Ex Vivo Lung Perfusion as a Human Platform for Preclinical Small Molecule Testing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE118566 | GEO | 2018/08/16
REPOSITORIES: GEO
Similar Datasets
Project description:Ex Vivo Lung Perfusion as a Human Platform for Preclinical Small Molecule Testing
| PRJNA486099 | ENA
Project description:The acute respiratory distress syndrome (ARDS) causes an estimated 70,000 US deaths annually. Multiple pharmacologic interventions for ARDS have been tested and failed. An unmet need is a suitable laboratory human model to predictively assess emerging therapeutics on organ function in ARDS. We previously demonstrated that the small molecule BC1215 blocks actions of a proinflammatory E3 ligase-associated protein, FBXO3, to suppress NF-κB signaling in animal models of lung injury. Ex vivo lung perfusion (EVLP) is a clinical technique that maintains lung function for possible transplant after organ donation. We used human lungs unacceptable for transplant to model endotoxemic injury with EVLP for 6 hours. LPS infusion induced inflammatory injury with impaired oxygenation of pulmonary venous circulation. BC1215 treatment after LPS rescued oxygenation and decreased inflammatory cytokines in bronchoalveolar lavage. RNA sequencing transcriptomics from biopsies taken during EVLP revealed robust inflammatory gene induction by LPS with a strong signal for NF-κB-associated transcripts. BC1215 treatment reduced the LPS induction of genes associated with inflammatory and host defense gene responses by Gene Ontology (GOterm) and pathways analysis. BC1215 also significantly antagonized LPS-mediated NF-κB activity. EVLP may provide a unique human platform for preclinical study of chemical entities such as FBXO3 inhibitors on tissue physiology.
| S-EPMC6237445 | biostudies-literature
Project description:Proteins that were newly-synthesized during ex vivo lung perfusion were labeled with an azido-sugar Ac4GalNAz in the perfusate. These proteins were enriched using click chemistry to attach an alkyne-desthiobiotin group to the azido-labeled proteins, then pulled out of solution using streptavidin beads. The overall goal is to better understand the effects of warm ischemia injury in lungs destined for lung transplantation.
2022-10-07 | MSV000090491 | MassIVE
Project description:We report the first use of ex vivo lung perfusion (EVLP) in the genetic and physiologic modification of lungs from deceased pulmonary arterial hypertension (PAH) patients and propose this as a translational platform to both (1) derive clinically relevant mechanistic insights into pulmonary pathophysiology and (2) to test treatments on human lungs. The EVLP consist in the perfusion of the lungs out of the body during 6 hours. It is a well established protocol in where basically lungs are on a table connected to a close circuit containing a special perfusion solution that is circulated through the pulmonary vein and artery using a pump. The circuit contains also a deoxygenator. The perfusion temperature and flow are adjusted gradually and after 20 mins of perfusion the ventilation is initiated. Every hour lungs are recruited in order to assess pulmonary function and collect perfusate samples. In addition to perfusate, tissue samples from the lower lobe of the left lung and bronchial alveolar lavage (BAL) are collected at times T0, 3 and 6 hr.
2015-06-02 | GSE69416 | GEO
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
Project description:ABSTRACT: Background. Ex situ normothermic perfusion (ESNP) is a method to evaluate and potentially recondition organs before transplantation. However, increased expression of inflammatory molecules, including by tissue-resident immune cells, may occur during the perfusion process, potentially negating the beneficial effects of perfusion. Methods. We used RNA sequencing to assess gene expression in 31 livers undergoing ESNP, including 23 donated after circulatory death (DCD) and 8 donated after brain death. In 7 DCD livers, a leucocyte filter was added to the circuit during perfusion. Biopsies were available for transcriptomic assessment in all cases at the start of perfusion and at varying time points postperfusion. Results. During ESNP in DCD livers, we observed an increase in proinflammatory, profibrinolytic, and prorepair pathway genes. SERPINE1, encoding plasminogen activator inhibitor-1, was among the genes most significantly upregulated during perfusion in DCD livers, potentially promoting fibrin clot persistence in vasculature. We also found increased expression of monocyte and neutrophil recruiting chemokine and proinflammatory cytokine transcripts during ESNP, but several prorepair molecules, including thymic stromal lymphopoietin, were also upregulated. In both DCD and donation after brain death livers, interferon-gamma response genes were enriched, whereas oxidative phosphorylation genes decreased in organs with high perfusate alanine transaminase, a biomarker associated with adverse clinical outcomes. The inclusion of a leukocyte filter in the perfusion circuit mitigated the induction of inflammation/immune pathway genes during perfusion and was associated with enrichment in oxidative phosphorylation genes. Conclusions. Leukocyte removal during ESNP abrogates transcriptional changes that are associated with unfavorable clinical outcomes, potentially benefiting human livers undergoing ESNP.
2024-10-01 | GSE245976 | GEO
Project description:Expression of Human Lung Before and After Ex Vivo Lung Perfusion
| PRJNA524140 | ENA
Project description:Ex vivo lung perfusion (EVLP) has extended the number of transplantable lungs by reconditioning marginal organs. However EVLP is performed at 37°C without homeostatic regulation leading to metabolic wastes accumulation in the perfusate, and as a corrective measure, the costly perfusate is repeatedly replaced during the standard of care procedure. As an interesting alternative, a hemodialyzer could be placed on the EVLP circuit, that was previously shown to rebalance the perfusate composition, maintain lung function and viability without appearing to impact the global gene expression in the lung. Here, we assessed the biological effects of a hemodialyzer during EVLP by performing biochemical and refined functional genomic analyses over a 12 h procedure in a pig model. We found that dialysis stabilized electrolytic and metabolic parameters of the perfusate but enhanced the gene expression and protein accumulation of several inflammatory cytokines, and promoted a genomic profile predicting higher endothelial activation already at 6 h and immune cytokine signaling at 12 h. Therefore epuration of EVLP with a dialyzer, while correcting features of perfusate composition and maintaining respiratory function, promotes inflammatory responses in the tissue. This finding suggests that modifying the metabolite composition of the perfusate by dialysis during EVLP can have detrimental effects on the tissue response and that this strategy should not be transferred as such to the clinic.
2024-03-04 | GSE241921 | GEO
Project description:Potential Therapeutic Targets for Donor Lung Repair During Human Ex Vivo Lung Perfusion Prior to Transplantation
| PRJNA524402 | ENA
Project description:As donor organ shortages persist, functional machine perfusion is under investigation to improve preservation of the donor liver. The transplantation of donation after circulatory death (DCD) livers is limited by poor outcomes, but its application may be expanded by ex vivo repair and assessment of the organ before transplantation. Here we employed subnormothermic (21 °C) machine perfusion of discarded human livers combined with metabolomics to gain insight into metabolic recovery during machine perfusion. Improvements in energetic cofactors and redox shifts were observed, as well as reversal of ischemia-induced alterations in selected pathways, including lactate metabolism and increased TCA cycle intermediates. We next evaluated whether DCD livers with steatotic and severe ischemic injury could be discriminated from ‘transplantable’ DCD livers. Metabolomic profiling was able to cluster livers with similar metabolic patterns based on the degree of injury. Moreover, perfusion parameters combined with differences in metabolic factors suggest variable mechanisms that result in poor energy recovery in injured livers. We conclude that machine perfusion combined with metabolomics has significant potential as a clinical instrument for the assessment of preserved livers.
2016-06-30 | ST000412 | MetabolomicsWorkbench