{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T05:46:16Z","timestamp":1768887976457,"version":"3.49.0"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007477","name":"Tekke Huizinga Fonds","doi-asserted-by":"publisher","award":["THF 2014-01-04"],"award-info":[{"award-number":["THF 2014-01-04"]}],"id":[{"id":"10.13039\/501100007477","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The process of brain death (BD) detrimentally affects donor lung quality.<jats:italic>Ex vivo<\/jats:italic>lung perfusion (EVLP) is a technique originally designed to evaluate marginal donor lungs. Nowadays, its potential as a treatment platform to repair damaged donor lungs is increasingly studied in experimental models. Rat models for EVLP have been described in literature before, yet the pathophysiology of BD was not included in these protocols and prolonged perfusion over 3 hours without anti-inflammatory additives was not achieved. We aimed to establish a model for prolonged EVLP of rat lungs from brain-dead donors, to provide a reliable platform for future experimental studies. Rat lungs were randomly assigned to one of four experimental groups (n = 7\/group): 1) healthy, directly procured lungs, 2) lungs procured from rats subjected to 3 hours of BD and 1 hour cold storage (CS), 3) healthy, directly procured lungs subjected to 6 hours EVLP and 4), lungs procured from rats subjected to 3 hours of BD, 1 hour CS and 6 hours EVLP. Lungs from brain-dead rats showed deteriorated ventilation parameters and augmented lung damage when compared to healthy controls, in accordance with the pathophysiology of BD. Subsequent<jats:italic>ex vivo<\/jats:italic>perfusion for 6 hours was achieved, both for lungs of healthy donor rats as for pre-injured donor lungs from brain-dead rats. The worsened quality of lungs from brain-dead donors was evident during EVLP as well, as corroborated by deteriorated ventilation performance, increased lactate production and augmented inflammatory status during EVLP. In conclusion, we established a stable model for prolonged EVLP of pre-injured lungs from brain-dead donor rats. In this report we describe tips and pitfalls in the establishment of the rat EVLP model, to enhance reproducibility by other researchers.<\/jats:p>","DOI":"10.1371\/journal.pone.0260705","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T19:30:36Z","timestamp":1638473436000},"page":"e0260705","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["A translational rat model for ex vivo lung perfusion of pre-injured lungs after brain death"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-2098","authenticated-orcid":true,"given":"Judith E.","family":"van Zanden","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henri G. D.","family":"Leuvenink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik A. M.","family":"Verschuuren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiel E.","family":"Erasmus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilia C.","family":"Hottenrott","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"pone.0260705.ref001","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1097\/01.TP.0000066351.87480.9E","article-title":"Pulmonary transplantation: The role of brain death in donor lung injury","volume":"75","author":"VS Avlonitis","year":"2003","journal-title":"Transplantation"},{"key":"pone.0260705.ref002","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1513\/pats.200808-098GO","article-title":"Lung Donor Selection and Management","volume":"6","author":"D Van Raemdonck","year":"2009","journal-title":"Proc Am Thorac Soc"},{"key":"pone.0260705.ref003","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1111\/tri.12470","article-title":"A decade of extended-criteria lung donors in a single center: Was it justified?","volume":"28","author":"J Somers","year":"2015","journal-title":"Transpl Int"},{"key":"pone.0260705.ref004","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jtcvs.2019.06.123","article-title":"Normothermic ex vivo lung perfusion: Does the indication impact organ utilization and patient outcomes after transplantation?","volume":"159","author":"M Cypel","year":"2020","journal-title":"J Thorac Cardiovasc Surg"},{"key":"pone.0260705.ref005","doi-asserted-by":"crossref","first-page":"S1871","DOI":"10.21037\/jtd.2018.04.119","article-title":"Ex vivo lung perfusion: A potential platform for molecular diagnosis and ex vivo organ repair","volume":"10","author":"M Hsin","year":"2018","journal-title":"J Thorac Dis"},{"key":"pone.0260705.ref006","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1258\/002367707781282848","article-title":"The gradual onset brain death model: a relevant model to study organ donation and its consequences on the outcome after transplantation","volume":"41","author":"JLP Kolkert","year":"2007","journal-title":"Lab Anim"},{"key":"pone.0260705.ref007","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1097\/00000658-200012000-00009","article-title":"Effects of brain death and hemodynamic status on function and immunologic activation of the potential donor liver in the rat","volume":"232","author":"JAB Van Der Hoeven","year":"2000","journal-title":"Ann Surg"},{"key":"pone.0260705.ref008","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1164\/ajrccm\/137.5.1159","article-title":"High Inflation Pressure Pulmonary Edema Respective Effects of High Airway Pressure, High Tidal Volume, and Positive End-expiratory Pressure1-3","volume":"137","author":"D Dreyfuss","year":"1988","journal-title":"Am Rev Respir Dis"},{"key":"pone.0260705.ref009","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"TD Schmittgen","year":"2008","journal-title":"Nat Protoc"},{"key":"pone.0260705.ref010","doi-asserted-by":"crossref","first-page":"R183","DOI":"10.1186\/cc9291","article-title":"Open lung approach associated with high-frequency oscillatory or low tidal volume mechanical ventilation improves respiratory function and minimizes lung injury in healthy and injured rats","volume":"14","author":"J Krebs","year":"2010","journal-title":"Crit Care"},{"key":"pone.0260705.ref011","doi-asserted-by":"crossref","first-page":"521369","DOI":"10.1155\/2013\/521369","article-title":"Inflammatory signalling associated with brain dead organ donation: from brain injury to brain stem death and posttransplant ischaemia reperfusion injury","volume":"2013","author":"RP Watts","year":"2013","journal-title":"J Transplant"},{"key":"pone.0260705.ref012","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/ctr.12680","article-title":"Ex vivo lung perfusion","volume":"30","author":"J Reeb","year":"2016","journal-title":"Clinical Transplantation"},{"key":"pone.0260705.ref013","doi-asserted-by":"crossref","first-page":"7","DOI":"10.5493\/wjem.v4.i2.7","article-title":"Animal models of ex vivo lung perfusion as a platform for transplantation research","volume":"4","author":"K Nelson","year":"2014","journal-title":"World J Exp Med"},{"key":"pone.0260705.ref014","first-page":"54","article-title":"Successful Prolonged Ex Vivo Lung Perfusion for Graft Preservation in Rats","volume":"45","author":"K Noda","year":"2014"},{"key":"pone.0260705.ref015","doi-asserted-by":"crossref","first-page":"e0167898","DOI":"10.1371\/journal.pone.0167898","article-title":"Ex vivo lung perfusion in the rat: Detailed procedure and videos","volume":"11","author":"GA Bassani","year":"2016","journal-title":"PLoS One"},{"key":"pone.0260705.ref016","first-page":"49","article-title":"Catecholamines reduce dose-dependent oedema formation and inflammatory reaction in an isolated rat lung model\u2014PubMed","volume":"27","author":"C Dacho","year":"2013","journal-title":"In Vivo"},{"key":"pone.0260705.ref017","doi-asserted-by":"crossref","first-page":"e532","DOI":"10.1097\/TXD.0000000000000968","article-title":"Donor Leukocyte Trafficking and Damage-associated Molecular Pattern Expression during Ex Vivo Lung Perfusion","volume":"6","author":"RP Davis","year":"2020","journal-title":"Transplant Direct"},{"key":"pone.0260705.ref018","doi-asserted-by":"crossref","first-page":"e0173916","DOI":"10.1371\/journal.pone.0173916","article-title":"Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia","volume":"12","author":"C Francioli","year":"2017","journal-title":"PLoS One"},{"key":"pone.0260705.ref019","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1159\/000050513","article-title":"Addition of ATP and MgCl2 to the preservation solution attenuates lung reperfusion injury following cold ischemia","volume":"68","author":"T Hirata","year":"2001","journal-title":"Respiration"},{"key":"pone.0260705.ref020","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s11748-018-1038-3","article-title":"Long agonal period deteriorates cardiac death donor lung function in a rat EVLP model","volume":"67","author":"K Hijiya","year":"2019","journal-title":"Gen Thorac Cardiovasc Surg"},{"key":"pone.0260705.ref021","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.healun.2008.05.019","article-title":"Pre-arrest Administration of the Cell-permeable Free Radical Scavenger Tempol Reduces Warm Ischemic Damage of Lung Function in Non-Heart-beating Donors.","volume":"27","author":"D Hodyc","year":"2008","journal-title":"J Hear Lung Transplant"},{"key":"pone.0260705.ref022","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.athoracsur.2006.05.004","article-title":"Ex-Vivo Perfusion and Ventilation of Rat Lungs From Non-Heart-Beating Donors Before Transplant","volume":"82","author":"H Inokawa","year":"2006","journal-title":"Ann Thorac Surg"},{"key":"pone.0260705.ref023","first-page":"1071","article-title":"Alterations of nitric oxide synthase expression and activity during rat lung transplantation","volume":"278","author":"M Liu","year":"2000","journal-title":"Am J Physiol"},{"key":"pone.0260705.ref024","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1016\/j.jtcvs.2014.04.037","article-title":"Lung injury after simulated cardiopulmonary bypass in an isolated perfused rat lung preparation: Role of mitogen-activated protein kinase\/Akt signaling and the effects of theophylline","volume":"148","author":"T Markou","year":"2014","journal-title":"J Thorac Cardiovasc Surg"},{"key":"pone.0260705.ref025","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.healun.2013.02.007","article-title":"Protective effect of plasmin in marginal donor lungs in an ex vivo lung perfusion model","volume":"32","author":"H Motoyama","year":"2013","journal-title":"J Hear Lung Transplant"},{"key":"pone.0260705.ref026","first-page":"52309","article-title":"Method of isolated ex vivo lung perfusion in a rat model: Lessons learned from developing a rat EVLP program.","author":"K Nelson","year":"2015","journal-title":"J Vis Exp"},{"key":"pone.0260705.ref027","doi-asserted-by":"crossref","first-page":"L61","DOI":"10.1152\/ajplung.00256.2019","article-title":"A method for translational rat ex vivo lung perfusion experimentation","volume":"319","author":"A Ohsumi","year":"2020","journal-title":"Am J Physiol\u2014Lung Cell Mol Physiol"},{"key":"pone.0260705.ref028","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.transproceed.2010.01.016","article-title":"Experimental Model of Isolated Lung Perfusion in Rats: First Brazilian Experience Using the IL-2 Isolated Perfused Rat or Guinea Pig Lung System","volume":"42","author":"PM P\u00eago-Fernandes","year":"2010","journal-title":"Transplant Proc"},{"key":"pone.0260705.ref029","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.3390\/molecules23123061","article-title":"Proteome investigation of rat lungs subjected to Ex vivo perfusion (EVLP).","volume":"23","author":"V Roffia","year":"2018","journal-title":"Molecules"},{"key":"pone.0260705.ref030","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.jacc.2003.08.059","article-title":"The impact of mode of donor brain death on cardiac allograft vasculopathy: an intravascular ultrasound study","volume":"43","author":"MR Mehra","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"pone.0260705.ref031","doi-asserted-by":"crossref","first-page":"e0242827","DOI":"10.1371\/journal.pone.0242827","article-title":"Rat donor lung quality deteriorates more after fast than slow brain death induction","volume":"15","author":"JE van Zanden","year":"2020","journal-title":"PLoS One"},{"key":"pone.0260705.ref032","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1097\/00007890-199806270-00001","article-title":"Effects of explosive brain death on cytokine activation of peripheral organs in the rat","volume":"65","author":"M Takada","year":"1998","journal-title":"Transplantation"},{"key":"pone.0260705.ref033","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1111\/j.1600-6143.2005.00755.x","article-title":"The hemodynamic mechanisms of lung injury and systemic inflammatory response following brain death in the transplant donor","volume":"5","author":"VS Avlonitis","year":"2005","journal-title":"Am J Transplant"},{"key":"pone.0260705.ref034","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.healun.2012.08.016","article-title":"Physiologic assessment of the ex vivo donor lung for transplantation","volume":"31","author":"JC Yeung","year":"2012","journal-title":"J Hear Lung Transplant"},{"key":"pone.0260705.ref035","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1097\/00007890-198801000-00008","article-title":"Change from aerobic to anaerobic metabolism after brain death, and reversal following triiodothyronine therapy","volume":"45","author":"D Novitzky","year":"1988","journal-title":"Transplantation"},{"key":"pone.0260705.ref036","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1111\/ajt.14717","article-title":"Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant","volume":"18","author":"Q Cheng","year":"2018","journal-title":"Am J Transplant"},{"key":"pone.0260705.ref037","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1007\/s00134-019-05568-3","article-title":"Ex vivo perfusion techniques: state of the art and potential applications.","volume":"45","author":"M Cypel","year":"2019","journal-title":"Intensive Care Medicine"},{"key":"pone.0260705.ref038","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.healun.2008.09.003","article-title":"Technique for Prolonged Normothermic Ex Vivo Lung Perfusion.","volume":"27","author":"M Cypel","year":"2008","journal-title":"J Hear Lung Transplant"},{"key":"pone.0260705.ref039","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1111\/j.1600-6143.2009.02775.x","article-title":"Normothermic Ex Vivo perfusion prevents lung injury compared to extended cold preservation for transplantation","volume":"9","author":"M Cypel","year":"2009","journal-title":"Am J Transplant"},{"key":"pone.0260705.ref040","unstructured":"XVIVO | STEEN SolutionTM\u2014XVIVO, https:\/\/www.xvivoperfusion.com\/products\/steen-solution\/ (accessed 24 July 2021)."},{"key":"pone.0260705.ref041","doi-asserted-by":"crossref","first-page":"14","DOI":"10.4266\/acc.2019.00430","article-title":"Medical management of brain-dead organ donors","volume":"34","author":"ASM Tanim Anwar","year":"2019","journal-title":"Acute Crit Care"},{"key":"pone.0260705.ref042","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1111\/tri.12113","article-title":"Flush at room temperature followed by storage on ice creates the best lung graft preservation in rats","volume":"26","author":"AJ Munneke","year":"2013","journal-title":"Transpl Int"},{"key":"pone.0260705.ref043","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1111\/tri.12295","article-title":"Ex vivo lung perfusion to improve donor lung function and increase the number of organs available for transplantation","volume":"27","author":"F Valenza","year":"2014","journal-title":"Transpl Int"},{"key":"pone.0260705.ref044","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13054-017-1645-x","article-title":"Anti-inflammatory properties of anesthetic agents","volume":"21","author":"FF Cruz","year":"2017","journal-title":"Critical Care"},{"key":"pone.0260705.ref045","first-page":"47","article-title":"The anti-inflammatory effects of ketamine: state of the art","volume":"62","author":"S Loix","year":"2011","journal-title":"Acta Anaesthesiol Belg"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260705","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T23:56:31Z","timestamp":1673913391000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0260705"}},"subtitle":[],"editor":[{"given":"Frank JMF","family":"Dor","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0260705","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,2]]}}}