{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:19:36Z","timestamp":1783084776993,"version":"3.54.6"},"reference-count":32,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 \u00b0C 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 &lt; 0.001), pulmonary vascular resistance (PVR) lower and dynamic compliance (Cdyn) higher when compared to the 37 \u00b0C EVLP. During an end-of-EVLP stress test, we recorded significantly higher flow (p &lt; 0.05), lower PVR (p &lt; 0.05) and higher Cdyn (p &lt; 0.01) in the 28 \u00b0C group when compared to the 37 \u00b0C group. After the left lung transplantation, Cdyn and oxygenation improved in the 28 \u00b0C group, which were comparable to the 37 \u00b0C group. Chemokines RANTES, MIP-3\u03b1, MIP-1\u03b1 MCP-1 GRO\/KC and pro-inflammatory mediators GM-CSF, G-CSF and TNF\u03b1 were significantly lower after the 28 \u00b0C EVLP and remained low in the plasma of the recipient rats after transplantation. The lungs of the 28 \u00b0C group showed significantly lowered myeloperoxidase activity and lowered levels of TNF\u03b1 and IL-1\u03b2. Conclusions: Compared to the normothermic perfusion, the 28 \u00b0C 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 \u00b0C EVLP significantly improved biochemical, physiological and inflammatory parameters in lung donors.<\/jats:p>","DOI":"10.3390\/cells10040748","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T04:29:14Z","timestamp":1616992154000},"page":"748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Subnormothermic Ex Vivo Lung Perfusion Temperature Improves Graft Preservation in Lung Transplantation"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5497-8256","authenticated-orcid":false,"given":"Stephan","family":"Arni","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Zurich, R\u00e4mistrasse 100, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3632-4328","authenticated-orcid":false,"given":"Tatsuo","family":"Maeyashiki","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Zurich, R\u00e4mistrasse 100, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4122-9197","authenticated-orcid":false,"given":"Necati","family":"Citak","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Zurich, R\u00e4mistrasse 100, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5900-9040","authenticated-orcid":false,"given":"Isabelle","family":"Opitz","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Zurich, R\u00e4mistrasse 100, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3937-7705","authenticated-orcid":false,"given":"Ilhan","family":"Inci","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Zurich, R\u00e4mistrasse 100, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.athoracsur.2005.08.015","article-title":"Ex vivo evaluation of nonacceptable donor lungs","volume":"81","author":"Wierup","year":"2006","journal-title":"Ann. Thorac. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/aps.2017.182","article-title":"Organ preservation: From the past to the future","volume":"39","author":"Jing","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1093\/ejcts\/ezt598","article-title":"Successful prolonged ex vivo lung perfusion for graft preservation in rats","volume":"45","author":"Noda","year":"2014","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/ajt.15695","article-title":"Treatment with 3-aminobenzamide during ex vivo lung perfusion of damaged rat lungs reduces graft injury and dysfunction after transplantation","volume":"20","author":"Wang","year":"2020","journal-title":"Am. J. Transpl."},{"key":"ref_5","unstructured":"Council, N.R. (2011). Guide for the Care and Use of Laboratory Animals: Eighth Edition, The National Academies Press."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Nelson, K., Bobba, C., Eren, E., Spata, T., Tadres, M., Hayes, D., Black, S.M., Ghadiali, S., and Whitson, B.A. (2015). Method of isolated ex vivo lung perfusion in a rat model: Lessons learned from developing a rat EVLP program. J. Vis. Exp.","DOI":"10.3791\/52309"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e109","DOI":"10.1016\/j.jtcvs.2019.12.128","article-title":"Perfusate adsorption during ex vivo lung perfusion improves early post-transplant lung function","volume":"161","author":"Iskender","year":"2021","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/ajt.12991","article-title":"Liver preservation with machine perfusion and a newly developed cell-free oxygen carrier solution under subnormothermic conditions","volume":"15","author":"Fontes","year":"2015","journal-title":"Am. J. Transpl."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/s41587-019-0374-x","article-title":"An integrated perfusion machine preserves injured human livers for 1 week","volume":"38","author":"Eshmuminov","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1016\/j.transproceed.2018.03.055","article-title":"Optimum perfusate volume of purified subnormothermic machine perfusion for porcine liver donated after cardiac death","volume":"50","author":"Obara","year":"2018","journal-title":"Transpl. Proc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1016\/j.transproceed.2007.06.002","article-title":"Subnormothermic machine perfusion protects against rat liver preservation injury: A comparative evaluation with conventional cold storage","volume":"39","author":"Vairetti","year":"2007","journal-title":"Transpl. Proc."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Knaak, J.M., Spetzler, V.N., Goldaracena, N., Louis, K.S., Selzner, N., and Selzner, M. (2014). Technique of subnormothermic ex vivo liver perfusion for the storage, assessment, and repair of marginal liver grafts. J. Vis. Exp., e51419.","DOI":"10.3791\/51419-v"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1097\/TP.0000000000002967","article-title":"Renal protection against ischemia reperfusion injury: Hemoglobin-based oxygen carrier-201 versus blood as an oxygen carrier in Ex Vivo subnormothermic machine perfusion","volume":"104","author":"Bhattacharjee","year":"2020","journal-title":"Transplantation"},{"key":"ref_14","first-page":"181","article-title":"The patho-physiological basis for tests of viability in isolated perfused organs","volume":"30","author":"Ward","year":"1979","journal-title":"Biomedicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"32436","DOI":"10.1074\/jbc.272.51.32436","article-title":"A primary role for K+ and Na+ efflux in the activation of apoptosis","volume":"272","author":"Bortner","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.healun.2011.07.014","article-title":"Kinetics of lactate metabolism during acellular normothermic ex vivo lung perfusion","volume":"30","author":"Koike","year":"2011","journal-title":"J. Heart Lung Transpl."},{"key":"ref_17","first-page":"208","article-title":"Prognostic value of serum lactate levels in patients undergoing urgent heart transplant: A subanalysis of the ASIS-TC Spanish multicenter study","volume":"72","year":"2019","journal-title":"Rev. Esp. Cardiol. (Engl. Ed.)"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.cmet.2015.12.009","article-title":"A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury","volume":"23","author":"Chouchani","year":"2016","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1097\/00007890-200202270-00001","article-title":"The role of mitochondria in ischemia\/reperfusion injury","volume":"73","author":"Jassem","year":"2002","journal-title":"Transplantation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1515\/BC.2002.050","article-title":"Mammalian cell injury induced by hypothermia- the emerging role for reactive oxygen species","volume":"383","author":"Rauen","year":"2002","journal-title":"Biol. Chem."},{"key":"ref_21","first-page":"944","article-title":"Role of oxygen during hypothermic machine perfusion preservation of the liver","volume":"23","author":"Luer","year":"2010","journal-title":"Transpl. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1097\/SLA.0000000000003513","article-title":"Novel real-time prediction of liver graft function during hypothermic oxygenated machine perfusion before liver transplantation","volume":"270","author":"Muller","year":"2019","journal-title":"Ann. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1097\/TP.0000000000000254","article-title":"Hydrogen preconditioning during ex vivo lung perfusion improves the quality of lung grafts in rats","volume":"98","author":"Noda","year":"2014","journal-title":"Transplantation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S1471-4914(03)00031-5","article-title":"Protein carbonylation in human diseases","volume":"9","author":"Giustarini","year":"2003","journal-title":"Trends Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1582-4934.2006.tb00407.x","article-title":"Protein carbonylation, cellular dysfunction, and disease progression","volume":"10","author":"Aldini","year":"2006","journal-title":"J. Cell Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1196\/annals.1341.022","article-title":"Mitochondria and ischemia\/reperfusion injury","volume":"1047","author":"Honda","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1097\/SLA.0000000000000974","article-title":"Protein expression profiling predicts graft performance in clinical ex vivo lung perfusion","volume":"261","author":"Machuca","year":"2015","journal-title":"Ann. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1600-6143.2008.02497.x","article-title":"Plasma cytokines and chemokines in primary graft dysfunction post-lung transplantation","volume":"9","author":"Hoffman","year":"2009","journal-title":"Am. J. Transpl."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1016\/j.athoracsur.2012.02.041","article-title":"Preoperative recipient cytokine levels are associated with early lung allograft dysfunction","volume":"93","author":"Allen","year":"2012","journal-title":"Ann. Thorac. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gloria, J.N., Yerxa, J., Kesseli, S.J., Davis, R.P., Samoylova, M.L., Barbas, A.S., Hartwig, M.G., Duke Ex Vivo Organ, L., Zhang, M., and Parker, W. (2021). Subnormothermic exvivo lung perfusion attenuates graft inflammation in a rat transplant model. J. Thorac. Cardiovasc. Surg.","DOI":"10.1016\/j.jtcvs.2021.01.066"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/j.healun.2010.06.017","article-title":"Prevention of primary graft dysfunction in lung transplantation by N-acetylcysteine after prolonged cold ischemia","volume":"29","author":"Inci","year":"2010","journal-title":"J. Heart Lung Transpl."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1097\/TP.0000000000001798","article-title":"Targeting circulating leukocytes and pyroptosis during Ex Vivo lung perfusion improves lung preservation","volume":"101","author":"Noda","year":"2017","journal-title":"Transplantation"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/748\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:33:04Z","timestamp":1760362384000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":32,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["cells10040748"],"URL":"https:\/\/doi.org\/10.3390\/cells10040748","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]}}}