Clinical Lung Transplantation Research Articles

Hyaluronan Contributes to Bronchiolitis Obliterans Syndrome and Stimulates Lung Allograft Rejection through Activation of Innate Immunity

Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain. To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low- or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells. HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low- or high-molecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4- and myeloid differentiation protein 88-dependent fashion and drove expansion of alloantigen-specific T lymphocytes. Additionally, TLR-dependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation. These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia.

Effects of exogenous surfactant on the non‐heart‐beating donor lung graft in experimental lung transplantation – a stereological study

The use of non-heart-beating donor (NHBD) lungs may help to overcome the shortage of lung grafts in clinical lung transplantation, but warm ischaemia and ischaemia/reperfusion injury (I/R injury) resulting in primary graft dysfunction represent a considerable threat. Thus, better strategies for optimized preservation of lung grafts are urgently needed. Surfactant dysfunction has been shown to contribute to I/R injury, and surfactant replacement therapy is effective in enhancing lung function and structural integrity in related rat models. In the present study we hypothesize that surfactant replacement therapy reduces oedema formation in a pig model of NHBD lung transplantation. Oedema formation was quantified with (SF) and without (non-SF) surfactant replacement therapy in interstitial and alveolar compartments by means of design-based stereology in NHBD lungs 7 h after cardiac arrest, reperfusion and transplantation. A sham-operated group served as control. In both NHBD groups, nearly all animals died within the first hours after transplantation due to right heart failure. Both SF and non-SF developed an interstitial oedema of similar degree, as shown by an increase in septal wall volume and arithmetic mean thickness as well as an increase in the volume of peribron-chovascular connective tissue. Regarding intra-alveolar oedema, no statistically significant difference could be found between SF and non-SF. In conclusion, surfactant replacement therapy cannot prevent poor outcome after prolonged warm ischaemia of 7 h in this model. While the beneficial effects of surfactant replacement therapy have been observed in several experimental and clinical studies related to heart-beating donor lungs and cold ischaemia, it is unlikely that surfactant replacement therapy will overcome the shortage of organs in the context of prolonged warm ischaemia, for example, 7 h. Moreover, our data demonstrate that right heart function and dysfunctions of the pulmonary vascular bed are limiting factors that need to be addressed in NHBD.

Elevated CXCL10 (IP-10) in Bronchoalveolar Lavage Fluid Is Associated With Acute Cellular Rejection After Human Lung Transplantation

CXCL10 (IP-10) is a potent chemoattractant for T cells that has been postulated to play a role in infection and acute cellular rejection (ACR) in animal models. We measured CXCL10 (IP-10) (and other cytokines previously implicated in the pathogenesis of ACR) in the bronchoalveolar lavage (BAL) of lung transplant recipients (LTRs) to determine the association between CXCL10 (IP-10) and ACR in LTRs. In a prospective study of 85 LTRs, expression of cytokines (tumor necrosis factor, interferon-γ, interleukin [IL]-6, IL-8, IL-15, IL-16, IL-17, CXCL10 [IP-10], and MCP-1 [CCL2]) in BAL samples (n=233) from patients with episodes of ACR (n=44), infection ("Infect"; n=25), concomitant "Infect+ACR" (n=10), and "No Infect and No ACR" (n=154) were analyzed. The levels of both CXCL10 (IP-10) and IL-16 were significantly increased in histologically proven ACR compared with the "No Infect and No ACR" group (CXCL10 [IP-10]: 107.0 vs. 31.9 pg/mL [P=0.001] and IL-16: 472.1 vs. 283.01 pg/mL [P=0.01]). However, in a linear mixed-effects model, significant association was found only between CXCL10 (IP-10) and ACR. A one-log increase of CXCL10 (IP-10) was associated with a 40% higher risk of ACR (odds ratio, 1.4; 95% confidence interval, 1.12-1.84). Higher values of CXCL10 (IP-10) in BAL fluid are associated with ACR in LTRs, suggesting a potential mechanistic role in the pathogenesis of ACR in LTRs. These results suggest that therapeutic strategies to inhibit CXCL10 (IP-10) and or its cognate receptor, CXCR3, warrant investigation to prevent and/or treat ACR in clinical lung transplantation.

Overview of clinical lung transplantation.

Since the first successful lung transplant 30 years ago, lung transplantation has rapidly become an established standard of care to treat end-stage lung disease in selected patients. Advances in lung preservation, surgical technique, and immunosuppression regimens have resulted in the routine performance of lung transplantation around the world for an increasing number of patients, with wider indications. Despite this, donor shortages and chronic lung allograft dysfunction continue to prevent lung transplantation from reaching its full potential. With research into the underlying mechanisms of acute and chronic lung graft dysfunction and advances in personalized diagnostic and therapeutic approaches to both the donor lung and the lung transplant recipient, there is increasing confidence that we will improve short- and long-term outcomes in the near future.

Finding the optimal balance between extending limits and achieving outcomes

Finding the optimal balance between extending limits and achieving outcomes

Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles

Airway tissue ischemia and hypoxia in human lung transplantation is a consequence of the sacrifice of the bronchial circulation during the surgical procedure and is a major risk factor for the development of airway anastomotic complications. Augmented expression of hypoxia-inducible factor (HIF)-1α promotes microvascular repair and alleviates allograft ischemia and hypoxia. Deferoxamine mesylate (DFO) is an FDA-approved iron chelator which has been shown to upregulate cellular HIF-1α. Here, we developed a nanoparticle formulation of DFO that can be topically applied to airway transplants at the time of surgery. In a mouse orthotopic tracheal transplant (OTT) model, the DFO nanoparticle was highly effective in enhancing airway microvascular perfusion following transplantation through the production of the angiogenic factors, placental growth factor (PLGF) and stromal cell-derived factor (SDF)-1. The endothelial cells in DFO treated airways displayed higher levels of p-eNOS and Ki67, less apoptosis, and decreased production of perivascular reactive oxygen species (ROS) compared to vehicle-treated airways. In summary, a DFO formulation topically-applied at the time of surgery successfully augmented airway anastomotic microvascular regeneration and the repair of alloimmune-injured microvasculature. This approach may be an effective topical transplant-conditioning therapy for preventing airway complications following clinical lung transplantation.

Heparin does not seem to improve the function of pulmonary grafts for lung transplantation

Background. It has been debated whether or not heparin infusion before or after non-heart-beating donors are declared dead improves the quality of pulmonary grafts. In clinical lung transplantation with heart-beating donors (HBDs) heparin is routinely infused prior to organ harvesting since it is believed to improve pulmonary grafts by minimizing thrombosis formation in the pulmonary grafts. Here, we raise the question of whether or not the use of heparin in HBDs improves the quality of the pulmonary grafts. Methods. Twelve landrace pigs were divided into two groups of six animals; heparin was given prior to lung harvesting in one group, while the other group did not receive any heparin. The lungs were evaluated using an ex vivo lung perfusion (EVLP) method. Results. No significant difference in arterial oxygen partial pressure (PaO2) was observed between the two groups at an inspired oxygen fraction (FiO2) of 1.0 (mean 69.2 kPa, range 46.1–77.0 in the non-heparin group, and 61.6 kPa, range 47.9–71.4 in the heparin group, p = 0.44), neither in pulmonary vascular resistance: mean 543 ((dyne × s)/cm5) (range 280–615) in the non-heparin group and 533 ((dyne × s)/cm5) (320–762) in the heparin group (p = 0.99). Conclusions. Heparin did not seem to improve pulmonary graft function in our animal model using conventional HBDs.

Ex Vivo Lung Perfusion

There is a critical mismatch between the number of donor lungs available and the demand for lungs for transplantation. This has created unacceptably high waiting-list mortality for lung transplant recipients. Currently (2012) in the United Kingdom, there are 216 patients on the lung transplant waiting list and 17 on heart and lung transplant list. The waiting times for suitable lungs average 412 days, with an increasing mortality and morbidity among the patients on the lung transplant list. Ex vivo lung perfusion (EVLP) has emerged as a technique for the assessment, resuscitation, and potential repair of suboptimal donor lungs. This is a rapidly developing field with significant clinical implications. In this review article, we critically appraise the background developments that have led to our current clinical practice. In particular, we focus on the human and animal experience, the different perfusion-ventilation strategies, and the impact of different perfusates and leukocyte filters. Finally, we examine EVLP as a potential research tool. This will provide insight into EVLP and its future development in the field of clinical lung transplantation.

Hemoconcentration in ex vivo lung perfusion: A case report of a novel technique used in clinical lung transplantation

Reconditioning of initially rejected donor lungs during ex vivo lung perfusion (EVLP) may increase the number of patients treated with a lung transplantation. Multiorgan donors often suffer from circulatory instability and therefore may be treated with massive crystalloid fluid infusions, which can result in pulmonary edema. EVLP of the donor lungs with a hyperoncotic perfusate theoretically can decrease the lung water content by absorbing alveolar and interstitial edema. The oncotic pressure of the perfusate, however, will decrease during per-

Metabolites in Human Ex Vivo Lung Perfusates Are Differentially Affected in Brain Death (BDD) vs. Cardiac Death Donors (DCD) and Modified by Duration of Normothermic Perfusion

Purpose Normothermic Ex Vivo Lung Perfusion (EVLP) has increased our clinical lung transplantation (LTx) activity by 20% by salvaging marginal lungs, with satisfactory clinical outcomes. Rewarming these lungs on EVLP from 4°C to 37°C normalizes metabolic activity, and studying the dynamic metabolomic profile may help us understand lung injury and predict the ultimate function of the transplanted lung. Metabolic profiling of EVLP perfusate may elucidate the metabolic changes of donor lungs on EVLP. Methods and Materials Donor lungs from 28 BDD and 22 DCD donors were assessed on EVLP for 4 hours prior to LTx. For each lung, EVLP perfusate was sampled at 1 hr and 4 hr perfusion, and global metabolomic profiling was performed with Mass Spectrometry. We examined the results over time and with respect to BDD vs. DCD status. Results Global metabolomics detected 312 metabolites. Statistical analysis with Random Forest (RF) classification showed a dramatic difference in metabolite profiles between EVLP 1hr and 4hr with a 96% accuracy in predicting whether a sample was taken at the start or end of EVLP perfusion. Interestingly, the metabolic profiles grouped by donor status were sufficiently different to be able to predict with RF whether a sample belongs to BDD or DCD donor, with an accuracy of 80% at 1hr and 78% at 4 hr EVLP. Conclusions As we search for opportunities to personalize the diagnosis and treatment of the donor lung, it is evident that EVLP perfusate is easily accessible and is imminently suitable for metabolomics. The changes in metabolites in donor lungs as EVLP progresses confirms that cellular metabolism is active and modified over time in normothermic EVLP. The metabolomic profile demonstrates significant differences between BDD and DCD donor lungs during EVLP as well as dynamic changes over time. Further work is required to determine which of these metabolic changes are important to guide diagnosis, treatment and outcome prediction in EVLP donor lungs used for LTx.

Three Center Experience with Clinical Normothermic Ex Vivo Lung Perfusion

Purpose Normothermic ex vivo lung perfusion (EVLP) is a method to evaluate and improve function of injured donor lungs. We reviewed 3-center experience using the previously described Toronto EVLP technique. Methods and Materials A retrospective study of independently collected data from 3 centers and then combined for this analysis. Brain death donor (BDD) and cardiac death donor (DCD) lungs considered to be of high risk for transplantation were subjected to 3-6h of EVLP. Lungs that achieved stable airway and vascular pressures, and a delta PaO 2 /FiO 2 over 350mmHg during EVLP were considered for transplantation. Utilization rates after EVLP, incidence of primary graft dysfunction (PGD) ISHLT grade 3 at 24h and 72h after transplantation, duration of mechanical ventilation, hospital length of stay (LOS), airway complications, and proportional survival at 1year were analyzed. Results Between Sept 2008 and Aug 2012, a total of 125 clinical EVLP were performed. Ninety (72%) were BDD lungs and 35(28%) were DCD lungs. Of the 125 procedures, 103 lungs (82.5% utilization after EVLP) were subsequently transplanted. Median donor PaO 2 /FiO 2 was 268(92-529) mmHg. Recipient diagnosis was emphysema (n=32), pulmonary fibrosis (n=31), cystic fibrosis (n=28), and other (n=12). Seven patients (7%) were on extracorporeal life support prior to LTx. Incidence of PGD 3 at 24h and 72h were 7% and 5% respectively. Median time to extubation, and hospital LOS were 2 (1-99) and 23(7-120) days. Thirty-day mortality was 4% and proportional survival at 1 year was 88%. Airway complications requiring intervention occurred in 6 patients (6%). Conclusions This is the largest report to date of EVLP in clinical lung transplantation. 85% of lungs treated with EVLP were successfully transplanted with excellent short and intermediate outcomes. This strategy promises to further increase the safe utilization rates of questionable donor lungs and the overall outcomes of lung transplantation.

The Selective JAK1/3 Inhibitor R507 Prevents Acute Rejection and Chronic Obliteration of Transplanted Rat Tracheas

Purpose Despite advances in the field of immunosuppression, obliterative airway disease remains an unsolved problem after clinical lung transplantation and the incidence of chronic renal failure remains high. The efficacy of the highly selective JAK1/3 inhibitor R507 on preclinical airway transplantation was investigated. Methods and Materials Orthotopic Lew-BN trachea transplantations were performed. Treatment groups received oral R507 (60mg/kg BID) or everolimus (4mg/kg QD). Mechanistic studies were performed in vitro using full-thickness human airway epithelium and R507-enriched medium. Results On postoperative day 6, mononuclear CD3 and CD68 graft infiltration were significantly reduced in both treatment groups compared to the control group, but significantly more potently with R507. IFN-γ Elispot frequencies were significantly lower with R507 and everolimus treatment. At 60 days, airway obliteration was significantly reduced from 32±5% in the control group to 24±6% (p=0.004) and 14±5% (p Conclusions R507 is a potent lymphocyte-targeting immunosuppressant without kidney and airway toxicity. It effectively prevents acute graft rejection as well as the development of obliterative airway disease. We believe it will be a valuable drug for lung transplantation.

The effect of age and emphysematous and fibrotic injury on the re-cellularization of de-cellularized lungs

Use of de-cellularized cadaveric lungs as 3-dimensional scaffolds for ex vivo lung tissue generation offers a new potential therapeutic approach for clinical lung transplantation. However, it is likely that some of the available cadaveric human lungs may be from older donors or from donors with previously existing structural lung diseases such as emphysema or pulmonary fibrosis. It is not known whether these lungs will be suitable for either de-cellularization or re-cellularization. To investigate this, we assessed the effects of advanced age, representative emphysematous and fibrotic injuries, and the combination of advanced age and emphysematous injury and found significant differences both in histologic appearance and in the retention of extracellular matrix (ECM) and other proteins, as assessed by immunohistochemistry and mass spectrometry, between the different conditions. However, despite these differences, binding, retention and growth of bone marrow-derived mesenchymal stromal cells (MSCs) over a 1-month period following intratracheal inoculation were similar between the different experimental conditions. In contrast, significant differences occurred in the growth of C10 mouse lung epithelial cells between the different conditions. Therefore, age, lung injury, and the cell type used for re-cellularization may significantly impact the usefulness of de-cellularized whole lungs for ex vivo lung tissue regeneration.

The selective JAK1/3 inhibitor R507 prevents acute rejection and chronic obliteration of transplanted rat tracheas

Purpose Despite advances in the field of immunosuppression, obliterative airway disease remains an unsolved problem after clinical lung transplantation and the incidence of chronic renal failure remains high. The efficacy of the highly selective JAK1/3 inhibitor R507 on preclinical airway transplantation was investigated. Methods and Materials Orthotopic Lew-BN trachea transplantations were performed. Treatment groups received oral R507 (60mg/kg BID) or everolimus (4mg/kg QD). Mechanistic studies were performed in vitro using full-thickness human airway epithelium and R507-enriched medium. Results On postoperative day 6, mononuclear CD3 and CD68 graft infiltration were significantly reduced in both treatment groups compared to the control group, but significantly more potently with R507. IFN-γ Elispot frequencies were significantly lower with R507 and everolimus treatment. At 60 days, airway obliteration was significantly reduced from 32±5% in the control group to 24±6% (p=0.004) and 14±5% (p Conclusions R507 is a potent lymphocyte-targeting immunosuppressant without kidney and airway toxicity. It effectively prevents acute graft rejection as well as the development of obliterative airway disease. We believe it will be a valuable drug for lung transplantation.

Editorial Comment: Expanding lung donation: the use of uncontrolled non-heart beating donors

cadaver up to six hours after cardiac arrest. J Heart Lung Transplant 1999;18:582–6. [19] Wierup P, Bolys R, Steen S. Gas exchange function one month after transplantation of lungs topically cooled for 2 hours in the non-heart-beating cadaver after failed resuscitation. J Heart Lung Transplant 1999;18:133–8. [20] Steen S, Kimblad PO, Sjoberg T, Lindberg L, Ingemansson R, Massa G. Safe lung preservation for twenty-four hours with Perfadex. Ann Thorac Surg 1994;57:450–7. [21] Marasco SF, Bailey M, McGlade D, Snell G, Westall G, Oto T et al. Effect of donor preservation solution and survival in lung transplantation. J Heart Lung Transplant 2011;30:414–9. [22] Okazaki M, Date H, Inokawa H, Okutani D, Aokage K, Nagahiro I et al. Optimal time for post-mortem heparinization in canine lung transplantation with non-heart-beating donors. J Heart Lung Transplant 2006;25: 454–60. [23] Cypel M, Yeung JC, Liu M, Anraku M, Chen F, Karolak W et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011;364:1431–40.

Update on lung transplantation: programmes, patients and prospects

The will is infinite and the execution confined…the desire is boundless and the act a slave to limit Shakespere W. Troilus and Cressida . Act III, Scene ii. Discovery consists of seeing what everyone has seen and thinking what nobody has thought Anonymous It has been over 30 yrs since the modern era of lung transplantation commenced and what was then the “new frontier and exceptional” has now become “routine and expected”. Strong vision, bold action and creative thinking have led to outstanding progress in the management of end-stage lung and pulmonary vascular disease. The purpose of this article is to highlight what has been achieved, critically assess where we are in terms of a “cure” for severe lung disease, and (re)stimulate the creative thinking, action and vision that are still very much required to solve the ongoing impediments to achieving a durable lung allograft and long-term recipient survival following the life-giving procedure that lung transplantation is, and can be. ### History and programme evolution: from cottage industry to just expected Lung transplantation has evolved over the last 60 yrs from a series of remarkable animal experiments to an established treatment of severe end-stage lung and pulmonary vascular disease fully funded in many jurisdictions. In its infancy it was swept along by the determination and drive of surgical pioneers. Amongst them the names Demikhov, Hardy, Schumway, Cooley, Reitz, Cooper and Patterson have exemplified the surgeons’ drive to bring lung transplantation to clinical fruition. With long-term survivors of heart–lung transplantation (HLTx) from 1981 [1], single lung transplantation (SLT) from 1983 [2] and bilateral lung transplantation (BLTx) from 1985 [3], this decade saw the true genesis of clinical lung transplant programmes. HLTx became the early option for lung replacement with Stanford University (Stanford, CA, USA) leading the way under the leadership of Bruce Reitz. A second key …

Warm Perfusion of the Donor Lung for Preservation Might Have Positive Immunomodulatory Effects after Transplantation

Purpose: The Organ Care system (OCS) used for warm donor lung perfusion in a pilot study in our clinical lung transplant program might have more positive effects in the postoperative course besides an influence on reperfusion injury. In order to monitor a favourable immunological course after lung transplantation, we compared the presence of regulatory T cells (Treg) between patients who received standard lung conservation and those which lungs were treated with OCS. Methods and Materials: 89 donor lungs were treated with regular cold lung preservation, whereas 7 donor lungs were treated with warm cellular preservation and concomitant ventilation. In all patients receving these grafts, the number of circulating Tregs was measured by flow cytometry preoperatively as well as 3 weeks and 3 months after transplantation. Putative Treg were defined as CD4+CD25high T cells and were further analyzed for different surface as well as intracellular molecules such as CD152, CD127 as well as FoxP3. Results: A total of 89 patients receving standard lung conservation were included into the study and compared to 7 patients receiving OCS treatment. OCS treated patients showed significantly more CD4+CD25+ Treg in the early postoperative course (until 3months postop) (p< 0.05) as well as CD127low Treg (p< 0.05). There was no significant difference in the proportion of CD152+- or FoxP3+-Treg. Conclusions: The number of circulating Treg in the peripheral blood and therefore potentially the clinical course after transplantation may be influenced by the modus of lung preservation.

Ex Vivo Adenoviral Vector Gene Delivery Results in Decreased Vector-associated Inflammation Pre- and Post–lung Transplantation in the Pig

Acellular normothermic ex vivo lung perfusion (EVLP) is a novel method of donor lung preservation for transplantation. As cellular metabolism is preserved during perfusion, it represents a potential platform for effective gene transduction in donor lungs. We hypothesized that vector-associated inflammation would be reduced during ex vivo delivery due to isolation from the host immune system response. We compared ex vivo with in vivo intratracheal delivery of an E1-, E3-deleted adenoviral vector encoding either green fluorescent protein (GFP) or interleukin-10 (IL-10) to porcine lungs. Twelve hours after delivery, the lung was transplanted and the post-transplant function assessed. We identified significant transgene expression by 12 hours in both in vivo and ex vivo delivered groups. Lung function remained excellent in all ex vivo groups after viral vector delivery; however, as expected, lung function decreased in the in vivo delivered adenovirus vector encoding GFP (AdGFP) group with corresponding increases in IL-1β levels. Transplanted lung function was excellent in the ex vivo transduced lungs and inferior lung function was seen in the in vivo group after transplantation. In summary, ex vivo delivery of adenoviral gene therapy to the donor lung is superior to in vivo delivery in that it leads to less vector-associated inflammation and provides superior post-transplant lung function.

Clinical lung transplantation from uncontrolled non–heart-beating donors revisited

The aim of our study is to review and update the long-term results from our previously published series of lung transplantation in uncontrolled non-heart-beating donors (NHBDs). A prospective collection of data was undertaken from all lung transplants performed among uncontrolled NHBDs between 2002 and December 2009. The statistical analysis was performed using SPSS software and survival was estimated using the Kaplan-Meier method. Twenty-nine lung transplants were performed. Mean total ischemic times for the first and second lung were 575 minutes (SD 115.6) and 701 minutes (SD 111.3), respectively. Primary graft dysfunction (PGD) G1, G2 and G3 occurred in 5 cases (17%), 5 cases (17%) and 11 cases (38%), respectively. Overall hospital mortality rate was 17% (5 patients). Statistical analysis revealed a statistically significant association of mortality with ischemic times and with PGD. In terms of overall survival, 3-month, 1-year, 2-year and 5-year survival rates were 78%, 68%, 57% and 51%, respectively, and the conditional survival rates in those who survived the first 3 months were 86%, 72% and 65%, respectively. The cumulative incidence of bronchiolitis obliterans syndrome (BOS) was 11%, 35% and 45% at 1, 3 and 5 years, respectively. Lung transplantation from uncontrolled non-heart-beating donors shows acceptable results for both mid- and long-term survival and BOS; however, the higher rates of PGD and its impact on early mortality must make us more demanding with respect to the acceptance criteria and methods of evaluation used with these donors.

Possibility of clinical lung transplantation from non-heart-beating donors based on our experiences of animal experimental models

Possibility of clinical lung transplantation from non-heart-beating donors based on our experiences of animal experimental models