{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:05:40Z","timestamp":1789567540255,"version":"build-2803163510"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ischemia\/reperfusion injury (IRI) still represents a major determinant of both early and late complications of lung transplantation. Increasing evidence indicates that ischemia-induced molecular damage and energetic impairment are established before ex vivo lung perfusion (EVLP) and continue to progress over perfusion. Thyroid hormones support mitochondrial metabolism and cellular energetics and show multiple protective effects in different models of lung injury. We investigated, for the first time, the potential effects of 3,3\u2032,5-triiodothyronine (T3) supplementation during experimental EVLP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      An established rat model of EVLP was used. After procurement, lungs were either immediately perfused for 3\u202fh (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f10) or exposed to 2\u202fh of ischemia (1\u202fh-warm + 1\u202fh-cold), followed by 3\u202fh of EVLP (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f10). In each condition, T3 (EVLP\u202f+\u202fT3 and Ischemia\u202f+\u202fEVLP\u202f+\u202fT3,\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f5 each) or an equal volume of saline (EVLP and Ischemia\u202f+\u202fEVLP,\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f5 each) were directly added to the perfusion fluid. Lung hemodynamics and airway pressure were monitored throughout the procedure. Perfusate samples were collected at time intervals to assess gas pressures, electrolyte balance, biomarkers of cell damage, and mitochondrial DNA (mtDNA) release. Biopsies were taken at the end of EVLP for cellular energetics evaluation and selected gene expression profiling. Samples collected from rats in resting conditions were used as reference (Native,\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f5).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>T3 supplementation was associated with reduced pulmonary artery pressure and vascular resistance in uninjured lungs, while ischemic lungs showed improved CO\u2082 clearance. However, at the molecular level, T3-treated lungs showed no significant advantage compared to the corresponding control groups. Indeed, T3 administration was associated with an increased mtDNA release into the perfusate and induction of pro-apoptotic signaling. Moreover, T3 failed to restore the ATP depletion induced by ischemia and did not improve cell energy charge. Gene expression analysis showed only modest transcriptional modulation of stress and inflammatory pathways, without evidence of a protective molecular signature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Despite promising results in several lung injury models, our evidence indicates that T3 administration during EVLP does not exert protective effects but could rather exacerbate mitochondrial stress in lungs exposed to ischemia. These results suggest caution when considering T3-based interventions for organ reconditioning during EVLP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1924438","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:31:44Z","timestamp":1789018304000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of 3,3\u2032,5-triiodothyronine supplementation during ex vivo lung perfusion on ischemia\/reperfusion injury in rat lungs"],"prefix":"10.3389","volume":"13","author":[{"given":"Ilaria","family":"Righi","sequence":"first","affiliation":[{"name":"Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Lonati","sequence":"additional","affiliation":[{"name":"Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]},{"name":"Renal Research Laboratory, Unit of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Battistin","sequence":"additional","affiliation":[{"name":"Center for Preclinical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Damarco","sequence":"additional","affiliation":[{"name":"Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Vivona","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia and Intensive Care, IRCCS MultiMedica San Giuseppe Hospital","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Bonetti","sequence":"additional","affiliation":[{"name":"Emergency and Intensive Care Department, ASST Papa Giovanni XXIII","place":["Bergamo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Pinti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences","place":["Modena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Selleri","sequence":"additional","affiliation":[{"name":"Department of Life Sciences","place":["Modena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fugazzola","sequence":"additional","affiliation":[{"name":"Department of Health Science, University of Milan","place":["Milan, Italy"]},{"name":"Department of Endocrinology, ASST Santi Paolo e Carlo","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Campi","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Lombardi","sequence":"additional","affiliation":[{"name":"Precision Medicine and Biological Resource Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Cherubini","sequence":"additional","affiliation":[{"name":"Precision Medicine and Biological Resource Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Nosotti","sequence":"additional","affiliation":[{"name":"Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]},{"name":"Department of Pathophysiology and Transplantation, University of Milan","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Rosso","sequence":"additional","affiliation":[{"name":"Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico","place":["Milan, Italy"]},{"name":"Department of Pathophysiology and Transplantation, University of Milan","place":["Milan, 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