18 (p = 0.033) and a trend towards high levels of anti-inflammatory interleukin-10 (p = 0.080) and low levels of pro-inflammatory interleukin-12 (p = 0.146). Conclusion Findings from this preliminary study demonstrated that NAD+ is a promising agent with both anti-inflammatory properties and the ability to improve ischemic lung function. This observation should be validated in a large animal model.

scholarly journals Cellular and acellular ex vivo lung perfusion preserve functional lung ultrastructure in a large animal model: a stereological study

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Jasmin Steinmeyer ◽  
Simon Becker ◽  
Murat Avsar ◽  
Jawad Salman ◽  
Klaus Höffler ◽  
...  
Keyword(s):  
Animal Model ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Large Animal Model ◽  
Large Animal ◽  
Ex Vivo Lung Perfusion ◽  
Lung Ultrastructure

scholarly journals A neutrophil elastase inhibitor improves lung function during ex vivo lung perfusion

2015 ◽  
Vol 63 (12) ◽  
pp. 645-651 ◽  
Author(s):  
Masaaki Harada ◽  
Takahiro Oto ◽  
Shinji Otani ◽  
Kentaroh Miyoshi ◽  
Masanori Okada ◽  
...  
Keyword(s):  
Lung Function ◽  
Neutrophil Elastase ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Neutrophil Elastase Inhibitor ◽  
Ex Vivo Lung Perfusion ◽  
Elastase Inhibitor

Transcriptomic investigation reveals donor specific gene signatures in human lung transplants

2020 ◽  
pp. 2000327
Author(s):  
Cristina Baciu ◽  
Andrew Sage ◽  
Ricardo Zamel ◽  
Jason Shin ◽  
Xiao-Hui Bai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ex Vivo ◽  
Specific Gene ◽  
Organ Shortage ◽  
Ex Vivo Lung Perfusion ◽  
Ischemic Time ◽  
Protein Assay ◽  
Cold Ischemic Time ◽  
Donor Lung ◽  
Lung Transplants

RationaleTransplantation of lungs from donation after circulatory death (DCD) in addition to donation after brain death (DBD) became routine worldwide to address the global organ shortage. The development of ex vivo lung perfusion (EVLP) for donor lung assessment and repair contributed to the increased use of DCD lungs. We hypothesise that better understanding of the differences between lungs from DBD and DCD donors, and between EVLP and directly transplanted (non-EVLP) lungs, will lead to discovery of the injury specific targets for donor lung repair and reconditioning.MethodsTissue biopsies from human DBD (n=177) and DCD (n=65) donor lungs assessed with or without EVLP, were collected at the end of cold ischemic time. All samples were processed with microarray assay. Gene expression, network and pathway analyses were performed using R, Ingenuity Pathway Analysis and STRING. Results were validated with protein assay, multiple logistic regression and 10-fold cross validation.ResultsOur analyses showed that lungs from DBD donors have up-regulation of inflammatory cytokines and pathways. In contrast, DCD lungs display a transcriptome signature of pathways associated with cell death, apoptosis and necrosis. Network centrality revealed specific drug targets to rehabilitate the DBD lungs. Moreover, in DBD lungs, TNFR1/2 signalling pathways and macrophage migration inhibitory factor associated pathways were activated in the EVLP group. A panel of genes that differentiate the EVLP from non-EVLP group in DBD lungs was identified.ConclusionThe examination of gene expression profiling indicates that DBD and DCD lungs have distinguishable biological transcriptome signatures.

scholarly journals Perfusate adsorption during ex vivo lung perfusion improves early post-transplant lung function

2020 ◽  
Author(s):  
Ilker Iskender ◽  
Stephan Arni ◽  
Tatsuo Maeyashiki ◽  
Necati Citak ◽  
Mareike Sauer ◽  
...  
Keyword(s):  
Lung Function ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Ex Vivo Lung Perfusion ◽  
Post Transplant
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