Search

Background: Despite the benefits of ex vivo lung perfusion (EVLP) such as lung reconditioning, preservation, and evaluation before transplantation, deleterious effects, including activation of proinflammatory cascades and alteration of metabolic profiles have been reported. Although patient outcomes have been favorable, further studies addressing optimal conditions are warranted. In this study, we investigated the role of the immunosuppressant drug cyclosporine A (CyA) in preserving mitochondrial function and subsequently preventing proinflammatory changes in lung grafts during EVLP., Methods: Using rat heart-lung blocks after 1-hour cold preservation, an acellular normothermic EVLP system was established for 4 hours. CyA was added into perfusate at a final concentration of 1 μM. The evaluation included lung graft function, lung compliance, and pulmonary vascular resistance as well as biochemical marker measurement in the perfusate at multiple time points. After EVLP, single orthotopic lung transplantation was performed, and the grafts were assessed 2 hours after reperfusion., Results: Lung grafts on EVLP with CyA exhibited significantly better functional and physiological parameters as compared with those without CyA treatment. CyA administration attenuated proinflammatory changes and prohibited glucose consumption during EVLP through mitigating mitochondrial dysfunction in lung grafts. CyA-preconditioned lungs showed better posttransplant lung early graft function and less inflammatory events compared with control., Conclusions: During EVLP, CyA administration can have a preconditioning effect through both its anti-inflammatory and mitochondrial protective properties, leading to improved lung graft preservation, which may result in enhanced graft quality after transplantation.

Although lung transplantation is an effective treatment for end-stage lung failure, its limitations have led to renewed interest in artificial lung support for patients with lung failure. The use of ventricular assist devices has significantly improved the quality of life and survival of patients with end-stage heart failure. In contrast, there are no devices that can be used long term as destination therapy for end-stage lung failure, and there is a strong need for them. Extracorporeal membrane oxygenation is widely used as a temporary treatment for acute lung failure and as a bridge to lung transplant. Many patients with advanced lung failure cannot return home with good quality of life once they are hospitalized. In this review, the authors discuss the history, status, and future of artificial lungs, focusing on long-term artificial respiratory support as a destination therapy. Respiratory assist devices, such as artificial lungs, could eventually become analogous to ventricular assist devices., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Chronic allograft dysfunction (CLAD) remains a major complication, causing the poor survival after lung transplantation (Tx). Although strenuous efforts have been made at preventing CLAD, surgical approaches for lung Tx have not been updated over the last 2 decades. The bronchial artery (BA), which supplies oxygenated blood to the airways and constitutes a functional microvasculature, has occasionally been revascularized during transplants, but this technique did not gain popularity and is not standard in current lung Tx protocols, despite the fact that a small number of studies have shown beneficial effects of BA revascularization on limiting CLAD. Also, recent basic and clinical evidence has demonstrated the relationship between microvasculature damage and CLAD. Thus, the protection of the bronchial circulation and microvasculature in lung grafts may be a key factor to overcome CLAD. This review revisits the history of BA revascularization, discusses the role of the bronchial circulation in lung Tx, and advocates for novel bronchial-arterial-circulation sparing approaches as a future direction for overcoming CLAD. Although there are some already published review articles summarizing the surgical techniques and their possible contribution to outcomes in lung Tx, to the best of our knowledge, this review is the first to elaborate on bronchial circulation that will contribute to prevent CLAD from both scientific and clinical perspectives: from bedside to bench to bedside, and beyond.

Background: The role of the circulating leukocytes in lungs and their relationship with circulating proinflammatory cytokines during ischemia-reperfusion injury is not well understood. Using ex vivo lung perfusion (EVLP) to investigate the pathophysiology of isolated lungs, we aimed to identify a therapeutic target to optimize lung preservation leading to successful lung transplantation., Methods: Rat heart-lung blocks were placed on EVLP for 4 hours with or without a leukocyte-depleting filter (LF). After EVLP, lung grafts were transplanted, and posttransplant outcomes were compared., Results: Lung function was significantly better in lung grafts on EVLP with a LF than in lungs on EVLP without a LF. The interleukin (IL)-6 levels in the lung grafts and EVLP perfusate were also significantly lower after EVLP with a LF. Interestingly, IL-6 levels in the perfusate did not increase after the lungs were removed from the EVLP circuit, indicating that the cells trapped by the LF were not secreting IL-6. The trapped cells were analyzed with flow cytometry to detect apoptosis and pyroptosis; 26% were pyroptotic (Caspase-1-positive). After transplantation, there was better graft function and less inflammatory response if a LF was used or a caspase-1 inhibitor was administered during EVLP., Conclusions: Our data demonstrated that circulating leukocytes derived from donor lungs, and not circulating proinflammatory cytokines substantially impaired the quality of lung grafts through caspase-1-induced pyroptotic cell death during EVLP. Removing these cells with a LF and/or inhibiting pyroptosis of the cells can be a new therapeutic approach leading to long-term success after lung transplantation.

Ex vivo lung perfusion (EVLP) promises to be a comprehensive platform for assessment, reconditioning, and preservation of donor lungs and has been dramatically changing the face of clinical lung transplantation. Besides its increasing role in lung transplantation, EVLP has also been recognized as a useful tool for translational research involving the lungs. Based on recent remarkable evidence and experience using EVLP in lung transplantation, there is growing interest in, and expectations for, the use of EVLP beyond the field of lung transplantation. By combining EVLP with advances in regenerative medicine, stem cell biology, and oncology, the evolving technology of EVLP has tremendous potential to advance pulmonary medicine and science. In this review, we revisit recent advances in EVLP technology and research and discuss the future translation of EVLP applications into life-changing medicine., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Although the benefits of ex vivo lung perfusion (EVLP) have been globally advocated, the potentially deleterious effects of applying EVLP, in particular activation of proinflammatory cascades and alteration of metabolic profiles, are rarely discussed. This study examined proinflammatory events and metabolic profiles in lung grafts on EVLP and tested whether preconditioning lung grafts with inhaled hydrogen, a potent, cytoprotective gaseous signaling molecule, would alter the lungs' response to EVLP., Methods: Rat heart-lung blocks were mounted on an acellular normothermic EVLP system for 4 hr and ventilated with air or air supplemented with 2% hydrogen. Arterial and airway pressures were monitored continuously; perfusate was sampled hourly to examine oxygenation. After EVLP, the lung grafts were transplanted orthotopically into syngeneic rats, and lung function was examined., Results: Placing lung grafts on EVLP resulted in significant upregulation of the messenger RNAs for several proinflammatory cytokines, higher glucose consumption, and increased lactate production. Hydrogen administration attenuated proinflammatory changes during EVLP through upregulation of the heme oxygenase-1. Hydrogen administration also promoted mitochondrial biogenesis and significantly decreased lactate production. Additionally, in the hydrogen-treated lungs, the expression of hypoxia-inducible factor-1 was significantly attenuated during EVLP. These effects were maintained throughout EVLP and led to better posttransplant lung graft function in the recipients of hydrogen-treated lungs., Conclusions: Lung grafts on EVLP exhibited prominent proinflammatory changes and compromised metabolic profiles. Preconditioning lung grafts using inhaled hydrogen attenuated these proinflammatory changes, promoted mitochondrial biogenesis in the lungs throughout the procedure, and resulted in better posttransplant graft function.

Background: Most of the experimental work assessing optimal lung inflation during lung graft preservation was performed in the late 1990s. Since that time, lung preservation before transplantation has been more standardized, and the optimal lung inflation techniques used during lung preservation in the current clinical setting remain undefined. Nonetheless, lung inflation during storage may play a pivotal role in optimal lung preservation., Materials and Methods: Lewis rat lungs were perfused with and stored in cold, low-potassium dextran solution (Perfadex, Vitrolife, Göteborg, Sweden) for 6 hours at different levels of lung inflation (25, 50, 75, or 100% of vital capacity [VC]). Orthotopic left lung transplantation using cuff techniques was performed in syngeneic Lewis rats. Posttransplant allograft function, expression of proinflammatory mediators, and expression of lung surfactants were evaluated., Results: Lungs inflated to 75 or 100% VC showed a significantly better oxygenation in blood gas analysis than lungs inflated to 25 or 50% VC. The levels of mRNAs for tumor necrosis factor-α, pro-interleukin-1β, intracellular adhesion molecule 1 were attenuated in lungs inflated to 75 or 100% VC as compared with deflated lungs, suggesting reduced ischemia/reperfusion injury. In addition, transmission electron microscopy demonstrated better preserved lung surfactants in the alveolar space in the lungs inflated to 75 or 100% VC., Conclusions: Inflating lungs to 75 or 100% VC during preservation may be beneficial and result in better posttransplant allograft function through attenuated reperfusion injury and better preserved lung surfactants., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Ex vivo lung perfusion (EVLP) strategies represent a new frontier in lung transplantation technology, and there have been many clinical studies of EVLP in lung transplantation. The establishment of a reliable EVLP model in small animals is crucial to facilitating translational research using an EVLP strategy. The main objective of this study was to develop a reproducible rat EVLP (R-EVLP) model that enables prolonged evaluation of the explanted lung during EVLP and successful transplantation after EVLP., Methods: The donor heart-lung blocks were procured with cold low-potassium dextran solution and immersed in the solution for 1 h at 4 °C. And then, the heart-lung blocks were flushed retrogradely and warmed up to 37 °C in a circuit perfused antegradely with acellular perfusate. The perfusate was deoxygenated with a gas mixture (6% O2, 8% CO2, 86% N2). The perfusion flow was maintained at 20% of the entire cardiac output. At 37 °C, the lungs were mechanically ventilated and perfusion continued for 4 h. Every hour, the perfused lung was evaluated for gas exchange, dynamic lung compliance (Cdyn) and pulmonary vascular resistance (PVR)., Results: R-EVLP was performed for 4 h. Pulmonary oxygenation ability (pO2/pCO2) was stable for 4 h during EVLP. It was noted that Cdyn and PVR were also stable. After 4 h of EVLP, pO2 was 303 ± 19 mmHg, pCO2 was 39.6 ± 1.2 mmHg, PVR was 1.75 ± 0.10 mmHg/ml/min and Cdyn was 0.37 ± 0.03 ml/cmH2O. Lungs that were transplanted after 2 h of R-EVLP resulted in significantly better post-transplant oxygenation and compliance when compared with those after standard cold static preservation., Conclusions: Our R-EVLP model maintained stable lung oxygenation, compliance and vascular resistance for up to 4 h of perfusion duration. This reliable model should facilitate further advancement of experimental work using EVLP.

Background: Staphylococcus aureus infections among lung transplant recipients are poorly studied., Methods: We conducted a 5-year retrospective study of the epidemiology, clinical manifestations, risk factors, and outcomes of patients infected with S aureus within the first 90 days after lung transplantation., Results: An S aureus infection developed in 109 of 596 lung transplant (18%) recipients. Methicillin-susceptible S aureus (MSSA; 62%) was more common than methicillin-resistant S aureus (MRSA; 38%); however, the proportion of infections caused by MRSA increased over time. Pneumonia (48%) was the most common infection, followed by tracheobronchitis (26%), bacteremia (12%), intrathoracic infections (7%), and skin/soft tissue infections (7%). Risk factors included mechanical ventilation for > 5 days and isolation of S aureus from recipients' sterility cultures. Patients with MRSA cultured from the nares or respiratory tract at the time of transplant were at an increased risk for MRSA infection (p < 0.0001 and p = 0.02, respectively). Infected patients required longer hospital and intensive care unit stays (p < 0.0001 for both), but the 30- and 90-day mortality rates from the onset of infection were only 7% and 12%, respectively. However, infected patients had higher rates of acute and chronic rejection at 1 (p = 0.048) and 3 years (p = 0.002), and higher rates of mortality at 1 (p = 0.058) and 3 years (p = 0.009)., Conclusions: S aureus infections within the first 90 days of lung transplant were associated with low short-term mortality but increased long-term rates of mortality and acute and chronic rejection. Future studies are needed to explore the utility of S aureus eradication strategies in reducing disease burden and improving outcomes., (Published by Elsevier Inc.)

Background: We previously demonstrated that donor treatment with inhaled hydrogen protects lung grafts from cold ischemia/reperfusion (I/R) injury during lung transplantation. To elucidate the mechanisms underlying hydrogen's protective effects, we conducted a gene array analysis to identify changes in gene expression associated with hydrogen treatment., Methods: Donor rats were exposed to mechanical ventilation with 98% oxygen and 2% nitrogen or 2% hydrogen for 3 h before harvest; lung grafts were stored for 4h in cold Perfadex. Affymetrix gene array analysis of mRNA transcripts was performed on the lung tissue prior to implantation., Results: Pretreatment of donor lungs with hydrogen altered the expression of 229 genes represented on the array (182 upregulated; 47 downregulated). Hydrogen treatment induced several lung surfactant-related genes, ATP synthase genes and stress-response genes. The intracellular surfactant pool, tissue adenosine triphosphate (ATP) levels and heat shock protein 70 (HSP70) expression increased in the hydrogen-treated grafts. Hydrogen treatment also induced the transcription factors C/EBPα and C/EBPβ, which are known regulators of surfactant-related genes., Conclusion: Donor ventilation with hydrogen significantly increases expression of surfactant-related molecules, ATP synthases and stress-response molecules in lung grafts. The induction of these molecules may underlie hydrogen's protective effects against I/R injury during transplantation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Concomitant tricuspid valve repair (TVR) and double lung transplantation (DLTx) has been a surgical option at our institution since 2004 in an attempt to improve the outcome of DLTx for end-stage pulmonary hypertension, severe tricuspid regurgitation, and right ventricle (RV) dysfunction. This study is a review of that single institutional experience., Methods: Consecutive cases of concomitant TVR and DLTx performed between 2004 and 2009 (TVR group, n = 20) were retrospectively compared with cases of DLTx alone for severe pulmonary hypertension without TVR (non-TVR group, n = 58)., Results: There was one in-hospital death in the TVR group. The 90-day and 1- and 3-year survival rates for the TVR group were 90%, 75%, and 65%, respectively, which were not significantly different from those for the non-TVR group. The TVR group required less inotropic support and less prolonged mechanical ventilation in the ICU. Follow-up echocardiography demonstrated immediate elimination of both volume and pressure overload in the RV and tricuspid regurgitation in the TVR group. Notably, there was a significantly lower incidence of primary graft dysfunction following transplantation in the TVR group (P < .05). Pulmonary functional improvement shown by an FEV(1) increase after 6 months was also significantly better in the TVR group (40% vs 20%, P < .05)., Conclusions: Combined TVR and DLTx procedures were successfully performed without an increase in morbidity or mortality and contributed to decreased primary graft dysfunction. In our experience, this combined operative approach achieves clinical outcomes equal or superior to the outcomes seen in DLTx patients without RV dysfunction and severe tricuspid regurgitation.

Background: Because inhaled hydrogen provides potent anti-inflammatory and antiapoptotic effects against acute lung injury, we hypothesized that treatment of organ donors with inhaled hydrogen during mechanical ventilation would decrease graft injury after lung transplantation., Methods: Orthotopic left lung transplants were performed using a fully allogeneic Lewis to Brown Norway rat model. The donors were exposed to mechanical ventilation with 98% oxygen plus 2% nitrogen or 2% hydrogen for 3 h prior to harvest, and the lung grafts underwent 4 h of cold storage in Perfadex (Vitrolife, Göteborg, Sweden). The graft function, histomorphologic changes, and inflammatory reactions were assessed., Results: The combination of mechanical ventilation and prolonged cold ischemia resulted in marked deterioration of gas exchange when the donors were ventilated with 2% nitrogen/98% oxygen, which was accompanied by upregulation of proinflammatory cytokines and proapoptotic molecules. These lung injuries were attenuated significantly by ventilation with 2% hydrogen. Inhaled hydrogen induced heme oxygenase-1, an antioxidant enzyme, in the lung grafts prior to implantation, which might contribute to protective effects afforded by hydrogen., Conclusion: Preloaded hydrogen gas during ventilation prior to organ procurement protected lung grafts effectively from ischemia/reperfusion-induced injury in a rat lung transplantation model., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: Optimal size matching is critical to avoid problems from oversized grafts used in lung transplantation for restrictive pulmonary diseases in patients with a small chest cavity. Although graft volume reduction (GVR) is useful to overcome related disparities, its merits and demerits remain unclear., Methods: We performed 342 lung transplants during the period of January 2003 to April 2007. Of the lung transplant recipients, 167 recipients had end-stage restrictive pulmonary diseases, with 25 (15%) receiving grafts considered to be oversized because of height disparity. The present retrospective analysis was conducted to compare between patients with size-matched and oversized grafts, and patients who did (GVR group, n = 9) and did not (non-GVR group, n = 16) undergo GVR for an oversized graft., Results: Pulmonary functional improvement after 6 months was better in size-matched patients in view of percent forced vital capacity (FVC%) increase (29.8% vs 21.2%, p < 0.05), whereas long-term survival was not significantly different between the size-matched and oversized groups. Compared with the GVR group, the non-GVR group had a significantly higher incidence of short-term complications leading to respiratory failure (50% vs 11.1%, p < 0.05), whereas functional improvement was significantly worse in the non-GVR group (FVC% increase: 32.8% vs 19.9%, p < 0.05). However, overall patient survival at 3 years was not significantly different (non-GVR: 67%; GVR: 75%)., Conclusions: An oversized graft may lead to a higher incidence of short-term clinical complications with reduced pulmonary function improvement post-operatively in lung transplantation recipients with end-stage restrictive pulmonary diseases. The decision of whether to carry-out GVR at the time of transplantation with an oversized graft to improve outcome is of critical importance.

Rationale and Objectives: Although lung volume reduction surgery (LVRS) has been widely used as a therapeutic strategy for pulmonary emphysema, the procedure carries significant disadvantages, including significant operative mortality and a limited duration of effective response. Pulmonary resection is known to elicit compensatory growth in remnant lung tissues; however, it remains unclear whether and how compensatory growth occurs and contributes to clinical outcomes after LVRS. The goal of the present study was to characterize the role of hepatocyte growth factor (HGF) in compensatory lung growth after LVRS in a rat model of elastase-induced emphysema, since HGF is a potent pulmotrophic factor responsible for the regeneration of lung parenchyma in damaged lungs, including after a pulmonary resection., Methods and Main Results: Unexpectedly, LVRS did not cause apparent increases in the endogenous HGF profiles of emphysematous lungs. Further, the lowered HGF production reflected a histologically inferior regenerative capacity in remnant lungs and was linked with impaired pulmonary functional recoveries after LVRS. When HGF was exogenously supplemented by gene transfection into emphysematous lungs simultaneously with LVRS, compensatory lung growth (as evidenced by increased lobe weight and alveolar regeneration and angiogenesis) was significantly enhanced as compared with rats that underwent LVRS alone. Consequently, pulmonary function and gas exchange were also significantly improved., Conclusions: We concluded that the induction of compensatory growth by growth factors after LVRS may be a new strategy to further improve clinical outcomes of LVRS in patients with pulmonary emphysema.

AimTo systematically review reports on deceased-donor-lobar lung transplantation (ddLLTx) and uniformly describe size matching using the donor-to-recipient predicted-total lung-capacity (pTLC) ratio.MethodsWe set out to systematically review reports on ddLLTx and uniformly describe size matching using the donor-to-recipient pTLC ratio and to summarize reported one-year survival data of ddLLTx and conventional-LTx. We searched in PubMed, CINAHL via EBSCO, Cochrane Database of Systematic Reviews via Wiley (CDSR), Database of Abstracts of Reviews of Effects via Wiley (DARE), Cochrane Central Register of Controlled Trials via Wiley (CENTRAL), Scopus (which includes EMBASE abstracts), and Web of Science for original reports on ddLLTx.ResultsNine observational cohort studies reporting on 301 ddLLTx met our inclusion criteria for systematic review of size matching, and eight for describing one-year-survival. The ddLLTx-group was often characterized by high acuity; however there was heterogeneity in transplant indications and pre-operative characteristics between studies. Data to calculate the pTLC ratio was available for 242 ddLLTx (80%). The mean pTLCratio before lobar resection was 1.25 ± 0.3 and the transplanted pTLCratio after lobar resection was 0.76 ± 0.2. One-year survival in the ddLLTx-group ranged from 50%-100%, compared to 72%-88% in the conventional-LTx group. In the largest study ddLLTx (n = 138) was associated with a lower one-year-survival compared to conventional-LTx (n = 539) (65.1% vs 84.1%, P < 0.001).ConclusionFurther investigations of optimal donor-to-recipient size matching parameters for ddLLTx could improve outcomes of this important surgical option.

Little is known about the use of lung transplantation in the management of sickle cell disease-associated pulmonary arterial hypertension (SCD-PAH). We present clinical and pathological data and report the first successful outcome of bilateral lung transplantation in a patient with severe SCD-PAH and pulmonary veno-occlusive disease (PVOD). We discuss the complexities of multidisciplinary planning and management of lung transplantation in patients with SCD-associated pulmonary vascular complications. This case reports the first documented successful lung transplant and first case of PVOD in a patient with SCD-PAH.

Objective To identify preoperative predictors of extracorporeal support in patients with pulmonary hypertension (PH) undergoing bilateral sequential lung transplantation (LTx), and to examine outcomes associated with the use of extracorporeal support. Design Retrospective, observational study. Setting Single organ transplantation and tertiary care university medical center. Participants Adults with PH (preoperative mean pulmonary artery pressure (mPAP)≥25 mmHg) who underwent primary bilateral sequential LTx during 2007 to 2013. Measurements and Main Results Of 262 patients with PH undergoing LTx, extracorporeal support was initiated intraoperatively in 149 (57%). Preoperative severe right ventricle (RV) dysfunction and moderate or severe tricuspid regurgitation (TR) were associated with extracorporeal support. In the remaining 208 patients without those factors, increasing preoperative oxygen requirement (odds ratio [OR] 1.30 per 1 L/min, 95% confidence intervals [CI] 1.11-1.52, p = 0.001), presence of RV dilation (OR 2.77, 95% CI 1.28-6.02, p = 0.010), and mPAP (OR 1.33 per 5-mmHg increase in mPAP, 95% CI 1.04-1.70, p = 0.021) were associated independently with extracorporeal support in the multivariable model. Analysis of 49 propensity-matched pairs showed longer intensive care unit (5 v 14 days, p = 0.006) and hospital stays (27 v 39 days, p = 0.016) and increased need for tracheostomy (16% v 41%, p = 0.017) in patients exposed to extracorporeal support but no differences in 30-day mortality, stroke, myocardial infarction, or dialysis. Conclusions Severity of RV dysfunction, TR, RV dilatation, increasing oxygen requirement, and increasing mPAP showed significant associations with the need for extracorporeal support during LTX in patients with PH. Extracorporeal support was associated with increased length of stay and tracheostomy but not with mortality or other complications. © 2016 Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]