scholarly journals Perfluorocarbon-Based Oxygen Carriers and Subnormothermic Lung Machine Perfusion Decrease Production of Pro-Inflammatory Mediators

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2249
Author(s):  
Stephan Arni ◽  
Citak Necati ◽  
Tatsuo Maeyashiki ◽  
Isabelle Opitz ◽  
Ilhan Inci
Keyword(s):  
Inflammatory Cytokines ◽  
Lung Tissue ◽  
Ex Vivo ◽  
Dynamic Compliance ◽  
Myeloperoxidase Activity ◽  
Machine Perfusion ◽  
Oxygen Carriers ◽  
Ex Vivo Lung Perfusion ◽  
Inflammatory Parameters ◽  
Lactate Levels

The quality of marginal donor lungs is clinically assessed with normothermic machine perfusion. Although subnormothermic temperature and perfluorocarbon-based oxygen carriers (PFCOC) have proven favourable for other organ transplants, their beneficial use for ex vivo lung perfusion (EVLP) still requires further investigation. In a rat model, we evaluated on a 4 h EVLP time the effects of PFCOC with either 28 °C or 37 °C perfusion temperatures. During EVLP at 28 °C with PFCOC, we recorded significantly lower lung pulmonary vascular resistance (PVR), higher dynamic compliance (Cdyn), significantly lower potassium and lactate levels, higher lung tissue ATP content, and significantly lower myeloperoxidase tissue activity when compared to the 37 °C EVLP with PFCOC. In the subnormothermic EVLP with or without PFCOC, the pro-inflammatory mediator TNFα, the cytokines IL-6 and IL-7, the chemokines MIP-3α, MIP-1α, MCP-1, GRO/KC as well as GM-CSF, G-CSF and the anti-inflammatory cytokines IL-4 and IL-10 were significantly lower. The 28 °C EVLP improved both Cdyn and PVR and decreased pro-inflammatory cytokines and pCO2 levels compared to the 37 °C EVLP. In addition, the 28 °C EVLP with PFCOC produced a significantly lower level of myeloperoxidase activity in lung tissue. Subnormothermic EVLP with PFCOC significantly improves lung donor physiology and ameliorates lung tissue biochemical and inflammatory parameters.

scholarly journals Subnormothermic Ex Vivo Lung Perfusion Temperature Improves Graft Preservation in Lung Transplantation

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 748
Author(s):  
Stephan Arni ◽  
Tatsuo Maeyashiki ◽  
Necati Citak ◽  
Isabelle Opitz ◽  
Ilhan Inci
Keyword(s):  
Lung Transplantation ◽  
Ex Vivo ◽  
Stress Test ◽  
Left Lung ◽  
Dynamic Compliance ◽  
Lung Perfusion ◽  
Myeloperoxidase Activity ◽  
Solid Organ ◽  
Ex Vivo Lung Perfusion ◽  
Lung Physiology

Normothermic machine perfusion is clinically used to assess the quality of marginal donor lungs. Although subnormothermic temperatures have proven beneficial for other solid organ transplants, subnormothermia-related benefits of ex vivo lung perfusion (EVLP) still need to be investigated. Material and Methods: In a rat model, we evaluated the effects of 28 °C temperature on 4-h EVLPs with subsequent left lung transplantation. The recipients were observed for 2 h postoperatively. Lung physiology data were recorded and metabolic parameters were assessed. Results: During the 4-h subnormothermic EVLP, the lung oxygenation was significantly higher (p < 0.001), pulmonary vascular resistance (PVR) lower and dynamic compliance (Cdyn) higher when compared to the 37 °C EVLP. During an end-of-EVLP stress test, we recorded significantly higher flow (p < 0.05), lower PVR (p < 0.05) and higher Cdyn (p < 0.01) in the 28 °C group when compared to the 37 °C group. After the left lung transplantation, Cdyn and oxygenation improved in the 28 °C group, which were comparable to the 37 °C group. Chemokines RANTES, MIP-3α, MIP-1α MCP-1 GRO/KC and pro-inflammatory mediators GM-CSF, G-CSF and TNFα were significantly lower after the 28 °C EVLP and remained low in the plasma of the recipient rats after transplantation. The lungs of the 28 °C group showed significantly lowered myeloperoxidase activity and lowered levels of TNFα and IL-1β. Conclusions: Compared to the normothermic perfusion, the 28 °C EVLP improved Cdyn and PVR and reduced both the release of pro-inflammatory cytokines and myeloperoxidase activity in lung tissue. These observations were also observed after the left lung transplantation in the subnormothermic group. The 28 °C EVLP significantly improved biochemical, physiological and inflammatory parameters in lung donors.

scholarly journals Endothelial Glycocalyx Shedding Occurs during Ex Vivo Lung Perfusion: A Pilot Study

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Timothy M. Sladden ◽  
Stephanie Yerkovich ◽  
Douglas Wall ◽  
Maxine Tan ◽  
William Hunt ◽  
...  
Keyword(s):  
Ex Vivo ◽  
New Technology ◽  
Heparan Sulphate ◽  
Dynamic Compliance ◽  
Preliminary Evidence ◽  
Lung Perfusion ◽  
Endothelial Glycocalyx ◽  
Ex Vivo Lung Perfusion ◽  
Lung Dysfunction ◽  
Over Time

Background. Damage to the endothelium has been established as a key pathological process in lung transplantation and ex vivo lung perfusion (EVLP), a new technology that provides a platform for the assessment of injured donor lungs. Damage to the lung endothelial glycocalyx, a structure that lines the endothelium and is integral to vascular barrier function, has been associated with lung dysfunction. We hypothesised that endothelial glycocalyx shedding occurs during EVLP and aimed to establish a porcine model to investigate the mechanism underlying glycocalyx breakdown during EVLP. Methods. Concentrations of endothelial glycocalyx breakdown products, syndecan-1, hyaluronan, heparan sulphate, and CD44, were measured using the ELISA and matrix metalloproteinase (MMP) activity by zymography in the perfusate of both human (n = 9) and porcine (n = 4) lungs undergoing EVLP. Porcine lungs underwent prolonged EVLP (up to 12 hours) with perfusion and ventilation parameters recorded hourly. Results. During human EVLP, endothelial glycocalyx breakdown products in the perfusate increased over time. Increasing MMP-2 activity over time was positively correlated with levels of syndecan-1 (r = 0.886; p=0.03) and hyaluronan (r = 0.943; p=0.02). In the porcine EVLP model, hyaluronan was the only glycocalyx product detectable during EVLP (1 hr: 19 (13–84) vs 12 hr: 143 (109–264) ng/ml; p=0.13). Porcine hyaluronan was associated with MMP-9 activity (r = 0.83; p=0.02) and also with dynamic compliance (r = 0.57; p=0.03). Conclusion. Endothelial glycocalyx products accumulate during both porcine and human EVLP, and this accumulation parallels an accumulation of matrix-degrading enzyme activity. Preliminary evidence in our porcine EVLP model suggests that shedding may be related to organ function, thus warranting additional study.

scholarly journals Suppression of Inflammatory Cytokines During Ex Vivo Lung Perfusion With an Adsorbent Membrane

2010 ◽  
Vol 89 (6) ◽  
pp. 1773-1779 ◽  
Author(s):  
Tomokazu Kakishita ◽  
Takahiro Oto ◽  
Shiro Hori ◽  
Kentaroh Miyoshi ◽  
Shinji Otani ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Ex Vivo Lung Perfusion

scholarly journals Custodiol-MP for ex vivo lung perfusion – A comparison in a porcine model of donation after circulatory determination of death

2021 ◽  
pp. 039139882199066
Author(s):  
Katharina Kalka ◽  
Zoe Keldenich ◽  
Henning Carstens ◽  
Björn Walter ◽  
Ursula Rauen ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Functional Outcomes ◽  
Porcine Model ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Determination Of Death ◽  
Ex Vivo Lung Perfusion ◽  
Lactate Dehydrogenase Activity ◽  
Lactate Levels

Introduction: Ex vivo lung perfusion (EVLP) is an established technique to evaluate and eventually recondition lungs prior to transplantation. Custodiol-MP (C-MP) solution is a new solution, designed for clinical machine perfusion, that has been used for kidneys. The aim of this study was to compare the effects of EVLP with Custodiol-MP on lung functional outcomes to the gold standard of EVLP with Steen Solution™. Material and Methods: In a porcine EVLP model of DCDD (Donation after Circulatory Determination of Death), lungs were perfused with Steen Solution™ (SS, n = 7) or Custodiol-MP solution supplemented with 55 g/l albumin (C-MP, n = 8). Lungs were stored cold for 4 h in low potassium dextran solution and subsequently perfused ex vivo for 4 h. During EVLP pulmonary gas exchange, activities of lactate dehydrogenase (LDH) and alkaline phosphatase (AP) as well as levels of lactate in the perfusate were recorded hourly. Results: Oxygenation capacity differed significantly between groups (averaged over 4 h: SS 274 ± 178 mmHg; C-MP 284 ± 151 mmHg p = 0.025). Lactate dehydrogenase activities and lactate concentrations were significantly lower in Custodiol-MP perfused lungs. In a porcine model of DCDD with 4 h of EVLP the use of modified Custodiol-MP as perfusion solution was feasible. The use of C-MP showed at least comparable lung functional outcomes to the use of Steen SolutionTM. Furthermore C-MP perfusion resulted in significantly lower lactate dehydrogenase activity and lactate levels in the perfusate and higher oxygenation capacity.

A Computer Stereo Vision Method For Regional Dynamic Compliance Measurement During Ex-Vivo Lung Perfusion

2021 ◽  
Author(s):  
Jason R Der ◽  
Katie Cameron ◽  
Steven Cruz Antunes ◽  
Calvin Jee ◽  
Reza Sabbagh ◽  
...  
Keyword(s):  
Stereo Vision ◽  
Ex Vivo ◽  
Dynamic Compliance ◽  
Lung Perfusion ◽  
Ex Vivo Lung Perfusion ◽  
Compliance Measurement ◽  
Regional Dynamic

scholarly journals Increased Arginase Expression and Decreased Nitric Oxide in Pig Donor Lungs after Normothermic Ex Vivo Lung Perfusion

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 300 ◽  
Author(s):  
Farshad Tavasoli ◽  
Mingyao Liu ◽  
Tiago Machuca ◽  
Riccardo Bonato ◽  
David R. Grant ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lung Transplantation ◽  
Lung Tissue ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Metabolizing Enzymes ◽  
Ex Vivo Lung Perfusion ◽  
Tissue Homogenates ◽  
Oxide Synthase ◽  
Nos Isoforms

An established pig lung transplantation model was used to study the effects of cold ischemia time, normothermic acellular ex vivo lung perfusion (EVLP) and reperfusion after lung transplantation on l-arginine/NO metabolism in lung tissue. Lung tissue homogenates were analyzed for NO metabolite (NOx) concentrations by chemiluminescent NO-analyzer technique, and l-arginine, l-ornithine, l-citrulline and asymmetric dimethylarginine (ADMA) quantified using liquid chromatography-mass spectrometry (LC-MS/MS). The expression of arginase and nitric oxide synthase (NOS) isoforms in lung was measured by real-time polymerase chain reaction. EVLP preservation resulted in a significant decrease in concentrations of NOx and l-citrulline, both products of NOS, at the end of EVLP and after reperfusion following transplantation, compared to control, respectively. The ratio of l-ornithine over l-citrulline, a marker of the balance between l-arginine metabolizing enzymes, was increased in the EVLP group prior to reperfusion. The expression of both arginase isoforms was increased from baseline 1 h post reperfusion in EVLP but not in the no-EVLP group. These data suggest that EVLP results in a shift of the l-arginine balance towards arginase, leading to NO deficiency in the lung. The arginase/NOS balance may, therefore, represent a therapeutic target to improve lung quality during EVLP and, subsequently, transplant outcomes.

scholarly journals Subnormothermic ex vivo lung perfusion attenuates ischemia reperfusion injury from donation after circulatory death donors

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255155
Author(s):  
Stephan Arni ◽  
Tatsuo Maeyashiki ◽  
Isabelle Opitz ◽  
Ilhan Inci
Keyword(s):  
Lung Tissue ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Atp Content ◽  
Donation After Circulatory Death ◽  
Immunological Parameters ◽  
Ex Vivo Lung Perfusion ◽  
Ischemic Time ◽  
Physiological Variables ◽  
Circulatory Death

Use of normothermic ex vivo lung perfusion (EVLP) was adopted in clinical practice to assess the quality of marginal donor lungs. Subnormothermic perfusion temperatures are in use among other solid organs to improve biochemical, clinical and immunological parameters. In a rat EVLP model of donation after circulatory death (DCD) lung donors, we tested the effect of four subnormothermic EVLP temperatures that could further improve organ preservation. Warm ischemic time was of 2 hours. EVLP time was of 4 hours. Lung physiological data were recorded and metabolic parameters were assessed. Lung oxygenation at 21°C and 24°C were significantly improved whereas pulmonary vascular resistance and edema formation at 21°C EVLP were significantly worsened when compared to 37°C EVLP. The perfusate concentrations of potassium ions and lactate exiting the lungs with 28°C EVLP were significantly lower whereas sodium and chlorine ions with 32°C EVLP were significantly higher when compared to 37°C EVLP. Also compared to 37°C EVLP, the pro-inflammatory chemokines MIP2, MIP-1α, GRO-α, the cytokine IL-6 were significantly lower with 21°C, 24°C and 28°C EVLP, the IL-18 was significantly lower but only with 21°C EVLP and IL-1β was significantly lower at 21°C and 24°C EVLP. Compared to the 37°C EVLP, the lung tissue ATP content after 21°C, 24°C and 28°C EVLP were significantly higher, the carbonylated protein content after 28°C EVLP was significantly lower and we measured significantly higher myeloperoxidase activities in lung tissues with 21°C, 24°C and 32°C. The 28°C EVLP demonstrated acceptable physiological variables, significantly higher lung tissue ATP content and decreased tissue carbonylated proteins with reduced release of pro-inflammatory cytokines. In conclusion, the 28°C EVLP is a non inferior setting in comparison to the clinically approved 37°C EVLP and significantly improve biochemical, clinical and immunological parameters and may reduce I/R injuries of DCD lung donors.

Normothermic Ex Vivo Lung Perfusion in Brain Dead Donors Reduces Inflammatory Cytokines and Toll-Like Receptor Expression

2017 ◽  
Vol 101 ◽  
pp. S89-S90
Author(s):  
Shadi Shafaghi ◽  
Esmaeil Mortaz ◽  
Azizollah Abbasi Dezfuli ◽  
Hoda Gudarzi ◽  
Kambiz Sheikhy ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Receptor Expression ◽  
Toll Like Receptor ◽  
Ex Vivo Lung Perfusion ◽  
Brain Dead

scholarly journals Development of ex vivo normothermic perfusion as an innovative method to assess pancreases after preservation

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
Ann Ogbemudia
Keyword(s):  
Cold Storage ◽  
Ex Vivo ◽  
Gas Analysis ◽  
Machine Perfusion ◽  
Assessment Strategy ◽  
Hypothermic Machine Perfusion ◽  
Normothermic Perfusion ◽  
Pancreas Preservation ◽  
Normothermic Machine Perfusion ◽  
Lactate Levels

Ann Ogbemudia, Julien Branchereau (Joint first authors), Gabriella Hakim, Fungai Dengu, FaysalEl-Gilani, John Mulvey, Kaithlyn Rozenberg, Thomas Prudhomme, Letizia Lo Faro, James Hunter,Paul Johnson, Rutger Ploeg and Peter Friend   Objective Static cold storage (SCS) is the standard method for pancreas preservation but does not facilitate objective organ assessment prior to transplantation. Normothermic machine perfusion (NMP) has been used to test other abdominal and thoracic organs’ function and viability in transplantation settings. Our aim was to develop a NMP protocol specific for pancreases and then investigate its potential as an organ assessment strategy. Method 8 porcine pancreases were procured in conditions replicating donation after circulatory death with warm ischaemia time of 25 minutes. After 3 hours of static cold storage (SCS) the pancreases were divided into 3 experimental groups 1) the feasibility group (n=2) that underwent 2.5 hours of NMP 2) the SCS group (n = 2) that underwent an additional 6 hours of SCS prior to assessment on NMP for an hour and 3) the Oxygenated Hypothermic Machine Perfusion (oxyHMP) group (n = 4) that underwent 6 hours of oxyHMP followed by 1-hour assessment on NMP. The NMP protocol used autologous, leucodepleted blood delivered at a mean arterial pressure of 40mmHg with a temperature of 37oC. At timed intervals during NMP, perfusate samples were collected for gas analysis and perfusion parameters were recorded. Results The feasibility group was used to develop the NMP protocol and demonstrated stable perfusion parameters throughout NMP. Compared to the SCS group the oxyHMP group demonstrated better average perfusion characteristics with lower resistances, higher flow rates, lower mean lactate levels and physiological pH. The oxyHMP group maintained normal macroscopic appearances during NMP. At the end of NMP the SCS group had an average 32% weight increase compared to the oxyHMP group that were found to have a 17% weight reduction. Conclusion Normothermic machine perfusion of whole pancreases is feasible after cold preservation and potentially useful as an assessment strategy. Furthermore, it demonstrated that oxygenated HMP may be beneficial for pancreas preservation compared to SCS.

scholarly journals Ischaemia reperfusion induces the release of donor derived Passenger Leukocytes (PLs) during normothermic machine perfusion (NMP) of the liver- a new opportunity for ex situ graft leukodepletion?

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
Fungai Dengu
Keyword(s):  
Ex Vivo ◽  
Recipient Cell ◽  
Flow Cytometric Analysis ◽  
Ex Situ ◽  
Machine Perfusion ◽  
Ex Vivo Lung Perfusion ◽  
University Of Oxford ◽  
Mechanical Removal ◽  
Normothermic Machine Perfusion ◽  
Passenger Leukocytes

Fungai Dengu1, Tamsyn Clark1,3, Hussain Abbas1, Etohan Ann Ogbemudia1, Faysal El Gilani1,David Nasralla1, Peter Friend1, James Fildes2 1. Oxford Organ Perfusion Lab, Nuffield Department of Surgical Sciences and Oxford Biomedical ResearchCentre, University of Oxford, Oxford, UK2. The Ex-Vivo Lab, Division of Cell Matrix Biology and Regenerative Medicine, School of BiologicalSciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester AcademicHealth Science Centre, Manchester, UK3. Institute of Biomedical Engineering, University of Oxford, Oxford, UK   Background Passenger Leukocytes (PLs) are implicated in both the direct and semi-direct pathways of allorecognition which is the process that underpins acute allograft rejection1. The majority of liver-derived PLs are short lived and predominantly impact early recipient immune responses2. Removal of PLs has been shown in kidney, lung and vascularised composite allografts to reduce early allograft damage and abrogate ejection3. We aimed to assess the use normothermic machine perfusion (NMP) to investigate PL kinetics and explore PL depletion strategies in donor livers. Methods Porcine livers (N=4) procured in a donation after circulatory death (DCD) model were preserved with sequential static cold storage then NMP. During NMP, livers were subjected to repeated 20 min warm ischaemic hits (IH) followed by 30mins of NMP using a leukocyte depleted autologous RBC based perfusate. Leukocytes were quantified using the Sysmex® cell counter system and samples stored for flow cytometric analysis. Results In total, 3.4x106 PLs are effluxed into the circuit immediately after initiation of NMP, this falls rapidly to 1.35x106 by 30 mins. Following the first IH, a further efflux of occurs with a peak of 3.74x106 occurring. The second IH also induced an efflux of cells (1.61x106) with lymphocytes representing the predominant leukocyte sub-type in each efflux. Discussion During NMP, there is an inducible and reproducible efflux of graft derived PLs into the circuit that is composed of predominantly lymphocytes with unexpectedly low numbers of monocytes. Removal of these PLs from the perfusate during NMP may therefore be feasible using an in-line leukocyte-filter.   References 1. Alsughayyir, J., Motallebzadeh, R. & Pettigrew, G. J. Are donor lymphocytes a barrier to transplantation tolerance? Curr. Opin. Organ Transplant. 23, 90–96 (2018).2. Mastoridis, S. et al. Impact of donor extracellular vesicle release on recipient cell “cross-dressing” following clinical liver and kidney transplantation. Am. J. Transplant. ajt.16123 (2020). doi:10.1111/ajt.161233. Stone, J. P. et al. Mechanical removal of dendritic cell–generating non-classical monocytes via ex vivo lung perfusion. J. Hear. Lung Transplant. 33, 864–869 (2014).

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