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Lung transplantation-induced cold ischemia–reperfusion injury in the murine lung

ABSTRACT: Cold ischemia-reperfusion induced injury contributes to poor lung transplant outcomes. We used transcriptome sequencing to study the biological response of mouse lungs to the cold ischemia-reperfusion process. Mouse orthotopic left LTx was performed with standard cuff techniques. Briefly, the donor lungs were recovered after being flushed with 10ml low potassium dextran (LPD) solution and inflated with 50% oxygen. Cold ischemia was induced by storing donor lungs in 20ml LPD at 4°C for 24 hours. Then, the left donor lung was cuffed and implanted into recipients within 45 minutes. After the 4-hour reperfusion, the recipient mice were sacrificed and the transplanted lungs were collected.

ORGANISM(S): Mus musculus

PROVIDER: GSE222957 | GEO | 2023/01/20

REPOSITORIES: GEO

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Macrophage infiltration induced by donor hypovolemia protects against severe primary graft dysfunction in mouse lung transplantation

Project description:BACKGROUND: Hypovolemia is common in lung donors before or after brain death. However, its impact on primary graft function (PGD) remains obscure. METHODS: A clinically relevant two-hit model of PGD was established by integrating hypovolemic shock (HS) and cold ischemia-reperfusion in a mouse model of orthotopic lung transplantation (LTx) from C57BL/6 to Balb/c. At -48 hours, HS was induced to donor by withdrawal of blood from femoral artery and keeping the mean arterial pressure at 15±5 mmHg for 4 h. At -24 hours, donor lungs were retrieved from mice with or without HS and stored at 0ºC until transplantation. CD11b-DTR mice were used as donor and treated with Diphtheria Toxin (DT) to deplete graft-infiltrating macrophages. RESULTS: HS mainly caused macrophage-predominant infiltration around pulmonary artery injury systemic inflammatory response, but little impairment of lung function even if in combination with cold ischemia-reperfusion. Transcriptional profiling showed HS pretreatment increased pulmonary damage and alveolar remodeling but ameliorated inflammatory infiltration when compared to one-hit model of 12 hours cold ischemia-reperfusion injury. The allografts with donor DT-treatment one day ahead of HS showed injury and dysfunction at donation and worsened further at 24 hours reperfusion, whereas the allografts with recipient DT-treatment immediately after transplantation showed similar function and histology to the control treated with saline. CONCLUSION: Donor hypovolemia causes pulmonary artery injury and infiltration but has little impact on allograft function, even in combination with 24 h cold ischemia. Graft-infiltrating macrophages are critical in protecting graft from HS-induced injury and cold ischemia-reperfusion injury.

2022-03-30 | GSE156322 | GEO

Expression of Human Lung Before and After Ex Vivo Lung Perfusion

Project description:Ex vivo lung perfusion restores normothermia, ventilation and circulation to donor lungs, typically after a period of cold ischemia. This allows donor lungs to be evaluated prior to transplantation. We used microarrays to study the biological response of human lungs to Ex Vivo Lung Perfusion. Samples were collected from donor lungs at Toronto General Hospital. Lungs were donation after brain death (DBD)

2020-06-22 | GSE127055 | GEO

Cardiac-dead mouse lungs may remain transplantable at 37ºC for 4 hours if gas exchange is preserved

Project description:Despite a potentially huge number, uncontrolled donation after circulatory death contributed little to alleviating donor lung shortage due to rapidly progressive warm ischemia. Many methods have been studied in animals, but the tolerable warm ischemic time (WIT) remains less than 90 minutes. Using a refined mouse model of pulmonary artery ligation (PAL), we firstly determined the maximum tolerable WIT. 4-hour PAL caused mild lung infiltration without dysfunction upon reperfusion, whereas 5-hour PAL triggered arterial endothelium injury and more significant infiltration with dysfunction. Transcriptional profiling showed a myeloid-dominant inflammation with mild injury in 4-hour PAL. The maximum WIT was then adapted in a clinically relevant scenario. Donor mice died of circulatory arrest without heparization and remained at 37ºC for 4 hours, followed by isogenic transplantation. As observed in 4-hour PAL, nonhypoxic warm ischemia-reperfusion hardly affected graft function and histology, no matter if warm ischemic lung preserved gas exchange by spontaneously breathing or by postmortem protective ventilation. If the dead donors were left untouched, however, the grafted lungs suffered severe hypoxic warm ischemia-reperfusion injury, varying from partially aerated totally lost. Taken together, the retrieval time can be extended to 4 hours at 37ºC by preventing cardiac-dead donor lung hypoxia.

2022-03-30 | GSE154939 | GEO

Expression of Human Lung Biopsies Before and at 6 hours of EVLP

Project description:Ex vivo lung perfusion restores normothermia, ventilation and circulation to donor lungs, typically after a period of cold ischemia. This allows donor lungs to be evaluated prior to transplantation. We used microarrays to study the biological response of human lungs to Ex Vivo Lung Perfusion. These are a subset of samples previously described in the paper: Yeung, Jonathan C., et al. Towards donor lung recovery—gene expression changes during ex vivo lung perfusion of human lungs. American Journal of Transplantation 18.6 (2018): 1518-1526.

2023-09-18 | GSE127057 | GEO

Reversible and irreversible PAH in a rat model for MCT+Shunt-induced PAH and hemodynamic unloading.

Project description:PAH was induced by 60mg/kg MCT and an aorto-caval shunt. At different timepoints of PAH progression (day 14, 21 and 28 after MCT-injection), the left lung with PAH was hemodynamically unloading by unilateral orthotopic transplatation into a syngeneic, healthy recipient. All day 14 and 7/10 day 21 transplanted lungs showed reversal of PAH after LTx. All day 28 and 3/10 day 21 transplanted lungs showed PAH progression after LTx. Lung tissue of Reversible and Irreversible PAH and normal controls, acquired at LTx, was compared using RNA-seq.

2020-07-01 | GSE149899 | GEO

Day2015 - Early cellular innate and adaptive immune responses to ischemia/reperfusion injury and solid organ allotransplantation

Project description:This is an ordinary differential equation model of the early inflammatory response during transplantion. Descriptions are included of the inflammatory events associated with the initial surgical procedure, the subsequent ischemia/reperfusion (I/R) events that cause tissue damage to the host as well as the donor graft, and the inflammatory effects of T cells.

2019-11-19 | MODEL1911190001 | BioModels

Expression data from donor lungs of cardiac death and brain death donors (re-analysis)

Project description:Ischemia reperfusion induced injury contributes to poor lung transplant outcomes.Microarrays were used to study the biological response of human lungs to the ischemia reperfusion process. Samples were collected from lung transplant cases at Toronto General Hospital. Lungs were donation after brain death (DBD)

2023-09-18 | GSE127242 | GEO

Expression of Human Lung Before and After Transplantation

Project description:Ischemia reperfusion induced injury contributes to poor lung transplant outcomes. We used microarrays to study the biological response of human lungs to the ischemia reperfusion process. Samples were collected from lung transplant cases at Toronto General Hospital. Lungs were donation after brain death (DBD)

2020-06-22 | GSE127003 | GEO

IL1β-dependent extravasation of pre-existing lung-restricted autoantibodies activates complement to promote primary graft dysfunction

Project description:Pre-existing lung restricted autoantibodies (LRA) are associated with a higher incidence of primary graft dysfunction (PGD) although it remains unclear whether LRA can drive its pathogenesis. In syngeneic murine left lung transplant recipients, pre-existing LRA worsened graft dysfunction, which was evident by impaired gas exchange, increased pulmonary edema, and activation of damage-associated pathways in lung epithelial cells. LRA-mediated injury was distinct from ischemia-reperfusion injury since deletion of donor non-classical monocytes as well as host neutrophils could not prevent graft dysfunction in LRA-pretreated recipients. Whole LRA IgG molecule was necessary for lung injury which was mediated by the classical and alternative complement pathways and reversed by complement inhibition. However, deletion of Fc receptors in donor macrophages or mannose-binding lectin proteins failed to rescue lung function. LRA- mediated injury was localized to the transplanted lung and dependent on IL1β-mediated permeabilization of pulmonary vascular endothelium which allowed extravasation of antibodies. Genetic deletion or pharmacological inhibition of IL1R in the donor lungs prevented LRA-induced graft injury. In humans, pre-existing LRA was an independent risk factor for severe PGD and could be treated with plasmapheresis and complement blockade. We conclude that pre-existing LRA can compound ischemia-reperfusion injury to worsen PGD for which complement inhibition may be effective.

2022-10-19 | GSE211501 | GEO

Rat LAD IR study

Project description:Rats underwent surgery for LAD ligation for 30 min followed by reperfusion. Heart ventricles were collected 2d or 7d after reperfusion. Keywords: rat heart ventricles, LAD - left anterior descending coronary artery, IR - ischemia-reperfusion

2006-03-24 | GSE4105 | GEO

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