{"doi":"10.1016/j.ebiom.2023.104861","title":"Mitochondrial injury during normothermic regional perfusion (NRP) and hypothermic oxygenated perfusion (HOPE) in a rodent model of DCD liver transplantation","abstract":"BACKGROUND: Normothermic regional perfusion (NRP) and hypothermic-oxygenated-perfusion (HOPE), were both shown to improve outcomes after liver transplantation from donors after circulatory death (DCD). Comparative clinical and mechanistical studies are however lacking. METHODS: A rodent model of NRP and HOPE, both in the donor, was developed. Following asystolic donor warm ischemia time (DWIT), the abdominal compartment was perfused either with a donor-blood-based-perfusate at 37 °C (NRP) or with oxygenated Belzer-MPS at 10 °C (donor-HOPE) for 2 h. Livers were then procured and underwent 5 h static cold storage (CS), followed by transplantation. Un-perfused and HOPE-treated DCD-livers (after CS) and healthy livers (DBD) with direct implantation after NRP served as controls. Endpoints included the entire spectrum of ischemia-reperfusion-injury. FINDINGS: Healthy control livers (DBD) showed minimal signs of inflammation during 2 h NRP and achieved 100% posttransplant recipient survival. In contrast, DCD livers with 30 and 60 min DWIT suffered from greater mitochondrial injury and inflammation as measured by increased perfusate Lactate, FMN- and HMGB-1-levels with subsequent Toll-like-receptor activation during NRP. In contrast, donor-HOPE (instead of NRP) led to significantly less mitochondrial-complex-I-injury and inflammation. Results after donor-HOPE were comparable to ex-situ HOPE after CS. Most DCD-liver recipients survived when treated with one HOPE-technique (86%), compared to only 40% after NRP (p = 0.0053). Following a reduction of DWIT (15 min), DCD liver recipients achieved comparable survivals with NRP (80%). INTERPRETATION: High-risk DCD livers benefit more from HOPE-treatment, either immediately in the donor or after cold storage. Comparative prospective clinical studies are required to translate the results. FUNDING: Funding was provided by the Swiss National Science Foundation (grant no: 32003B-140776/1, 3200B-153012/1, 320030-189055/1, and 31IC30-166909) and supported by University Careggi (grant no 32003B-140776/1) and the OTT (grant No.: DRGT641/2019, cod.prog. 19CT03) and the Max Planck Society. Work in the A.G. laboratory was partially supported by the NIH R01NS112381 and R21NS125466 grants.","journal":"EBioMedicine","year":2023,"id":334131,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9309,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1062490,"name":"Mauricio Flores Carvalho","orcid":"0000-0001-6860-5733","position":1,"is_corresponding":false},{"id":1062491,"name":"Janina Eden","orcid":"0000-0002-8724-9313","position":2,"is_corresponding":false},{"id":1063092,"name":"Marilena Fazi","orcid":null,"position":3,"is_corresponding":false},{"id":712492,"name":"Fariha Ansari","orcid":null,"position":4,"is_corresponding":false},{"id":1063093,"name":"Leandro Mancina","orcid":null,"position":5,"is_corresponding":false},{"id":30737,"name":"Nadia Navari","orcid":"0000-0003-0371-7990","position":6,"is_corresponding":false},{"id":1062492,"name":"Richard X. Sousa Da Silva","orcid":"0000-0001-8970-7077","position":7,"is_corresponding":false},{"id":1062493,"name":"Daniele Dondossola","orcid":"0000-0002-4374-3184","position":8,"is_corresponding":false},{"id":1062494,"name":"Lucía Bautista Borrego","orcid":"0000-0001-7709-8024","position":9,"is_corresponding":false},{"id":1062495,"name":"Matthias Pietzke","orcid":"0000-0002-6901-8511","position":10,"is_corresponding":false},{"id":1062496,"name":"Adriano Peris","orcid":"0000-0002-9729-2331","position":11,"is_corresponding":false},{"id":240933,"name":"David Meierhofer","orcid":"0000-0002-0170-868X","position":12,"is_corresponding":false},{"id":240930,"name":"Paolo Muiesan","orcid":"0000-0002-7389-6691","position":13,"is_corresponding":false},{"id":240932,"name":"Alexander Galkin","orcid":"0000-0001-8469-2283","position":14,"is_corresponding":false},{"id":30749,"name":"Fabio Marra","orcid":"0000-0001-8629-0878","position":15,"is_corresponding":false},{"id":240934,"name":"Philipp Dutkowski","orcid":"0000-0002-3016-604X","position":16,"is_corresponding":false},{"id":240924,"name":"Andrea Schlegel","orcid":"0000-0002-9385-9847","position":17,"is_corresponding":false},{"id":1062489,"name":"Rebecca Panconesi","orcid":"0000-0003-2708-1261","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T01:09:48.843291Z","pmid":"37924707","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}