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CRISPR/Cas9-mediated gene editing often generates founder generation (F0) mice that exhibit somatic mosaicism in the targeted gene(s). It has been known that Fibroblast growth factor 10 (Fgf10)-null mice exhibit limbless and lungless phenotypes, while intermediate limb phenotypes (variable defective limbs) are observed in the Fgf10-CRISPR F0 mice. However, how the lung phenotype in the Fgf10-mosaic mutants is related to the limb phenotype and genotype has not been investigated. In this study, we examined variable lung phenotypes in the Fgf10-targeted F0 mice to determine if the lung phenotype was correlated with percentage of functional Fgf10 genotypes. Firstly, according to a previous report, Fgf10-CRISPR F0 embryos on embryonic day 16.5 (E16.5) were classified into three types: type I, no limb; type II, limb defect; and type III, normal limbs. Cartilage and bone staining showed that limb truncations were observed in the girdle, (type I), stylopodial, or zeugopodial region (type II). Deep sequencing of the Fgf10-mutant genomes revealed that the mean proportion of codons that encode putative functional FGF10 was 8.3 ± 6.2% in type I, 25.3 ± 2.7% in type II, and 54.3 ± 9.5% in type III (mean ± standard error of the mean) mutants at E16.5. Histological studies showed that almost all lung lobes were absent in type I embryos. The accessory lung lobe was often absent in type II embryos with other lobes dysplastic. All lung lobes formed in type III embryos. The number of terminal tubules was significantly lower in type I and II embryos, but unchanged in type III embryos. To identify alveolar type 2 epithelial (AECII) cells, known to be reduced in the Fgf10-heterozygous mutant, immunostaining using anti-surfactant protein C (SPC) antibody was performed: In the E18.5 lungs, the number of AECII was correlated to the percentage of functional Fgf10 genotypes. These data suggest the Fgf10 gene dose-related loss of the accessory lobe and decrease in the number of alveolar type 2 epithelial cells in mouse lung. Since dysfunction of AECII cells has been implicated in the pathogenesis of parenchymal lung diseases, the Fgf10-CRISPR F0 mouse would present an ideal experimental system to explore it., Competing Interests: Supported by an academic grant from Pfizer Japan, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Postoperative changes in pulmonary function (PF) and morphology due to surgical chest wall damage by thoracotomy with rib resection are unclear. Therefore, we evaluated the effects of surgical damage on PF and morphology at > 6 months postoperatively by comparing different lung lobectomy approaches., Methods: A total of 140 patients who underwent lobectomy for lung diseases between January 2006 and March 2016 were analyzed. Patients who underwent PF tests and computed tomography (CT) scans preoperatively and postoperatively were divided into posterolateral thoracotomy with one rib resection (PT) group and video-assisted thoracoscopic surgery (VATS) group. A 1:1 propensity score-matched (PSM) analysis was used to balance clinically important confounders between the groups. Regarding morphology, lung volume was measured semi-automatically using image analysis software and reconstructed three-dimensional (3D) images., Results: After PSM, 31 patients in each group were compared. Perioperative reduction ratios in forced vital capacity (FVC) (- 23% vs. - 13%; P = 0.006) and forced expiratory volume in 1 s (FEV1) (- 19% vs. - 12%; P = 0.02) were significantly larger for the PT group. No significant differences in lung volume values based on 3D CT volumetry (PT vs. VATS; total lung volume: - 7.9% vs. - 7.2%, P = 0.82; non-resected ipsilateral lung volume: + 36% vs. + 40%, P = 0.69; contralateral lung volume: + 9.3% vs. + 9.4%, P = 0.98) were found in either group., Conclusions: Among the patients underwent lobectomy, classic thoracotomy decreased PF by an additional FVC loss of 10% and FEV1 loss of 7% compared with VATS, without affecting residual lung volume.

We report a case with suggestive antiprogrammed death-1 inhibitor-related pneumonitis in an endometrial cancer patient. This case presented with fever and cough after three dosages of nivolumab. Computed tomography initially showed centrilobular nodularities in a unilateral lung, which was compatible with aspiration pneumonia. However, diffuse ground-glass opacities (GGO) rapidly developed in the unilateral lung over 4 days despite the use of broad-spectrum antibiotics. Development of GGO was considered to be related to a nivolumab-mediated immune reaction. Corticosteroid was administered and the GGO subsequently disappeared. The present report focuses on the computed tomography diagnostic features of nivolumab-related pneumonitis. The accumulation of knowledge regarding various types of antiprogrammed death-1-related pneumonitis will lead to appropriate treatment for this newly emerging adverse event.

Because of the severe donor shortage in Japan, even after the revision of the Organ Transplant Law in 2010, the frequency of recovery of extended criteria lungs has increased in Japan. We developed a new lung preservation solution, "ET-Kyoto solution," to enhance lung preservation, to minimize primary graft dysfunction (PGD) and to improve the post-transplant outcomes. In this study, we retrospectively analyzed our results of lung transplantation using the ET-Kyoto solution. From 2002 to 2012, 26 patients underwent transplantation of lungs preserved with ET-Kyoto solution from brain-dead donors. We retrospectively reviewed the post-transplant pulmonary function and long-term survival. The graft performance was assessed by the PGD grading system. The mean graft ischemic time was 483.8 ± 19.0 min. The oxygenation capacity after reperfusion and recovery of respiratory function were both acceptable despite the long ischemic time. The survival rate at 5 years after transplantation was 85.1 %. Lungs preserved by ET-Kyoto solution had satisfactory postoperative lung function, despite the long preservation time, with excellent long-term survival. The results were acceptable for the use of grafts with a long ischemic time.

Background: Donor lung thrombus is considered a significant etiology for primary graft dysfunction (PGD). We hypothesized that thrombolysis in ex vivo lung perfusion (EVLP) before lung transplantation could alleviate ischemia-reperfusion injury (IRI), resulting in a decreased incidence of PGD., Methods: Rats were divided into control (n = 5), non-plasmin (n = 7) and plasmin (n = 7) groups. In the non-plasmin and plasmin groups, cardiac arrest was induced by withdrawal of ventilation without heparinization. After 120 minutes of warm ischemia, the lungs were ventilated and flushed. Hearts and both lungs were excised en bloc. The lungs were perfused and ventilated in the EVLP for 30 minutes, and plasmin or placebo was administered on EVLP initiation. The lungs were then stored at 4°C for 90 minutes and finally perfused with rat blood for 80 minutes. We assessed physiologic and histologic findings during reperfusion and the correlation between physiologic data during EVLP and after reperfusion., Results: Physiologic results were better in the plasmin group than in the non-plasmin group. The plasmin group lungs had fewer signs of histologic injury. Caspase-3 and -7 activity in the plasmin group was lower in the non-plasmin group. Pulmonary vascular resistance (PVR) during EVLP correlated with that at the end of reperfusion., Conclusions: Plasmin administration during EVLP protected the donor lungs after reperfusion. We also found that several physiologic values in EVLP may be predictive markers of lung function after reperfusion., (Copyright © 2014 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: Surgical lung biopsy (SLB) by videothoracoscopy for diffuse interstitial lung diseases is recommended for detailed diagnosis. Because substantial mortality and morbidity are associated with this procedure, its safety and diagnostic yield should be validated., Methods: Sixty-four patients with diffuse interstitial lung disease who received SLB by videothoracoscopy between 2007 and 2013 were retrospectively analyzed for mortality, surgical complication, and diagnosis. Criteria for the procedure included patients <70-year old, who had at least 60 % vital capacity and at least 40 % diffusion capacity. Patients with radiologically definite usual interstitial pneumonia were not eligible., Results: One conversion from the 3-port approach to thoracotomy due to bleeding occurred. Mean operation and anesthesia times were 63 and 133 min, respectively. The mean hospital stay was 6 days. Only 10 patients (16 %) received prophylactic steroid and/or elastase inhibitor administration. Neither deaths nor acute exacerbations of interstitial pneumonia occurred within 60 days after surgery. Pneumothorax occurred in four cases (6 %) after discharge, which was associated with lower % vital capacity and intraoperative steroid administration. Prolonged air leak and postoperative pneumonia were observed in 2 and 1 patients, respectively. Postoperative diagnosis was obtained in all patients. A group of connective tissue disease-related interstitial pneumonia (n = 15) and chronic hypersensitivity pneumonitis (n = 18) were the major diagnoses. Discordance between pre- and postoperative diagnoses was observed among usual interstitial pneumonia, non-specific interstitial pneumonia, and chronic hypersensitivity pneumonia., Conclusions: Surgical lung biopsy for diffuse interstitial lung diseases is safe under appropriate inclusion criteria and provides definite diagnosis.

Objective: Although double lung transplantation is performed more frequently for emphysema, single lung transplantation (SLT) continues to be performed owing to limited donor organ availability. Native lung hyperinflation (NLH) is a unique complication following SLT for emphysema. Three-dimensional computed tomography (3D-CT) volumetry has been introduced into the field of lung transplantation, which we used to assess NLH in emphysema patients undergoing SLT. The primary purpose of this study was to confirm the effectiveness of 3D-CT volumetry in the evaluation of NLH following SLT for emphysema., Methods: In 5 emphysema patients undergoing SLT at Kyoto University Hospital, 3D-CT volumetry data, pulmonary function test results, and clinical and radiological findings were retrospectively evaluated., Results: Three patients did not develop a significant mediastinal shift, whereas the other 2 patients developed a mediastinal shift. In the 3 patients without a mediastinal shift, 3D-CT volumetry did not show a significant increase in native lung volume. These patients had a history of sternotomy prior to lung transplantation and firm adhesion on the mediastinal side was detected during lung transplantation. One of 2 patients with a mediastinal shift developed severe dyspnea with significantly decreased pulmonary function, and 3D-CT volumetry showed a significant increase in the native lung volume. However, the other patient did not show any dyspnea and his native lung volume decreased postoperatively (preoperatively to 6 months postoperatively: +981 mL and -348 mL, respectively)., Conclusion: Although bilateral lung transplantation has become preferable for emphysema patients owing to postoperative NLH with SLT, patients with a history of sternotomy prior to lung transplantation might be good candidates for SLT. 3D-CT volumetry may be a useful method for detection of NLH., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Living-lung donors lose pulmonary function of a right or left lower lobe in exchange for a noble donation; however, Chen and colleagues reported postoperative pulmonary function of the donors was significantly better than the estimated values. The purpose of this study was to investigate if the improvement of postoperative pulmonary function is associated with hypertrophic phenomena of remnant lung., Methods: A total of 35 patients who underwent a right or left lower lobectomy for living-donor lobar lung transplantation in Kyoto University Hospital from 2008 to 2011 were evaluated by means of spirometry (forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide), and computed tomography scans both before and 1 year after the surgery. Postoperative predictions of pulmonary function and radiologic parameters were made based on the number of resected segments. The average radiologic density of the lung was determined as follows: (mean computed tomography number + 1000)/1000, and weight of the lung was calculated as follows: lung volume (mL) × average radiologic lung density (g/mL). The radiologic analysis was performed on both the surgical and contralateral sides., Results: Postoperative forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide were significantly higher than estimated values by 17.3% ± 10.2% (P < .0001), 14.7% ± 10.2% (P < .0001), and 10.9% ± 16. % (P < .002), respectively. Postoperative lung volume and weight of the surgical side were significantly higher than estimated values by 54.4% ± 30.4% (P < .0001) and 28.1% ± 15.7% (P < .0001), respectively. On the contralateral side, the postoperative lung volume was significantly higher than the estimated value by 12.6% ± 15.3% (P < .0001), but postoperative weight was comparable with the estimated value (-2.3% ± 8.8%; P = .07)., Conclusions: Hypertrophic change of the ipsilateral remnant lung may be recognized in living lung donors., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The success of living-donor lobar lung transplantation (LDLLT) largely depends on donor outcome; but to date, no authors have studied health-related quality of life (HRQOL) of donors. We prospectively evaluated multidimensional outcomes before and 1 year after donor lobectomies. Patient-reported HRQOL, dyspnea, psychological status and sleep quality, and physiological pulmonary function were determined. All donors were alive without any limitations in their activities of daily living after 1 year. Postoperative pulmonary function was better than the estimated preoperative values; but, with respect to HRQOL, four of the eight subscales of the Medical Outcomes Study 36-item short form (SF-36) deteriorated significantly after donation. In addition, dyspnea assessed by the modified Medical Research Council scale also worsened significantly. In contrast, postoperative anxiety assessed by the Hospital Anxiety and Depression Scale significantly improved from baseline. The donors whose recipients died reported lower SF-36 scores with worsening sleep quality measured by Pittsburgh Sleep Quality Index. Thus, although postoperative pulmonary functions in donors were preserved, their HRQOL and dyspnea deteriorated postoperatively. Moreover, HRQOL and sleep quality were impaired in recipients who experienced poor outcomes. To capture the comprehensive outcomes in LDLLT donors after donation, patient-reported outcomes should be analyzed separately from physiological outcomes., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Living-donor lobar lung transplantation (LDLLT), unlike deceased donor lung transplantation, often involves a wide range of size discrepancies between donors and recipients. The aim of this study was to evaluate the function of donor lung grafts in the recipient thorax in 14 cases of bilateral LDLLT involving 28 successfully transplanted lower-lobe grafts. Pulmonary function tests and three-dimensional computed tomography (3D-CT) volumetry were performed perioperatively. According to 3D-CT size matching, donor graft volumes ranged from 40% to 161% of the hemilateral thoracic volumes of the recipients. Graft forced vital capacity (FVC) values increased over time, reaching 102 ± 39% of preoperatively estimated values at 12 months postoperatively. Graft volumes also increased over time, reaching 120 ± 38% of the original values at 12 months postoperatively. Undersized donor grafts expanded more after LDLLT than oversized donor grafts, producing greater FVC values than those estimated preoperatively, whereas oversized donor grafts became inflated to their original size and maintained FVC values that approached the preoperative estimates. Thus, donor grafts were found to overinflate or underinflate to the extent that they could preserve their native function in the new recipient's environment., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Donor lung thrombi are considered an important etiology for primary graft dysfunction in lung transplantation. We hypothesized that thrombolysis before lung transplantation could alleviate ischemia-reperfusion injury. This study was designed to evaluate the effect of the fibrinolytic agent plasmin on lungs damaged by thrombi in an ex vivo lung perfusion (EVLP) system., Methods: Rats were divided into control, non-plasmin, and plasmin groups (n = 7 each). In the control and plasmin groups, cardiac arrest was induced by withdrawal of mechanical ventilation without heparinization. Ventilation was restarted 150 minutes after cardiac arrest. The lungs were flushed, and the heart and lungs were excised en bloc. The lungs were perfused in the EVLP system for 60 minutes, and plasmin or placebo was administered upon EVLP initiation., Results: Fibrin/fibrinogen degradation products in the perfusate were significantly higher in the plasmin group than in the control and non-control groups (p < 0.001 for both). Plasmin administration significantly decreased pulmonary vascular resistance (plasmin vs non-plasmin, p = 0.011) and inhibited the exacerbation of dynamic compliance (plasmin vs non-plasmin, p = 0.003). Lung weight gain was less in the plasmin group than in the non-plasmin group (p = 0.04)., Conclusions: Our results confirmed that plasmin administration in an EVLP model dissolved thrombi in the lungs, resulting in reconditioning of the lungs as assessed by various physiologic parameters., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

A combination of inspiratory and expiratory three-dimensional computed tomographic volumetry provides useful information on pulmonary function and lung volume. We previously reported an early outcome of a patient undergoing living-donor lobar lung transplantation with sparing of the bilateral native upper lobes. Long-term follow-up on such patients had not been reported, and therefore we herein, for the first time, reported the 2-year follow-up of the previously reported case. According to the inspiratory and expiratory three-dimensional computed tomographic volumetric data, we demonstrated that transplanted lower lobe grafts had been working efficiently and spared bilateral native upper lobes had not provided any adverse effects.

Background: Hypothermic machine perfusion (HMP) is widely used to preserve kidneys and livers for transplantation. This study investigated whether short-term HMP could improve the quality of lungs donated after cardiac death (DCD)., Methods: In a clinically relevant uncontrolled DCD model, beagles were divided into two groups (n=5 each): 4 hr warm ischemia + 14 hr static cold storage (SCS group) or 4 hr warm ischemia + 12 hr SCS followed by 2 hr HMP (HMP group). HMP was performed using centrifugal perfusion with STEEN solution at approximately 10°C. In both groups, the left lungs were then transplanted and reperfused for 4 hr to evaluate the posttransplantation lung functions., Results: HMP was performed safely, not inducing any oxidative damage. The dynamic pulmonary compliance was stable during HMP, whereas the pulmonary vascular resistance significantly decreased. HMP microscopically eliminated residual microthrombi in the donor lungs just before transplantation. The lung tissue adenosine triphosphate levels 4 hr after reperfusion were significantly higher in the HMP group compared with the SCS group. The serum malondialdehyde levels and proinflammatory cytokine levels in the bronchoalveolar lavage fluid 4 hr after reperfusion were significantly lower in the HMP group than in the SCS group. The physiologic lung functions during reperfusion were significantly better in the HMP group compared with the SCS group. HMP also significantly reduced ischemia-reperfusion injury in the microscopic findings., Conclusions: Short-term HMP could resuscitate ischemically damaged DCD lungs and ameliorate ischemia-reperfusion injury.

Warm ischemia-reperfusion injury related to donation after cardiac death donors is a crucial and inevitable issue. As surfactant function is known to deteriorate during warm ischemia, we hypothesized that surfactant inhalation during warm ischemia would mitigate warm ischemia-reperfusion injury. We used an isolated rat lung perfusion model. The rats were divided into three groups: sham, control, and surfactant. In the control and surfactant groups, cardiac arrest was induced by ventricular fibrillation. Ventilation was restarted 110 min later; subsequently, the lungs were flushed, and heart and lung block was recovered. In the surfactant group, a natural bovine surfactant Surfacten(®) was inhaled for 3 min at the end of warm ischemia. Then, the lungs were reperfused for 80 min. Surfactant inhalation significantly improved graft functions, effectively increased lung tissue ATP levels, and significantly decreased mRNA levels of IL-6 and IL-6/IL-10 ratio at the end of reperfusion. Histologically, lungs in the surfactant group showed fewer signs of interstitial edema and hemorrhage, and significantly less neutrophilic infiltration than those in the control group. Our results indicated that surfactant inhalation in the last phase of warm ischemia maintained lung tissue energy levels and prevented cytokine production, resulting in the alleviation of warm ischemia-reperfusion injury., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

Background: Warm ischemia-reperfusion injury related to donation after cardiac death is a crucial issue in transplantation. Because surfactant function deteriorates in lungs during warm ischemia, we hypothesized pre-recovery surfactant inhalation would mitigate warm ischemia-reperfusion injury., Methods: We rendered donor dogs cardiac dead and left them at room temperature. All animals received ventilation for 60 minutes starting at 240 minutes after cardiac arrest. The animals were divided into 2 groups: NS (normal saline, n = 7) group, which received aerosolized normal saline, and SF (surfactant; n = 5), which received aerosolized surfactant. The lungs were flushed and procured, and the left lung was transplanted into recipient dogs. At 45 minutes of reperfusion, the right pulmonary artery was ligated, and the left transplanted lung function was evaluated., Results: In the NS group, 2 of 7 dogs died at 75 minutes after reperfusion, whereas all 5 animals in the SF group survived for 240 minutes after reperfusion. The SF group showed significantly better dynamic compliance, oxygenation, and wet-to-dry weight ratio. Furthermore, the SF group had higher levels of high-energy phosphates in the lung tissues and lower levels of interleukin-8, tumor necrosis factor-α, and protein in the bronchoalveolar lavage fluid. Histologically, the lungs in the SF group showed fewer signs of interstitial edema and hemorrhage and significantly less neutrophilic sequestration than those of the NS group., Conclusions: Our results indicated pre-recovery surfactant inhalation improved graft function, maintained adenine nucleotide levels, and prevented alveolar-capillary barrier leakage, resulting in the attenuation of warm ischemia-reperfusion injury., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Living-donor lobar lung transplantation usually requires 2 healthy donors who donate either a right or a left lower lobe; however, finding 2 healthy donors is difficult. Several case reports have been published on successful living-donor lobar lung transplantation using a single donor; however, little is known about its outcome., Methods: We retrospectively investigated 14 critically ill patients who had undergone single living-donor lobar lung transplantation at 3 lung transplant centers in Japan. There were 10 female and 4 male patients, including 10 children and 4 adults. Size matching was assessed by estimated graft forced vital capacity and 3-dimensional computed tomography volumetry. The diagnoses included complications of allogeneic hematopoietic stem cell transplantation (n = 6), pulmonary hypertension (n = 4), and others (n = 4)., Results: At a mean follow-up of 45 months (range, 2-128), the 3- and 5-year survival rate was 70% and 56%, respectively. There were 4 early deaths, for a hospital mortality of 29%, with 1 additional death at 40 months. The main cause of early death was primary graft dysfunction, most likely related to size mismatching. The survival among these 14 patients was significantly worse than the survival in a group of 78 patients undergoing bilateral living-donor lobar lung transplantation during the same period (P = .044)., Conclusions: Single living-donor lobar lung transplantation provides acceptable results for sick patients who would die soon otherwise. However, bilateral living-donor lobar lung transplantation appears to be a better option if 2 living donors are found., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: It is a matter of great importance in a donation after cardiac death to attenuate ischemia-reperfusion injury (IRI) related to the inevitable warm ischemic time., Methods: Donor dogs were rendered cardiac-dead and left at room temperature. The dogs were allocated into 2 groups: the β-2 group (n = 5) received an aerosolized β-2 adrenoreceptor agonist (procaterol, 350 μg) and ventilation with 100% oxygen for 60 minutes starting at 240 minutes after cardiac arrest, and the control group (n = 6) received an aerosolized control solvent with the ventilation. Lungs were recovered 300 minutes after cardiac arrest. Recipient dogs underwent left single-lung transplantation to evaluate the functions of the left transplanted lung for 240 minutes after the reperfusion., Results: Oxygenation and dynamic compliance were significantly higher in the β-2 group than in the control group. The β-2 group revealed significantly higher levels of cyclic adenosine monophosphate and high-energy phosphates in the donor lung after the inhalation than before it. Histologic findings revealed that the β-2 group had less edema and fewer inflammatory cells., Conclusion: Our results suggest that β-2 adrenoreceptor agonist inhalation during the pre-procurement period may ameliorate IRI., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The use of donation-after-circulatory-death (DCD) donors for lung transplantation has come into practice. In this study we investigated whether DCD lungs can be resuscitated after warm ischemia with normothermic ex vivo lung perfusion (EVLP)., Methods: Four hours after cardiac arrest, beagle dogs were divided into two groups (n = 6 each): those with static cold storage (SCS group) and those with normothermic EVLP (EVLP group), for 3.5 hours. Physiologic lung functions were evaluated during EVLP. In both groups, the left lungs were then transplanted and reperfused for 4 hours to evaluate post-transplant lung functions. Lung tissue adenosine triphosphate (ATP) levels were measured at given time-points., Results: Lung oxygenation was significantly improved with EVLP (p < 0.01), and lung oxygenation at the end of EVLP significantly reflected post-transplant lung oxygenation (r = 0.99, p < 0.01). Post-transplant lung oxygenation was significantly better in the EVLP group than in the SCS group (p < 0.05). Both dynamic pulmonary compliance and wet-to-dry lung weight ratio 4 hours after transplantation were also significantly better in the EVLP group than in the SCS group (p < 0.05). Microthrombi in the donor lungs before transplantation were microscopically detected more often in the SCS group. The lung tissue ATP levels 4 hours after transplantation were significantly higher in the EVLP group compared with the SCS group (p = 0.03)., Conclusions: Normothermic ex vivo lung perfusion could resuscitate DCD lungs injured by warm ischemia, and may ameliorate ischemia-reperfusion injury., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Successful living-donor lobar lung transplantation (LDLLT) largely depends on donor outcome; however, there are few studies that have assessed outcomes of LDLLT donors, particularly pulmonary function. We investigated the outcomes and pulmonary function after donor lobectomy in LDLLT donors. Retrospective evaluation of consecutive 33 LDLLT donors was performed. Preoperative characteristics and perioperative and postoperative variables were investigated. Evaluation of pulmonary function 3, 6 and 12 months after donor lobectomy was performed prospectively. All donors were well alive after donor lobectomies. Morbidity was found in five donors (15%). Postoperative complications consisted of re-accumulation of pleural effusion requiring readmission in three donors and prolonged air leakage in two donors. Sacrifice of pulmonary arteries was performed in 20 donors (61%) with 1.4 ± 0.6 branches. Forced vital capacity was 77.8 ± 6.1%, 84.8 ± 6.0% and 89.4 ± 6.6% of the preoperative value 3, 6 and 12 months after donor lobectomy, respectively. Forced expiratory volume in 1 s was 80.5 ± 7.8%, 85.6 ± 8.9% and 89.3 ± 8.7% of the preoperative value 3, 6, and 12 months postoperatively. Living-donor lobectomy was performed with low morbidity. Pulmonary function even after lobectomy was better preserved than expected., (© 2011 The Authors. Transplant International © 2011 European Society for Organ Transplantation.)

Background: The use of non-heart-beating donors (NHBD) has come into practice to resolve the shortage of donor lungs. This study investigated whether hypothermic machine perfusion (HMP) can improve the quality of NHBD lungs., Methods: An uncontrolled NHBD model was achieved in male Lewis rats. Ninety minutes after cardiac arrest, HMP was performed for 60 min at 6°C to 10°C. The first study investigated the physiological lung functions during HMP and the lung tissue energy levels before and after HMP. The second study divided the rats into three groups (n=6 each): no ischemia group; 90-min warm ischemia+60-min HMP+120-min static cold storage (SCS) (HMP group); and 90-min warm ischemia+180-min SCS group. All lungs were reperfused for 60 min at 37°C. Lung functions were evaluated at given timings throughout the experiments. Oxidative damage during reperfusion was evaluated immunohistochemically with a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine., Results: The first study revealed that lung functions were stable during HMP. Lung tissue energy levels decreased during warm ischemia but were significantly increased by HMP (P<0.05). The second study confirmed that HMP significantly decreased pulmonary vascular resistance, increased pulmonary compliance, and improved pulmonary oxygenation. The ratio of 8-hydroxy-2'-deoxyguanosine positive cells to total cells significantly increased in the SCS group (P<0.01)., Conclusions: Short-term HMP improved lung tissue energy levels that decreased during warm ischemia and ameliorated ischemia-reperfusion injury with decreased production of reactive oxygen species.

Background: The ex vivo lung perfusion (EVLP) system has been used successfully to assess donor lungs. Perfadex (PX) is usually the flush and preservation solution in EVLP systems. We have used the extracellular-type-Kyoto (ET-K) solution containing 44 mEq/L potassium for clinical lung transplantation, investigating whether it rather than PX affects the EVLP system., Methods: We used domestic slaughterhouse pigs to analyze the EVLP system. After 20-minute warm ischemia and 6-hour cold ischemia, EVLP was performed for 2 hours. Pig heart-lung blocks were divided into the PX (n = 5) and ET-K (n = 5) groups depending on the flush/cold preservation solution. At the beginning, we discarded the first 100 mL of effluent in the PX group and the first 200 mL in the ET-K group. We measured pulmonary physiological data and potassium levels., Results: In both groups, perfusion for 2 hours showed no differences between the 2 groups with respect to the final flow, pulmonary arterial pressure, pulmonary vascular resistance, PaO(2)/FiO(2), and shunt fraction. The potassium level in the perfusate was 4.4 mEq/L for the PX and 5.4 mEq/L for the ET-K group., Conclusion: The pig EVLP system was not affected when ET-K was used instead of PX as the flush/preservation solution. The initial 200 mL of effluent should be discarded when using the ET-K to ensure that the potassium level does not increase., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: We previously proposed calculating forced vital capacity (FVC) by the number of segments for size matching in living-donor lobar lung transplantation (LDLLT). The primary purpose of this study was to compare spirometry-obtained calculations of lower lobe volumes with three-dimensional (3D) computed tomography (CT) volumetric images. Our second goal was to compare the data of pulmonary function tests with CT volumetry in living lung donors., Methods: Pulmonary function test, including FVC and total lung capacity (TLC), and 3D CT volumetry were performed pre-operatively in 21 healthy donor candidates for LDLLT. The relationship of 3D CT volumetric data and calculated volume of lower lobes by the number of segments was investigated. Also studied were 3D CT volumetric data in relation to FVC and TLC. Various pre-operative variables were analyzed retrospectively., Results: According to 3D CT volumetry, the right and left lower lobe volume was 26.3% ± 2.9% and 22.6% ± 3.1% of the total lung volume, respectively. We found a significant, strong correlation between each lower lobe volume and the total lung volume. Because the calculated volumes of right and left lower lobes by the number of segments were 26.3% and 21.1%, respectively, our results implied that the volume of both lower lobes was accurately described by the number of segments. FVC was significantly associated with TLC and the total lung volume., Conclusions: We confirmed that it would be justified to estimate graft FVC by the number of segments according to the CT volumetric data in LDLLT., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

An 8-year-old girl became ventilator-dependent due to severe bronchiolitis obliterans/interstitial pneumonia caused by cord-blood cell transplantation for neuroblastoma. Her mother's right lower lobe was twice as large as her right chest cavity. She successfully underwent living-donor, right, single-lobe lung transplantation and simultaneous left pneumonectomy under conditions of cardiopulmonary bypass. At 18 months after transplantation, the patient returned to school life and is currently able to carry out daily activities without supplemental oxygen., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background/aims: For lung preservation, one of two types of solutions is commonly employed: Euro-Collins (EC) or low potassium dextran glucose (LPDG). These two solutions have been compared regarding biological, morphometrical and physiological outcomes in many experiments. However, the dynamic mechanics of perfused lung are not well understood because the dynamic characteristics cannot be assessed under static conditions; hence, the primary goal of the present study was to assess this in perfused rat lungs during the preservation period, comparing EC with LPDG at 0 or 9 h at 4°C., Methods: Lung impedance was measured using a forced oscillation technique. Lung resistance and elastance values were obtained by the fast Fourier transform algorithm. The instability of central airways and heterogeneity of ventilation were estimated., Results: In the EC group, airway resistance and instability were high after perfusion, and the lung elastance was high and more heterogeneous after cold storage. In contrast, those parameters were stable in the LPDG group during cold storage., Conclusion: Such dynamic stability might facilitate the handling of lung grafts and eliminate injurious cyclic ventilation stress after reperfusion. Thus, we conclude that the impedance frequency characteristic represents a novel informative parameter for investigating lung preservation techniques., (Copyright © 2011 S. Karger AG, Basel.)

Background: Functional evaluation of potentially damaged lungs donated after cardiac death is crucial for widespread clinical transplantation. To date, the mean weight of animals used in studies of ex vivo lung perfusion (EVLP) has been 60 kg; however, in the clinical setting, donor weight may be greater., Objective: To investigate EVLP using lungs from large pigs (mean weight, 115 kg) to simulate human adult lungs donated after cardiac death., Materials and Methods: Five heart-lung blocks were obtained at 20 minutes after death at the slaughterhouse. The lungs were flushed and preserved on ice for 6 hours before being connected to an ex vivo lung circuit, and were perfused for at least 2 hours., Results: In all cases, perfusion was sustained for at least 2 hours. Mean (SEM) final flow rate was 4.9 (0.1) L/min, pulmonary artery pressure was 14.8 (1.7) mm Hg, and oxygen tension/fraction of inspired oxygen was 518.0 (18.0) mm Hg. The shunt fraction was 20.5% (4.0%). Histologic analysis demonstrated no significant pulmonary edema at the end of perfusion., Conclusion: We successfully completed EVLP using lungs from large pigs.

Here we present the case of a 26-year-old man in whom peripheral primitive neuroectodermal tumour of chest wall origin invaded the left lung with regional lymph node metastasis. He underwent initial resection of the left chest wall tumour with combined left lower lobectomy, left S5 segmentectomy, and lymph node dissection in order to facilitate a definitive diagnosis and also to obviate the risk of fatal bleeding due to tumour invasion of the pulmonary artery. Histological examination of the resected sample revealed small round cell proliferation with neural differentiation, and confirmed lymph node involvement within the left lower lobe. EWS/FLI-1 fusion gene transcripts were detected by the reverse-transcription polymerase-chain reaction. Diagnosis of peripheral primitive neuroectodermal tumour was confirmed. After surgery, combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, ifosphamide, and etoposide was given. Five years after resection, the patient remains alive and well, with no signs of recurrence.

Background: Thioredoxin is a ubiquitous protein with anti-oxidative, anti-apoptotic, and anti-inflammatory effects. It was reported [Fukuse T, Hirata T, Yokomise H et al. Attenuation of ischaemia reperfusion injury by human thioredoxin. Thorax 1995; 50: 387-391] that rhTRX protected lungs from ischemia-reperfusion injury as a radical scavenger; however, the mechanism was not elucidated. Therefore, we investigated the effect of perfusion and inhalation of rhTRX, and the associated mechanisms, by analyzing the concentrations and molecular states of the perfused rhTRX., Materials and Methods: Perfusion and inhalation studies of rhTRX were conducted with an isolated rat-lung perfusion model. The heart-lung block was perfused for 15 min and subsequently exposed to a 55-min ischemia followed by a 120-min reperfusion. Pulmonary artery pressure, weight gain, dynamic airway resistance, pulmonary compliance, and tidal volume were measured continuously. The concentrations and molecular states of the perfused rhTRX were measured., Results: A 350-microg/ml perfusion of rhTRX decreased post-ischemic pulmonary artery pressure (P < 0.05), while a 200-microg/ml perfusion did not. Throughout the experiment, the rhTRX concentrations were constant, and the rhTRX molecules were mostly dimeric. The inhalation of rhTRX showed adverse effects on the pulmonary function compared with the control group (P < 0.05)., Conclusions: A 350-microg/ml perfusion, but not inhalation, of rhTRX protected rat lungs from ischemia-reperfusion injury. rhTRX was effective in dimeric form without transit to the lung tissue. rhTRX may be effective by some mechanism other than radical scavenging.

Objective: A method to compensate for the donor shortage may be the utilization of donation after cardiac death. The control of lung injury against warm ischemia is crucial in manipulating donors after cardiac death. Nebulization is a simple and feasible drug delivery route after cardiac death. Herein we have examined the potential effect of nebulized milrinone, a phosphodiesterase III inhibitor, on pulmonary warm ischemia., Materials and Methods: Deeply anesthetized rats were euthanized by exsanguination. Lungs were exposed to warm ischemia with ventilation up to 2 hours. Milrinone was nebulized for 10 minutes at the beginning of warm ischemia (n = 5). In the control group (n = 5), normal saline was nebulized for the same time. At given intervals, the lungs were partially resected to measure adenine nucleotide and cyclic adenosine monophosphate levels., Results: In both groups, lung tissue cyclic adenosine monophosphate levels decreased significantly at 2 hours after warm ischemia; however, there was no significant difference between the groups. Lung tissue adenosine triphosphate levels significantly decreased at 2 hours after ischemia in the control group, while they did not drop up to 2 hours in the milrinone group. Further, lung tissue adenosine triphosphate levels at 2 hours after ischemia were higher in the milrinone group than the control group., Conclusions: Our results confirmed that milrinone nebulization during warm ischemia maintained lung tissue adenosine triphosphate levels. Therefore, milrinone nebulization may have potential for lung protection against warm ischemia.

Background: A lower temperature, namely below 0 degrees C, has been thought to be desirable for organ preservation because of the lower rate of metabolism; however, its benefits are still poorly understood. Supercooling is a non-freezing state of liquid below the freezing point, and the new development of a refrigerator for supercooling has now made it possible to preserve organs at sub-zero temperatures in a non-frozen state without cryoprotectants., Methods: Rat lungs were ventilated and perfused for 60 minutes in the 3 groups (n = 7 each): (1) the fresh group, in which the lungs were reperfused immediately after harvesting; (2) the 4 degrees C group, in which the lungs were stored after harvesting in ET-Kyoto solution at 4 degrees C for 17 hours before reperfusion; and (3) the supercooling group, in which lungs were preserved in ET-Kyoto solution at -2 degrees C for 17 hours., Results: Ischemia-reperfusion injury was significantly attenuated in the supercooling group, with a decrease in the pulmonary artery pressure (p < 0.02) and weight gain (p < 0.001), and an increase in the tidal volume (p = 0.001) and arterial oxygen tension (p < 0.001) compared with the 4 degrees C group. In the supercooling group, most of these indicators were equivalent to the fresh lung, with less damage to the endothelial cells of the pulmonary arteries and higher levels of adenosine triphosphate than in the 4 degrees C group., Conclusions: Lungs stored using this new supercooling method of lung preservation showed better organ function than conventional storage at 4 degrees C.

Objectives: A method to compensate for donor shortages could be donation after cardiac death. In this study, we considered endothelial cell-specific molecules, claudin-5 and VE-cadherin, as possible biomarkers predicting lung injury against warm ischemia. We investigated how the expression of these molecules could change after cardiac arrest in a mouse lung, comparing other molecules presumably relating with ischemia., Methods: At given intervals after cardiac arrest, the lungs were harvested. Quantitative analysis of mRNA expression of claudin-5, VE-cadherin, IL-1beta, IL-10, HIF-alpha, Egr-1, VEGF, Ang-1 and Ang-2 genes in lung tissues with several periods of warm ischemia was performed., Results: Regarding endothelial cell-specific molecules, there were significant differences in both claudin-5 and VE-cadherin mRNA expression between 0 h and 4 h after cardiac arrest. IL-1beta mRNA expression 1 h, 2 h and 4 h after cardiac arrest increased significantly, compared with that at 0 h. There were no significant differences with the other genes., Conclusions: We found that it took more time for claudin-5 and VE-cadherin mRNA expression to change significantly than IL-1beta mRNA expression; therefore, endothelial cell-specific molecules, claudin-5 and VE-cadherin, might be no better candidates for clinical use than IL-1beta.

Background: Non-heart-beating donors are expected to ameliorate shortages of donors for organ transplantation. The issue of preventing warm ischemic injury after circulatory arrest must be investigated. In the current study, we investigated whether isoflurane inhalation during warm ischemia could attenuate ischemia reperfusion injury (IRI) of the lung., Methods: An isolated perfused rat lung model was used. The rats were allocated into four groups: the no ischemia group; the ischemia-1 minimum alveolar concentration (MAC) iso group (ventilation with air and 1.38% isoflurane); the Ischemia-3MAC iso group (ventilation with air and 4.2% isoflurane); and the Ischemia-no treatment group (ventilation with only air). Lungs were subjected to 50 min of ischemia at 37 degrees C. Physiological lung functions were measured after reperfusion in experiment one. Mitochondrial control ratio (RCR), cytochrome-c release from mitochondria, and caspase activities just after warm ischemia were measured in experiment two., Results: Pulmonary functions in the Ischemia-1MAC iso group were significantly greater than those in the Ischemia-no treatment group for experiment one. There were no dose-dependent effects between 1MAC and 3MAC isoflurane. In experiment two, RCR in the Ischemia-1MAC iso group was significantly greater than that in the Ischemia-no treatment group. Cytochrome-c release and caspase-9 activity in the Ischemia-1MAC iso group were significantly decreased compared to those in the Ischemia-no treatment group., Conclusions: Isoflurane inhalation attenuates warm IRI with the protection of mitochondria. Our results suggest that isoflurane inhalation after circulatory arrest can be a simple and effective method to protect the lung against warm ischemia.

We report two cases of bilateral diffuse bronchiectasis in which early recurrence of the original lung disease occurred after bilateral lung transplantation (LT). Patient 1 underwent cadaveric LT. Recurrent bronchiectasis occurred 4 months later, and he died 6 years after LT. Patient 2 underwent living-related lobar LT, bronchiectasis relapsed 4 months later, and he died 13 months after LT. Both cases were finally diagnosed as bilateral diffuse bronchiectasis by the pathological features of the explanted lungs: infiltration of inflammatory cells predominantly in the conducting airways with dilation of the bronchi of bilateral lungs and scarcity of foamy macrophages in the wall of the respiratory bronchioles. Similar pathological features were seen in autopsy specimens from patient 1 and a transbronchial biopsy specimen from patient 2. LT should be carried out with caution in patients with bilateral diffuse bronchiectasis. When performing LT in such patients, it is suggested that sinusitis should be controlled perioperatively.

Background: It seems inevitable that non-beating-heart donors will be utilized to resolve the shortage of donors for clinical lung transplantation. The control of warm ischemia-reperfusion injury is crucial in manipulating non-beating-heart donors. We hypothesized that nebulization of a beta2-adrenoreceptor agonist, salmeterol xinafoate (SLM), during warm ischemia would increase lung tissue cyclic adenosine monophosphate (cAMP) levels, resulting in lung protection., Methods: Two studies were conducted. The first investigated the effect of SLM nebulization during ischemia on pulmonary ischemia-reperfusion injury, using an isolated rat lung-perfusion model. The heart-lung block was excised with cannulation of the pulmonary artery and vein, exposed to 55 minutes of ischemia at 37 degrees C, and subsequently reperfused for 60 minutes. Several parameters were measured during reperfusion. In the second study, to measure changes in lung tissue cAMP levels during warm ischemia with or without SLM nebulization, rat lungs were harvested and exposed to 60 minutes of warm ischemia with ventilation., Results: Salmeterol xinafoate nebulization significantly decreased the pulmonary shunt fraction, airway resistance, and pulmonary vascular resistance. It also inhibited pulmonary edema throughout the reperfusion period. Lung tissue cAMP was effectively maintained by SLM nebulization at the end of reperfusion. Myeloperoxidase activity in the lungs was decreased significantly by SLM nebulization. Lung tissue cAMP levels decreased during the 60 minutes of warm ischemia, but increased with SLM nebulization (p < 0.01)., Conclusions: Our results confirmed that SLM nebulization during warm ischemia maintained lung tissue cAMP levels, resulting in the alleviation of pulmonary warm ischemia-reperfusion injury.

The use of video-assisted thoracoscopic surgery (VATS) sometimes leads to additional and unnecessary risks compared with thoracotomy. We report a troubling case of VATS lung biopsy in a 43-year-old woman with mild pulmonary hypertension. A progressive elevation of pulmonary artery pressure (PAP) was noted after the commencement of right unilateral ventilation. When the systolic PAP reached 90 mm Hg (390 min after induction of anesthesia), a massive blood discharge through the chest drain occurred. At repeat thoracotomy, continuous blood spouting was seen from > 10 of the surgical sites. It was supposed that the endoscopic staplers were unable to maintain hemostasis with such a high PAP.

Objective: This study was undertaken to clarify what damage to a lung during cold storage influenced the function of transplanted lung after reperfusion., Methods: We examined the ultrastructural damage in preserved right lung before reperfusion, and the function of transplanted left lung, in a same dog and measured the pulmonary artery oxygen pressure after reperfusion and the wet-to-dry-weight ratio. We compared these findings between those dogs that survived until six hours after reperfusion (Alive Group) and those dogs that did not survive (Dead Group). We also investigated any correlation between the ultrastructural damage in the preserved lung and the function of the transplanted lung., Results: The frequency of protrusion and destruction of the endothelial cells in the small pulmonary artery, and vacuolization of pneumocytes, in the Dead Group was significantly higher than that in the Alive Group. A correlation was found between the frequency of two kinds of ultrastructural damage; vacuolization in the endothelial cells in the small pulmonary artery and vacuolization in the pneumocytes, and the pulmonary artery oxygen pressure at 1-hour after reperfusion. A correlation was also found between the frequency of the vacuolization of pneumocytes and the wet-to-dry-weight ratio., Conclusions: Findings suggested that a lung suffering severe damage to intracellular structure during hypothermic preservation is unable to function sufficiently after reperfusion and is at high risk for early graft failure.

Prevention of ischemia-reperfusion (IR) injury is crucial for successful lung transplantation. We investigated whether a nitric oxide donor, nitroglycerin (NTG), could suppress the oxidative stress of IR injury and improve pulmonary function after reperfusion in an ex vivo rat lung perfusion model. In Fresh group of animals, the lungs were flushed with perfusate, followed immediately by reperfusion, and no lung injury was observed. In NTG- and NTG+ groups of animals, the lungs were flushed with perfusate alone or perfusate containing NTG, respectively. Harvested lung and heart blocks from these latter two groups were immersed in the corresponding perfusate at 4 degrees C for 15 h, and were then reperfused for 60 min. Reperfusion induced pulmonary edema in the NTG- group, but not in the NTG+ group. Shunt fractions in NTG+ group were significantly lower than in the NTG- group throughout reperfusion. NTG had no effect on pulmonary arterial pressure or myeloperoxidase activity. In contrast, oxidative DNA damage assessed immunohistochemically with a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine (8-OHdG) was significantly increased in the NTG- group, in the order alveolar epithelium > pulmonary endothelium > bronchial epithelium. NTG treatment significantly decreased staining with the anti-8-OHdG antibody in all three areas of tissue. Therefore, administration of NTG attenuates the oxidative stress of IR injury, and may improve pulmonary function after reperfusion.

Early graft dysfunction after lung transplantation is a significant and unpredictable problem. Our study aimed at a detailed investigation of structure-function correlations in a rat isolated heart-lung model ofischemia/ reperfusion injury. Variable degrees of injury were induced by preservation with potassium-modified Euro-Collins solutions, 2 hr of cold ischemia, and 40 min of reperfusion. Pulmonary artery pressure (Ppa), pulmonary vascular resistance (PVR), peak inspiratory pressure (PIP), and perfusate gases (deltaPO2, deltaPCO2) were recorded during reperfusion. Right lungs were used to calculate W/D-weight ratios. Nineteen experimental and six control left lungs were fixed for light and electron microscopy by vascular perfusion. Systematic random samples were analyzed by stereology to determine absolute and relative volumes of lung structures, the amount of interstitial and intraalveolar edema, and the extent of epithelial injury. Lectin- and immunohistochemistry using established epithelial cell markers were performed in three animals per group to reveal sites of severe focal damage. Experimental lungs showed a wide range in severity of ischemia/ reperfusion injury. Intraalveolar edema fluid amounted to 77-909 mm3 with a mean of 448+/-250 mm3 as compared with 22+/-22 mm3 in control lungs (P<0.001). Perfusate oxygenation (deltaPO2) decreased from 30.5+/-15.2 to 21.7+/-15.2 mm Hg (P=0.05) recorded after 5 and 40 minutes of reperfusion. In experimental lungs, a surface fraction of 1% to 58% of total type I pneumocyte surface was damaged. Intraalveolar edema per gas exchange region (Vv ape,P) and deltaPO2 were related according to deltaPO2 = 96 - 60 x log10(Vv ape,P) [mm Hg]. The extent of epithelial injury did not correlate with deltaPO2 nor with intraalveolar edema, but increased significantly with PVR. Lectin- and immunohistochemistry revealed focal severe damage to the alveolar epithelium at the border of perivascular cuffs.

Background: Low-potassium solutions have been shown to improve lung preservation. The optimal potassium concentration, however, has not been investigated systematically. The purpose of this study was to evaluate the effect of solutions with different potassium concentrations on functional and structural preservation after flush-perfusion and ischemia. We used our established extracorporeal working heart-lung model and a modification of this model with isolated pulmonary perfusion at defined flow rates., Methods: In two sets of experiments 42 rat heart-lung blocks (experiment I and II: n=7/group) were used. Lungs were flush-preserved with 20 ml Euro-Collins solution (EC115; K+ 115 mmol/L), potassium-reduced Euro-Collins solution (EC40; K+ 40 mmol/L), or low-potassium Euro-Collins solution (EC10; K+ 10 mmol/L) and stored for 2 hours at 10 degrees C. Reperfusion was performed for 40 minutes with Krebs-Henseleit solution containing washed bovine red blood cells (38%) while the lungs were ventilated with room air. In experiment I pulsatile perfusion of the lungs was achieved by the working right side of the heart. In experiment II lungs were perfused at defined flow rates by a roller pump. Postischemic function was assessed by means of oxygenation capacity and pulmonary vascular resistance. The degree of structural damage to the air-blood barrier was assessed by quantitative stereologic light and electron microscopic evaluation., Results: In both experiments after 40 minutes reperfusion oxygenation capacity was significantly higher in EC40 than in EC115 and EC10, whereas pulmonary vascular resistance was significantly higher in EC115 than in EC40 and EC10. Quantitative histologic examination showed surprisingly modest damage to the endothelial side of the air-blood barrier but a considerable degree of damage to the epithelium in both experiments. The alterations in the pump-perfused isolated lung experiments exceeded those of the pulsatile perfused heart-lung experiments. The comparative analysis of the study groups revealed a minor degree of epithelial swelling and fragmentation in EC40 than in EC115 and EC10, respectively., Conclusions: The results obtained with two modifications of an extracorporeal model indicate that flush perfusion of the lung with a potassium-reduced solution results in better functional and structural preservation than flush perfusion with either high- or low-potassium solutions. The optimum may lie in the vicinity of 40 mmol/L. Further studies are necessary to verify these initial findings.

The optimal temperature of the pulmonary flush perfusate is still a matter of controversy. At present, a temperature of 10 degrees C is favored. This study deals with the structural and functional impact of different perfusate temperatures on lung preservation. In an extracorporeal rat heart-lung model lungs were preserved with Perfadex solution of 4, 15 and 25 degrees C and submitted to 2 h ischemia. Heart-lung blocks harvested from male rats were perfused with Krebs-Henseleit solution and ventilated with room air. Lungs were perfused with deoxygenated perfusate via the working right ventricle while the coronary arteries were retrogradely perfused with oxygenated perfusate. Oxygenation capacity (dPO2), peak inspiratory pressure (PIP) and pulmonary vascular resistance were measured. After establishment of baseline functional parameters hearts were arrested with 10 ml St. Thomas cardioplegia and lungs were flushed with 20 ml Perfadex solution. The heart-lung block was then stored for 2 h at 10 degrees C. Reperfusion was performed thereafter under the same conditions. At the end of the trial the lung tissue water was measured by the wet/dry ratio. The perfusion time of the groups flushed with 15 or 25 degrees C perfusate was significantly lower than that of the 4 degrees C group. After 20 min reperfusion dPO2 of the groups flushed with 15 or 25 degrees C was superior to those submitted to a 4 degrees C flush perfusion. PIP was significantly lower in the 15 degrees C group than in the 4 and 25 degrees C groups. The wet/dry ratio revealed the smallest water content in the 15 degrees C group. We conclude that the post-ischemic lung function is dependent on the temperature of the flush perfusate. Among the tested temperatures, perfusion at 15 degrees C showed the best results. The optimum may therefore lie in this range.

The present study was undertaken to clarify the effect of differences in the ionic composition of a preservation solution by investigating ultrastructures of pulmonary endothelial cells and oxygenation ability of preserved lungs after reperfusion. The relation between the ultrastructural changes and the oxygenation ability was also examined. Canine lungs flushed with an extracellular-type (ET)-Kyoto solution (group A, n = 6), with an intracellular-type-Kyoto solution and prostaglandin El (group B, n=6), or with Euro-Collins solution and prostaglandin E1 (group C, n=6) were stored at 4 degrees C for 20 hr. In transmission electron microscopic findings, the frequency of ultrastructural changes (protrusion of endothelial cells and cellular vacuolization) was significantly less in group A (23.3 +/- 9.1 and 13.3 +/- 5.2%, respectively) than in group B (64.4 +/- 6.1 and 42.2 +/- 8.8%, respectively). In group A, PaO2 after 40, 70, and 130 min of reperfusion was uniformly excellent (289.4 +/- 5.7, 303.3 +/- 7.0, and 303.0 +/- 19.6 mm Hg, respectively) and significantly higher than in groups B and C (202.6 +/- 32.0 and 185.9 +/- 23.0 mm Hg, respectively) after 70 min and higher than in group C (155.7 +/- 36.3 mm Hg) after 130 min of reperfusion. A negative correlation was noted between the frequency of cellular vacuolization and the PaO2 after reperfusion. These results indicated that extracellular ion composition has significantly better effect on pulmonary vascular ultrastructures than intracellular ion composition. This may be a factor making ET-Kyoto solution superior to the other two solutions in oxygenation ability after reperfusion. When attempting to develop better lung preservation solution, the ability to preserve the ultrastructures of preserved lung may be an important consideration in the evaluation.

Background: With the aim of developing a preservation solution that can preserve donor lungs reliably for a long time, we prepared a modified ET-Kyoto solution by adding N-acetylcysteine, nitroglycerin, and dibutyryl adenosine 3', 5'-cyclic phosphate to the previously reported ET-Kyoto solution, which contains trehalose, gluconate, and hydroxyethyl starch. In this study, we examined the efficacy of modified ET-Kyoto solution in 30-hour lung preservation., Methods: Twenty five pairs of adult mongrel dogs were divided into four groups. Donor lungs were flushed with modified ET-Kyoto solution (n = 9), with ET-Kyoto solution (n = 6), with University of Wisconsin solution group (n = 6), or with ET-Kyoto solution plus the solvents of nitroglycerin (ethanol and propylene glycol) (n = 4), then stored at 4 degrees C for 30 hours. All animals were treated with prostaglandin E1. Left lungs were transplanted and reperfused for 6 hours., Results: With respect to arterial oxygen tension, peak inspiratory pressure, and wet-to-dry lung weight ratio, modified ET-Kyoto solution was significantly superior to ET-Kyoto solution. The modified ET-Kyoto solution was significantly superior to University of Wisconsin solution with respect to survival rate, arterial oxygen tension, and wet-to-dry lung weight ratio. Ultrastructural findings supported these results., Conclusions: These results suggest that modified ET-Kyoto solution is superior to University of Wisconsin solution for 30-hour lung preservation.

Background: ET-Kyoto (ET-K) solution, proven safe for 20-hour lung preservation, was modified to achieve longer preservation: ET-K2 solution with more buffer capacity and ET-K3 with less potassium., Methods: Lungs were preserved with one of the three solutions (with prostaglandin E1 at 4 degrees C for 48 hours (n = 5 for each). Left lung transplantation was performed and evaluated for 6 hours., Results: Each solution became acidic after preservation (p < 0.01), though the change was lowest in the ET-K2 solution. All animals in the ET-K and ET-K3 groups survived for 6 hours after reperfusion, but only 1 survived in the ET-K2 group (p < 0.05). In all groups, partial pressure of oxygen in arterial blood decreased gradually after reperfusion. Pulmonary vascular resistance after reperfusion was significantly lower in the ET-K group than in the ET-K3 group (p < 0.01). Scanning electron microscopic examination showed that endothelial cell swelling and disruption were milder in the ET-K group (with the solution containing potassium of 44 mEq/L) than in the ET-K3 group., Conclusion: Lung preservation can be achieved for 48 hours in ET-K and ET-K3 solutions. Enhancement of buffer capacity provides no advantage. Potassium at 44 mEq/L does not cause deterioration of endothelial cells.

Abstract: Background: Resection for pulmonary metastasis from soft tissue sarcomas is an accepted method for treatment, but it is still debatable which patients will benefit from surgical intervention. To find an entity of patients benefiting from pulmonary metastasectomy, we reviewed our institutional experience. Methods: Between 1990 and 2007, 23 patients with pulmonary metastases from soft tissue sarcomas underwent complete pulmonary resection. All patients had obtained locoregional control of their primary tumors. Various perioperative variables were investigated retrospectively to confirm the role of pulmonary metastasectomy and to identify possible prognostic factors for survival after metastasectomy. Results: Overall survival rate after metastasectomy was 43% and 29% at 5 and 10 years, respectively. Disease-free survival rate was 9% at 1 year after pulmonary resection. On multivariate analysis, no tumor recurrence (neither locoregional recurrence nor extrapulmonary metastasis) before pulmonary metastasis provided a significantly favorable overall survival (P =0.038). In addition, repeat metastasectomy for recurrent pulmonary metastasis also provided a favorable overall survival (P =0.041). Conclusions: Our data suggested that patients most likely to benefit from pulmonary metastasectomy for soft tissue sarcoma have no tumor recurrence before pulmonary metastasis. Furthermore, patients with repeat metastasectomy for recurrent pulmonary metastasis also presented a significantly longer survival. [Copyright &y& Elsevier]