Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review
Abstract
:1. Introduction
2. Normothermic Machine Perfusion of the Liver
3. Ischaemia Reperfusion Injury
Gene Silencing with RNAi
4. Immunomodulation
4.1. Cell Therapy during NMP
4.2. Extra-Cellular Vesicles (EVs) during NMP
4.3. Tolerance
5. Microcirculation and Endothelial Protection
6. Microbial Transmission
7. Hepatic Steatosis and Implications on Liver Transplantation
7.1. NMP, Hepatic Steatosis and Pre-Clinical Animal Studies
7.2. NMP, Hepatic Steatosis and Discarded Human Livers
8. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
°C | Degrees Celsius |
% | Percent |
3R | Reduction, Refinement and Replacement |
ARLD | Alcohol-related liver disease |
ATP | Adenosine triphosphate |
BMI | Body mass index |
BQ-123 | D-tryptamine-D-aspartic acid-L-proline-D-valine-L-leucine |
cAMP | Cyclic adenosine monophosphate |
CD4 | Cluster of differentiation 4 |
CD25 | Cluster of differentiation 25 |
CD127 | Cluster of differentiation 127 |
CIT | Cold ischaemia time |
CO2 | Carbon dioxide |
COPE | Consortium for Organ Preservation in Europe |
Cy3 | Cyanine Cy3 |
DAA | Direct-acting antivirals |
DCD | Donors after circulatory death |
DNA | Deoxyribonucleic acid |
EAD | Early allograft dysfunction |
ECD | Extended criteria donor |
FOXP3 | Forkhead box P3 |
GMP | Good manufacturing practice |
GW7647 | 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)-phenyl-thio)-2-methyl-propionic acid |
GW501516 | 2-[2-Methyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolyl]methyl]thio]phenoxy]-acetic acid |
h | Hour/hours |
HBD | Heart-beating donor |
HCV | Hepatitis C virus |
HLSC | Human liver stem-like cells |
HMP | Hypothermic machine perfusion |
IFN-γ | Interferon gamma |
IL-1 | Interleukin 1 |
IL-6 | Interleukin 6 |
IL-17 | Interleukin 17 |
IRAK-4 | Interleukin-1 receptor-associated kinase 4 |
IRI | Ischaemia reperfusion injury |
kg/m2 | Kilogram per square meter |
LD | Lipid droplet |
LDLT | Living donor liver transplant |
MaS | Macrovesicular steatosis |
mRNA | Messenger RNA |
miRNA | MicroRNA |
MSC | Mesenchymal stem cells |
MSC-EV | Extracellular vesicles of mesenchymal stem cells |
NAFLD | Non-alcoholic fatty liver disease |
NMP | Normothermic machine perfusion |
O2 | Oxygen |
PGE1 | Prostaglandin E1 |
PNF | Primary non-function |
PPARα | Peroxisome proliferator-activated receptor alpha |
PPARδ | Peroxisome proliferator-activated receptor delta |
PRS | Post reperfusion syndrome |
RNA | Ribonucleic acid |
RNAi | RNA interference |
ROS | Reactive oxygen species |
SCS | Static cold storage |
SEC | Sinusoidal endothelial cell |
shRNA | Short hairpin RNA |
siRNA | Small interfering RNA |
SNMP | Sub-normothermic machine perfusion |
TG | Triacylglycerol |
TNF-α | Tumour necrosis factor alpha |
Treg | Regulatory T cell |
UNHBD | Uncontrolled non-heart-beating donor |
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Study | Model | N | Preservation Details/Groups | Length of NMP | Therapeutic Agent(s) | Outcome |
---|---|---|---|---|---|---|
Gillooly et al. 2019 [29] | Rat | N/A | HMP ± siRNA, NMP ± SiRNA, | 4 h | Fas-short interfering RNA (siRNA) | Diffuse uptake of siRNA in both NMP and HMP groups, with increased uptake in the latter. |
Beal et al. 2019 [30] | Rat | 6 per group | NMP, NMP + Enkephalin | 4 h | Enkephalin | Reduced hepatocyte oxidative stress and mitochondrial dysfunction via opioid receptor signalling. |
Moore et al. 2017 [27] | Rat | N/A | NMP | 6 h | p53 siRNA-cy3 | Positive fluorescence for cy3 detected in NMP livers. |
Study | Model | N | Perfusion Details/Groups | Length of NMP | Therapeutic Agent(s) | Outcome |
---|---|---|---|---|---|---|
Hara et al. 2013 [51] | Rat (Reperfusion) | 5 per group | HBD (SCS), UNHBD + NMP, UNHBD + NMP +PGE1 | 30 min | Prostaglandin E1 (PGE1) | Improved mitochondrial function and reduced inflammatory cytokines in NMP + PGE1 group |
Goldaracena et al. 2016 [50] | Porcine (Transplant) | 5 per group | NMP, SNMP + anti-inflammatory agents, HBD (SCS) | 4 h | Anti-inflammatory additives: BQ123, prostaglandin E1, Acetylcystine, prostacycline, gas composition 95% O2 and 5% CO2 | Significantly lower markers of hepatocellular damage in NMP groups, Improved endothelial (microcirulatory) function |
Key Benefits: |
---|
(i) Allows recovery from acute injury (hypoxia) sustained prior to or during retrieval [65]; |
(ii) Permits objective assessment of organ function prior to transplantation: a number of studies have shown that this enables identification of organs in the ‘high-risk’ category that can safely be transplanted [14,17,66]; |
(iii) Enables extended preservation times (up to 24 h) [14] |
(iv) Provides the opportunity for therapeutic intervention to a functioning organ before it is transplanted. |
Defatting Agent | Function |
---|---|
PPARδ ligand GW501516 | Increase fatty acid β-oxidation |
Peroxisome proliferator-activated receptor (PPAR) α ligand GW7647 | Increase mitochondrial fatty acid oxidation |
Cyclic adenosine monophosphate (cAMP) activator forskolin | A glucagon mimetic cAMP activator, increases lipolysis and fatty acid oxidation |
Pregnane X receptor ligand hypericin | Increase β-oxidation (very long chain fatty acids) |
Visfatin | An insulin-memetic adipokine, role not fully understood |
Scorparone | An androstane receptor ligand, upregulates PPAR |
Ref. | Defatting Interventions | Model | Total Ex-Situ Perfusion Time (h) | Percentage (%) Reduction in Macrosteatosis (MaS) | Main Outcomes |
---|---|---|---|---|---|
Jamieson et al. 2011 [67] | NMP alone | Porcine | 48 | 13 | Reduction in hepatic triglyceride content of 31% and markers of hepatocyte injury comparable to lean counterparts |
Nagarth et al. 2009 [68] | GW501516, GW7647, forskolin, hypericin, visfatin and scorparone | Zucker rats | 3 | 50 | Reduction in hepatic triglyceride content of 65% Increased hepatic lipid metabolism |
Raigani et al. 2019 [72] | GW501516, GW7647, forskolin, hypericin, visfatin, scorparone and L-carnitine | Zucker rats | 6 | 33 | Hepatic triglyceride content not reported Increased perfusate ketone content, bile bicarbonate content and lactate clearance |
Boteon et al. 2019 [69] | GW501516, GW7647, forskolin, hypericin, visfatin, scorparone and L-carnitine | Discarded human livers | 6 12 | 40 50 | Reduction in hepatic triglyceride level of 38% at 6 h and 30% at 12 h Increased hepatic lipid metabolism, improved metabolic liver function, reduced vascular resistance and reduced markers of hepatocyte injury Reduced immune cell activation and release of inflammatory cytokines |
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Dengu, F.; Abbas, S.H.; Ebeling, G.; Nasralla, D. Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review. J. Clin. Med. 2020, 9, 1046. https://doi.org/10.3390/jcm9041046
Dengu F, Abbas SH, Ebeling G, Nasralla D. Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review. Journal of Clinical Medicine. 2020; 9(4):1046. https://doi.org/10.3390/jcm9041046
Chicago/Turabian StyleDengu, Fungai, Syed Hussain Abbas, Georg Ebeling, and David Nasralla. 2020. "Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review" Journal of Clinical Medicine 9, no. 4: 1046. https://doi.org/10.3390/jcm9041046