{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:11:02Z","timestamp":1789495862326,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"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>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 \u00b0C or 37 \u00b0C perfusion temperatures. During EVLP at 28 \u00b0C 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 \u00b0C EVLP with PFCOC. In the subnormothermic EVLP with or without PFCOC, the pro-inflammatory mediator TNF\u03b1, the cytokines IL-6 and IL-7, the chemokines MIP-3\u03b1, MIP-1\u03b1, 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 \u00b0C EVLP improved both Cdyn and PVR and decreased pro-inflammatory cytokines and pCO2 levels compared to the 37 \u00b0C EVLP. In addition, the 28 \u00b0C 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.<\/jats:p>","DOI":"10.3390\/cells10092249","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T11:01:37Z","timestamp":1630321297000},"page":"2249","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Perfluorocarbon-Based Oxygen Carriers and Subnormothermic Lung Machine Perfusion Decrease Production of Pro-Inflammatory Mediators"],"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 Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4122-9197","authenticated-orcid":false,"given":"Citak","family":"Necati","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Hospital Z\u00fcrich, 8091 Z\u00fcrich, 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 Z\u00fcrich, 8091 Z\u00fcrich, 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 Z\u00fcrich, 8091 Z\u00fcrich, 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 Z\u00fcrich, 8091 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1055\/s-0037-1615797","article-title":"Primary Graft Dysfunction (PGD) Following Lung Transplantation","volume":"39","author":"Shah","year":"2018","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_2","first-page":"1","article-title":"Developments in lung transplantation over the past decade","volume":"29","author":"Hoek","year":"2020","journal-title":"Eur. Respir. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1067\/mtc.2002.120345","article-title":"Marginal donor lungs: A reassessment","volume":"123","author":"Pierre","year":"2002","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S910","DOI":"10.21037\/jtd.2018.02.85","article-title":"Machine perfusion of thoracic organs","volume":"10","author":"Rega","year":"2018","journal-title":"J. Thorac. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1111\/ajt.15123","article-title":"Ex vivo perfusion induces a time- and perfusate-dependent molecular repair response in explanted porcine lungs","volume":"19","author":"Dromparis","year":"2019","journal-title":"Am. J. Transplant."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1111\/j.1600-6143.2007.01779.x","article-title":"Organ donation and utilization in the United States, 1996\u20132005","volume":"7","author":"Punch","year":"2007","journal-title":"Am. J. Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103014","DOI":"10.1016\/j.ebiom.2020.103014","article-title":"Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation","volume":"60","author":"Schlegel","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.12659\/AOT.905406","article-title":"Strategies to restore adenosine triphosphate (ATP) level after more than 20 hours of cold ischemia time in human marginal kidney grafts","volume":"23","author":"Ravaioli","year":"2018","journal-title":"Ann. Transplant."},{"key":"ref_9","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. Transplant."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s40472-018-0183-z","article-title":"Hypothermic Machine Preservation of the Liver: State of the Art","volume":"5","author":"Schlegel","year":"2018","journal-title":"Curr. Transplant. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1097\/01.CCM.0000178186.37167.53","article-title":"Induced hypothermia as a new approach to lung rest for the acutely injured lung","volume":"33","author":"Hong","year":"2005","journal-title":"Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1097\/TP.0b013e31822d8778","article-title":"Hypothermic machine perfusion ameliorates ischemia-reperfusion injury in rat lungs from non-heart-beating donors","volume":"92","author":"Nakajima","year":"2011","journal-title":"Transplantation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6063","DOI":"10.1038\/s41598-020-62979-9","article-title":"Hypothermic oxygenated new machine perfusion system in liver and kidney transplantation of extended criteria donors:first italian clinical trial","volume":"10","author":"Ravaioli","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.jss.2014.01.045","article-title":"Effect of cold perfusion and perfluorocarbons on liver graft ischemia in a donation after cardiac death model","volume":"188","author":"Bezinover","year":"2014","journal-title":"J. Surg. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13054-018-1949-5","article-title":"Artificial oxygen carriers: A new future?","volume":"22","author":"Spahn","year":"2018","journal-title":"Crit. Care"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Riess, J.G., and Krafft, M.P. (2006). Fluorocarbon emulsions as in vivo oxygen delivery systems: Background and Chemistry. Blood Substitutes, Academic Press.","DOI":"10.1016\/B978-012759760-7\/50033-0"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"102407","DOI":"10.1016\/j.cis.2021.102407","article-title":"Therapeutic oxygen delivery by perfluorocarbon-based colloids","volume":"294","author":"Krafft","year":"2021","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1111\/j.1525-1594.2009.00944.x","article-title":"Perfluorocarbon-based oxygen carriers: Review of products and trials","volume":"34","author":"Castro","year":"2010","journal-title":"Artif. Organs"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1007\/s10753-013-9678-z","article-title":"Systemic administration of FC-77 dampens ischemia-reperfusion-induced acute lung injury in rats","volume":"36","author":"Chu","year":"2013","journal-title":"Inflammation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1097\/00003246-200002000-00032","article-title":"Partial liquid ventilation decreases serum tumor necrosis factor-alpha concentrations in a rat acid aspiration lung injury model","volume":"28","author":"Kawamae","year":"2000","journal-title":"Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Inci, I., Arni, S., Iskender, I., Citak, N., Rodriguez, J.M., Weisskopf, M., Opitz, I., Weder, W., Frauenfelder, T., and Krafft, M.P. (2020). Functional, metabolic and morphologic results of ex vivo donor lung perfusion with a perfluorocarbon-based oxygen carrier nanoemulsion in a large animal transplantation model. Cells, 9.","DOI":"10.3390\/cells9112501"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1097\/00003246-200004000-00034","article-title":"Perfluorocarbon blocks tumor necrosis factor-alpha-induced interleukin-8 release from alveolar epithelial cells in vitro","volume":"28","author":"Baba","year":"2000","journal-title":"Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1007\/s00134-005-2652-y","article-title":"Inhibition of inflammatory responses by FC-77, a perfluorochemical, in lipopolysaccharide-treated RAW 264.7 macrophages","volume":"31","author":"Chang","year":"2005","journal-title":"Intensive Care Med."},{"key":"ref_25","unstructured":"Council, N.R. (2011). Guide for the Care and Use of Laboratory Animals: Eighth Edition, The National Academies Press."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/nbm.3059","article-title":"Probing different perfluorocarbons for in vivo inflammation imaging by 19F MRI: Image reconstruction, biological half-lives and sensitivity","volume":"27","author":"Jacoby","year":"2014","journal-title":"NMR Biomed."},{"key":"ref_27","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_28","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":"Transplant. Proc."},{"key":"ref_29","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":"Transplant. Proc."},{"key":"ref_30","first-page":"e51419","article-title":"Technique of subnormothermic ex vivo liver perfusion for the storage, assessment, and repair of marginal liver grafts","volume":"90","author":"Knaak","year":"2014","journal-title":"J. Vis. Exp."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5982","DOI":"10.1039\/C5SM00926J","article-title":"Overcoming inactivation of the lung surfactant by serum proteins: A potential role for fluorocarbons?","volume":"11","author":"Krafft","year":"2015","journal-title":"Soft Matter"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00424-020-02482-2","article-title":"Perfluorocarbon-based oxygen carriers: From physics to physiology","volume":"473","author":"Jagers","year":"2021","journal-title":"Pflug. Arch."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Autilio, C., Echaide, M., De Luca, D., and Perez-Gil, J. (2018). Controlled hypothermia may improve surfactant function in asphyxiated neonates with or without meconium aspiration syndrome. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192295"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1073\/pnas.1008823108","article-title":"Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate","volume":"108","author":"Bouma","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1242\/jeb.052704","article-title":"Reversible remodeling of lung tissue during hibernation in the Syrian hamster","volume":"214","author":"Talaei","year":"2011","journal-title":"J. Exp. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/icb\/icu047","article-title":"Organ protective mechanisms common to extremes of physiology: A window through hibernation biology","volume":"54","author":"Quinones","year":"2014","journal-title":"Integr. Comp. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/j.bbamem.2013.03.005","article-title":"Adaptations to hibernation in lung surfactant composition of 13-lined ground squirrels influence surfactant lipid phase segregation properties","volume":"1828","author":"Suri","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","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_39","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_40","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 Transplant."},{"key":"ref_41","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_42","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_43","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., Zhang, M., Parker, W., and Zhu, M. (2021). Subnormothermic ex vivo lung perfusion attenuates graft inflammation in a rat transplant model. J. Thorac. Cardiovasc. Surg., In Press.","DOI":"10.1016\/j.jtcvs.2021.01.066"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Arni, S., Maeyashiki, T., Citak, N., Opitz, I., and Inci, I. (2021). subnormothermic ex vivo lung perfusion temperature improves graft preservation in lung transplantation. Cells, 10.","DOI":"10.3390\/cells10040748"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Arni, S., Maeyashiki, T., Opitz, I., and Inci, I. (2021). Subnormothermic ex vivo lung perfusion attenuates ischemia reperfusion injury from donation after circulatory death donors. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0255155"},{"key":"ref_46","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\/9\/2249\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:55:40Z","timestamp":1760165740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2249"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,30]]},"references-count":46,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cells10092249"],"URL":"https:\/\/doi.org\/10.3390\/cells10092249","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,30]]}}}