Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs.
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ABSTRACT:
SUBMITTER: Hozain AE
PROVIDER: S-EPMC9990469 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
Xenogeneic cross-circulation for extracorporeal recovery of injured human lungs.
Hozain Ahmed E AE O'Neill John D JD Pinezich Meghan R MR Tipograf Yuliya Y Donocoff Rachel R Cunningham Katherine M KM Tumen Andrew A Fung Kenmond K Ukita Rei R Simpson Michael T MT Reimer Jonathan A JA Ruiz Edward C EC Queen Dawn D Stokes John W JW Cardwell Nancy L NL Talackine Jennifer J Kim Jinho J Snoeck Hans-Willem HW Chen Ya-Wen YW Romanov Alexander A Marboe Charles C CC Griesemer Adam D AD Guenthart Brandon A BA Bacchetta Matthew M Vunjak-Novakovic Gordana G
Nature medicine 20200713 7
Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplantation, including a lung that failed to recover on EVLP, can be recovered by cross-circulation of whole blood between explanted human lungs and a Yorks ...[more]
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Project description:BackgroundXenogeneic cross-circulation (XC) is an experimental method for ex vivo organ support and recovery that could expand the pool of donor lungs suitable for transplantation. The objective of this study was to establish and validate a standardized, reproducible, and broadly applicable technique for performing xenogeneic XC to support and recover injured human donor lungs ex vivo.MethodsHuman donor lungs (n = 9) declined for transplantation were procured, cannulated, and subjected to 24 hours of xenogeneic XC with anesthetized xeno-support swine (Yorkshire/Landrace) treated with standard immunosuppression (methylprednisolone, mycophenolate mofetil, tacrolimus) and complement-depleting cobra venom factor. Standard lung-protective perfusion and ventilation strategies, including periodic lung recruitment maneuvers, were used throughout xenogeneic XC. Every 6 hours, ex vivo donor lung function (gas exchange, compliance, airway pressures, pulmonary vascular dynamics, lung weight) was evaluated. At the experimental endpoint, comprehensive assessments of the lungs were performed by bronchoscopy, histology, and electron microscopy. Student's t-test and 1-way analysis of variance with Dunnett's post-hoc test was performed, and p < 0.05 was considered significant.ResultsAfter 24 hours of xenogeneic XC, gas exchange (PaO2/FiO2) increased by 158% (endpoint: 364 ± 142 mm Hg; p = 0.06), and dynamic compliance increased by 127% (endpoint: 46 ± 20 ml/cmH2O; p = 0.04). Airway pressures, pulmonary vascular pressures, and lung weight remained stable (p > 0.05) and within normal ranges. Over 24 hours of xenogeneic XC, gross and microscopic lung architecture were preserved: airway bronchoscopy and parenchymal histomorphology appeared normal, with intact blood-gas barrier.ConclusionsXenogeneic cross-circulation is a robust method for ex vivo support, evaluation, and improvement of injured human donor lungs declined for transplantation.
| S-EPMC9985920 | biostudies-literature
Project description:ObjectivesLung remains the least-utilized solid organ for transplantation. Efforts to recover donor lungs with reversible injuries using ex vivo perfusion systems are limited to <24 hours of support. Here, we demonstrate the feasibility of extending normothermic extracorporeal lung support to 4 days using cross-circulation with conscious swine.MethodsA swine behavioral training program and custom enclosure were developed to enable multiday cross-circulation between extracorporeal lungs and recipient swine. Lungs were ventilated and perfused in a normothermic chamber for 4 days. Longitudinal analyses of extracorporeal lungs (ie, functional assessments, multiscale imaging, cytokine quantification, and cellular assays) and recipient swine (eg, vital signs and blood and tissue analyses) were performed.ResultsThroughout 4 days of normothermic support, extracorporeal lung function was maintained (arterial oxygen tension/inspired oxygen fraction >400 mm Hg; compliance >20 mL/cm H2O), and recipient swine were hemodynamically stable (lactate <3 mmol/L; pH, 7.42 ± 0.05). Radiography revealed well-aerated lower lobes and consolidation in upper lobes of extracorporeal lungs, and bronchoscopy showed healthy airways without edema or secretions. In bronchoalveolar lavage fluid, granulocyte-macrophage colony-stimulating factor, interleukin (IL) 4, IL-6, and IL-10 levels increased less than 6-fold, whereas interferon gamma, IL-1α, IL-1β, IL-1ra, IL-2, IL-8, IL-12, IL-18, and tumor necrosis factor alpha levels decreased from baseline to day 4. Histologic evaluations confirmed an intact blood-gas barrier and outstanding preservation of airway and alveolar architecture. Cellular viability and metabolism in extracorporeal lungs were confirmed after 4 days.ConclusionsWe demonstrate feasibility of normothermic maintenance of extracorporeal lungs for 4 days by cross-circulation with conscious swine. Cross-circulation approaches could support the recovery of damaged lungs and enable organ bioengineering to improve transplant outcomes.
| S-EPMC7094131 | biostudies-literature
Project description:Improved approaches to expanding the pool of donor lungs suitable for transplantation are critically needed for the growing population with end-stage lung disease. Cross-circulation (XC) of whole blood between swine and explanted human lungs has previously been reported to enable the extracorporeal recovery of donor lungs that declined for transplantation due to acute, reversible injuries. However, immunologic interactions of this xenogeneic platform have not been characterized, thus limiting potential translational applications. Using flow cytometry and immunohistochemistry, we demonstrate that porcine immune cell and immunoglobulin infiltration occurs in this xenogeneic XC system, in the context of calcineurin-based immunosuppression and complement depletion. Despite this, xenogeneic XC supported the viability, tissue integrity, and physiologic improvement of human donor lungs over 24 hours of xeno-support. These findings provide targets for future immunomodulatory strategies to minimize immunologic interactions on this organ support biotechnology.
| S-EPMC10065447 | biostudies-literature
Project description:Although machine perfusion has gained momentum as an organ preservation technique in liver transplantation, persistent organ shortages and high waitlist mortality highlight unmet needs for improved organ salvage strategies. Beyond preservation, extracorporeal organ support platforms can also aid the development and evaluation of novel therapeutics. Here, we report the use of veno-arterial-venous (V-AV) cross-circulation (XC) with a swine host to provide normothermic support to extracorporeal livers. Functional, biochemical, and morphological analyses of the extracorporeal livers and swine hosts were performed over 12 hours of support. Extracorporeal livers maintained synthetic function through alkaline bile production and metabolic activity through lactate clearance and oxygen consumption. Beyond initial reperfusion, no biochemical evidence of hepatocellular injury was observed. Histopathologic injury scoring showed improvements in sinusoidal dilatation and composite acute injury scores after 12 hours. Swine hosts remained hemodynamically stable throughout XC support. Altogether, these outcomes demonstrate the feasibility of using a novel V-AV XC technique to provide support for extracorporeal livers in a swine model. V-AV XC has potential applications as a translational research platform and clinical biotechnology for donor organ salvage.
| S-EPMC9984766 | biostudies-literature
Project description:The number of available donor organs limits lung transplantation, the only lifesaving therapy for the increasing population of patients with end-stage lung disease. A prevalent etiology of injury that renders lungs unacceptable for transplantation is gastric aspiration, a deleterious insult to the pulmonary epithelium. Currently, severely damaged donor lungs cannot be salvaged with existing devices or methods. Here we report the regeneration of severely damaged lungs repaired to meet transplantation criteria by utilizing an interventional cross-circulation platform in a clinically relevant swine model of gastric aspiration injury. Enabled by cross-circulation with a living swine, prolonged extracorporeal support of damaged lungs results in significant improvements in lung function, cellular regeneration, and the development of diagnostic tools for non-invasive organ evaluation and repair. We therefore propose that the use of an interventional cross-circulation platform could enable recovery of otherwise unsalvageable lungs and thus expand the donor organ pool.
| S-EPMC6504972 | biostudies-literature
Project description:BACKGROUND:Severe hypoperfusion can cause lung damage. We studied the effects of regional perfusion block in normal lungs and in the lungs that had been conditioned by lavage with 500 ml saline and high V T (20 ml kg-1) ventilation. METHODS:Nineteen pigs (61.2 ± 2.5 kg) were randomized to five groups: controls (n = 3), the right lower lobe block alone (n = 3), lavage and high V T (n = 4), lung lavage, and high V T plus perfusion block of the right (n = 5) or left (n = 4) lower lobe. Gas exchange, respiratory mechanics, and hemodynamics were measured hourly. After an 8-h observation period, CT scans were obtained at 0 and 15 cmH2O airway pressure. RESULTS:Perfusion block did not damage healthy lungs. In conditioned lungs, the left perfusion block caused more edema in the contralateral lung (777 ± 62 g right lung vs 484 ± 204 g left; p < 0.05) than the right perfusion block did (581 ± 103 g right lung vs 484 ± 204 g left; p n.s.). The gas/tissue ratio, however, was similar (0.5 ± 0.3 and 0.8 ± 0.5; p n.s.). The lobes with perfusion block were not affected (gas/tissue ratio right 1.6 ± 0.9; left 1.7 ± 0.5, respectively). Pulmonary artery pressure, PaO2/FiO2, dead space, and lung mechanics were more markedly affected in animals with left perfusion block, while the gas/tissue ratios were similar in the non-occluded lobes. CONCLUSIONS:The right and left perfusion blocks caused the same "intensity" of edema in conditioned lungs. The total amount of edema in the two lungs differed because of differences in lung size. If capillary permeability is altered, increased blood flow may induce or increase edema.
| S-EPMC5640557 | biostudies-literature
Project description:Neural stem cells (NSCs) differentiate into both neurons and glia, and strategies using human NSCs have the potential to restore function following spinal cord injury (SCI). However, the time period of maturation for human NSCs in adult injured CNS is not well defined, posing fundamental questions about the design and implementation of NSC-based therapies. This work assessed human H9 NSCs that were implanted into sites of SCI in immunodeficient rats over a period of 1.5 years. Notably, grafts showed evidence of continued maturation over the entire assessment period. Markers of neuronal maturity were first expressed 3 months after grafting. However, neurogenesis, neuronal pruning, and neuronal enlargement continued over the next year, while total graft size remained stable over time. Axons emerged early from grafts in very high numbers, and half of these projections persisted by 1.5 years. Mature astrocyte markers first appeared after 6 months, while more mature oligodendrocyte markers were not present until 1 year after grafting. Astrocytes slowly migrated from grafts. Notably, functional recovery began more than 1 year after grafting. Thus, human NSCs retain an intrinsic human rate of maturation, despite implantation into the injured rodent spinal cord, yet they support delayed functional recovery, a finding of great importance in planning human clinical trials.
| S-EPMC5669577 | biostudies-literature
Project description:Development of minimally invasive cardiac surgery (MICS) served the purpose of performing surgery while avoiding the surgical stress triggered by a full median sternotomy. Minimizing surgical trauma is associated with improved cosmesis and enhanced recovery leading to reduced morbidity. However, it has to be primarily appreciated that the extracorporeal circulation (ECC) stands for the basis of nearly all MICS procedures. With some fundamental modification and advancement in perfusion techniques, the use of ECC has become the enabling technology for the development of MICS. Less invasive cardiopulmonary bypass (CPB) techniques are based on remote cannulation and optimization of perfusion techniques with assisted venous drainage and use of centrifugal pump, so as to facilitate the demanding surgical maneuvers, rather than minimizing the invasiveness of the CPB. This is reflected in the increased duration of CPB required for MICS procedures. Minimal invasive Extracorporeal Circulation (MiECC) represents a major breakthrough in perfusion. It integrates all contemporary technological advancements that facilitate best applying cardiovascular physiology to intraoperative perfusion. Consequently, MiECC use translates to improved end-organ protection and clinical outcome, as evidenced in multiple clinical trials and meta-analyses. MICS performed with MiECC provides the basis for developing a multidisciplinary intraoperative strategy towards a "more physiologic" cardiac surgery by combining small surgical trauma with minimum body's physiology derangement. Integration of MiECC can advance MICS from non-full sternotomy for selected patients to a "more physiologic" surgery, which represents the real face of modern cardiac surgery in the transcatheter era.
| S-EPMC8024827 | biostudies-literature
Project description:The objective of this study was to assess the effects of hypercapnic acidosis on lung cell injury and repair by confocal microscopy in a model of ventilator-induced lung injury. Three groups of normocapnic, hypocapnic, and hypercapnic rat lungs were perfused ex vivo, either during or after injurious ventilation, with a solution containing the membrane-impermeant label propidium iodide. In lungs labeled during injurious ventilation, propidium iodide fluorescence identifies all cells with plasma membrane wounds, both permanent and transient, whereas in lungs labeled after injurious ventilation propidium iodide fluorescence identifies only cells with permanent plasma membrane wounds. Hypercapnia minimized the adverse effects of high-volume ventilation on vascular barrier function, whereas hypocapnia had the opposite effect. Despite CO2-dependent differences in lung mechanics and edema the number of injured subpleural cells per alveolus was similar in the three groups (0.48 +/- 0.34 versus 0.51 +/- 0.19 versus 0.43 +/- 0.20 for hypocapnia, normocapnia, and hypercapnia, respectively). However, compared with normocapnia the probability of wound repair was significantly reduced in hypercapnic lungs (63 versus 38%; p < 0.02). This finding was subsequently confirmed in alveolar epithelial cell scratch models. The potential relevance of these observations for lung inflammation and remodeling after mechanical injury is discussed.
| S-EPMC2718480 | biostudies-literature
Project description:BackgroundSarcoidosis is a systemic granulomatous disease of unknown cause. Natural improvement with favorable outcome is common, but a significant number of patients present with difficult to manage and progressive disease. The identification of biomarkers associated with disease activity and progression is warranted. Extracellular heat shock protein 90 (HSP90) α is a signaling molecule released by cells that induces proinflammatory signaling through interaction with certain receptors, such as lipoprotein receptor-related protein 1.Materials and methodsHSP90α protein expression in lung tissues derived from patients diagnosed with sarcoidosis and control subjects was assessed by immunohistochemistry. Serum HSP90α concentration was measured in sarcoidosis patients and healthy controls and correlated with clinical outcomes. Bronchoalveolar lavage fluid (BALF) was collected and analyzed for HSP90α expression. Extracellular HSP90α released from macrophages was examined in human primary cells and an immortalized cell line.ResultsMacrophages and granulomas in sarcoidosis-affected lungs showed high HSP90α expression. Serum HSP90α levels were elevated in sarcoidosis patients compared with controls and correlated with BALF HSP90α levels. HSP90α concentrations in the circulation were correlated with biomarkers of disease stage. Both primary and immortalized macrophages showed a high capacity for secreting extracellular HSP90α.ConclusionThese results demonstrate that macrophages in the lungs of sarcoidosis patients produce high levels of HSP90α, suggesting HSP90α as a potential biomarker and therapeutic target.
| S-EPMC11774731 | biostudies-literature