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Background: Lung volume reduction surgery (LVRS) as a bridge to lung transplantation was first advocated in 1995 and published studies have supported the concept but with limited data. The risk-benefit tradeoffs of the combined procedure have not been thoroughly examined, although substantial information regarding LVRS has emerged., Methods: Of 177 patients who underwent lung transplantation for end-stage emphysema between 2002 and 2009 at our center, 25 had prior LVRS (22 bilateral and 3 unilateral). Lung transplantation was performed 22.9±15.9 months after LVRS. We compared in-hospital morbidity, functional capacity, and long-term outcomes of patients who underwent LVRS before lung transplantation with a matched cohort of patients without prior LVRS to assess the influence of LVRS on posttransplantation morbidity and mortality., Results: The incidence of postoperative bleeding requiring reexploration and the incidence of renal dysfunction requiring dialysis were higher in patients with LVRS before lung transplantation. Posttransplantation peak forced expiratory volume in 1 s was worse in patients with LVRS before lung transplantation (56.7% vs. 78.8%; P<0.05). Five-year survival was not significantly different (59.7% in patients with LVRS before lung transplantation vs. 66.2% in patients with lung transplantation alone). In multivariate analysis, age more than 65 years, prolonged cardiopulmonary bypass time, and severe pulmonary hypertension were significant predictors for mortality (P<0.05)., Conclusions: Although LVRS remains a viable option as a bridge to lung transplantation in appropriately selected patients, LVRS before lung transplantation can impart substantial morbidity and compromised functional capacity after lung transplantation. LVRS should not be easily considered as a bridge to transplantation for all lung transplant candidates.

Objectives: During sequential double-lung transplantation (DLT), the newly implanted first lung receives the entire cardiac output during the implantation of the second one. This may be responsible for the increased hydrostatic pressure that causes severe interstitial and alveolar edema that can lead to allograft dysfunction. The authors tested the hypothesis that CPB started after first graft implantation and before second recipient lung removal should improve post-transplantation oxygenation and clinical outcomes., Design: Observational during 2 consecutive 1-year periods., Setting: University hospital., Participants: Nine consecutive patients undergoing sequential DLT with CPB started after first graft implantation and before second recipient lung removal were compared to controls, who were 10 consecutive patients who underwent sequential DLT but without CPB the year before., Measurements and Main Results: Oxygenation after transplantation was assessed. The use of CPB during the implantation of the second lung was associated with an increased mean postoperative ratio of PaO2 to the fraction of inspired oxygen at 1 hour (363±51 v 240±113, p = 0.01) and 6 hours (430±111 v 280±103, p = 0.03). The mean duration of CPB was 111±19 min. The occurrence of primary graft dysfunction and the need for extracorporeal membrane oxygenation tended to be lower, but did not reach significance. Similarly, mortality rate was comparable between both groups, as was the rate of blood transfusions., Conclusions: The authors' results suggest that the use of CPB started after first graft implantation and before second recipient lung removal appears to benefit oxygenation and reduces the occurrence of severe pulmonary edema in the first transplanted lung., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Microchimerism is the presence of foreign cells in an individual below 1% of total cells, which can occur in the setting of solid organ transplantation. This study quantitated donor-derived cellular subsets longitudinally in human leucocyte antigen (HLA)-mismatched lung transplant recipients (LTR) during the first post-operative year and evaluated the pattern of peripheral microchimerism with clinical outcomes. Peripheral blood mononuclear cells (PBMC) isolated from non-HLA-B44 LTR who received HLA-B44 allografts were sorted flow cytometrically into three cellular subsets. Real-time quantitative polymerase chain reaction (q-PCR) demonstrated that donor-derived HLA-B44 microchimerism is a common phenomenon, observed in 61% of patients. The level of donor-derived cells varied across time and between LTR with frequencies of 38% in the B cells/monocytes subset, 56% in the T/NK cells subset and 11% in the dendritic cells (DC) subset. Observations highlighted that microchimerism was not necessarily associated with favourable clinical outcomes in the first year post-lung transplantation., (© 2013 British Society for Immunology.)

Background: Advanced chronic lung allograft dysfunction limits survival after lung transplantation. We hypothesize that patients with chronic lung allograft dysfunction can be subdivided by exercise tolerance in two groups, and quality of life (QOL) and survival differ between the groups., Methods: A single-center, cross-sectional, partly prospective, study was performed in our outpatient clinic between July and November 2011, including all patients with a forced expiratory volume in 1 s <50% baseline. Respiratory parameters, 6-min walk test, and QOL were measured. Patients with low exercise capacity were defined as 6-min walk test <50% predicted or use of rollator or wheelchair., Results: Fifty-two patients consented to participating in the study and 22 demonstrated low exercise capacity. These patients had pathologic respiratory muscle function (P=0.005) and decreased inspiratory capacity (IC; P=0.001). QOL was significantly reduced. Multivariate analysis proved that low IC (hazard ratio, 17.9; 95% confidence interval, 2.8-111; P=0.002) and increased P0.1/Pimax (hazard ratio, 7.1; 95% confidence interval, 1.4-35.8; P=0.016) were independently associated with decrease exercise capacity., Conclusion: Heterogeneity of patients with advanced lung allograft dysfunction regarding exercise tolerance might result from altered IC and impaired respiratory muscle function.

Background: The number of available donor lungs is still the limiting factor in lung transplantation. We have recently shown that diluted surfactant lavage during ex vivo lung evaluation improved the graft function after gastric acid aspiration. In the present study, we hypothesized that diluted surfactant administration would recondition and improve the graft function after acid aspiration-induced lung injury in a porcine model of pulmonary transplantation., Methods: Left lung injury was induced by intrabronchial administration of 1 mL/kg betaine HCl and pepsin mixture. The animals were subsequently ventilated for 24 hours. After organ retrieval, the donor lungs were stored at 4°C for 4 hours. In the control group, left lung transplantation was performed without any surfactant treatment. In the surfactant group, the recipients received intratracheal diluted surfactant lavage just before reperfusion and ventilation. During 7 hours of reperfusion, the hemodynamic and respiratory variables were recorded on an hourly basis., Results: Surfactant lavage resulted in lower mean pulmonary artery pressure, higher mixed venous oxygen saturation, and better oxygenation compared with the control group (p = 0.001). Bronchoalveolar lavage interleukin-6 level, protein, and neutrophil percentage at the end of the experiment were significantly higher in the control group compared with the surfactant group (p = 0.03). Minimal surface tension was significantly lower in the surfactant group compared with controls (p = 0.03)., Conclusions: These results demonstrate that application of diluted surfactant before reperfusion can be used effectively to improve the graft function from donor lungs injured by gastric acid aspiration., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Little is known about physical activity in individuals with interstitial lung disease (ILD). The objectives of this study were (1) to objectively measure physical activity in lung transplant candidates with ILD, (2) to compare levels of physical activity on rehabilitation and nonrehabilitation days, and (3) to explore the relationships between physical activity and functional measures., Methods: Twenty-four (14 men) lung transplant candidates with ILD on long-term oxygen therapy, who were enrolled in an exercise-based rehabilitation program, underwent measurements of physical activity using accelerometry (daily steps and time spent in moderate-intensity physical activity per day), functional exercise capacity (6-minute walk distance), and muscle strength (isometric quadriceps torque)., Results: Lung transplant candidates with ILD had reduced levels of physical activity compared to the general population but were more active on rehabilitation versus nonrehabilitation days (M ± SD) (daily steps, 3780 ± 2196 vs 2138 ± 1353; P < .001; and time spent in moderate-intensity activity per day, 4.5 [interquartile range, 1.5-17] minutes vs 2 [interquartile range, 1-3.5] minutes). The 6-minute walk distance showed the strongest correlation to daily steps (r = 0.59, P < .01) and time spent in moderate-intensity physical activity per day (r = 0.56, P < .01)., Conclusions: Individuals with advanced ILD are markedly inactive; however, physical activity levels were significantly higher on rehabilitation days. The importance of physical activity as a rehabilitation outcome in ILD warrants further investigation.

Objectives: To evaluate the effects of 2 different levels of positive end-expiratory pressure on pigs who had unilateral lung transplants., Materials and Methods: A left lung transplant was performed in 12 pigs. The animals were randomized into 2 groups based on positive end-expiratory pressure: group 1 (5 cm H(2)O) and group 2 (10 cm H(2)O). Hemodynamics, gas exchange, and respiratory mechanics were measured before and after surgery. Cytokines, oxidative stress, and histologic scores were assessed in the lung tissue of each pig., Results: Pigs in group 2 exhibited a significantly higher mean heart rate (P = .006), static compliance (P = .001), lower mean arterial pressure (P = .003), and airway resistance (P = .001) than did pigs in group 1. There were no postoperative differences between the groups in concentrations of thiobarbituric acid reactive substances, superoxide dismutase, and interleukin 8. At the end of the observation period, pigs in group 2 had higher levels of thiobarbituric acid reactive substances (P = .001) and interleukin 8 (P = .05), and pigs in group 1 had higher levels of superoxide dismutase (P = .05) than they did at baseline., Conclusions: After unilateral lung transplant, higher positive end-expiratory pressure was associated with improved respiratory mechanics, a negative effect on hemodynamics, a stronger inflammatory response, and increased production of reactive oxygen species, but no effect on gas exchange.

Chronic lung allograft dysfunction is a major challenge in long-term management of lung transplant recipients. Both alloimmune-dependent factors (rejection) and alloimmune-independent factors contribute to the development of chronic lung allograft dysfunction. Thus, use of the term "chronic rejection" tends to be intentionally avoided among specialists in the field, although "chronic rejection" is still an acceptable lay word understood by many patients. Several different phenotypes have been identified in chronic lung allograft dysfunction, including restrictive allograft syndrome, neutrophilic reversible allograft dysfunction, and fibrous bronchiolitis obliterans syndrome. Restrictive allograft syndrome is characterized by restrictive physiology and peripheral foci of inflammation and fibrosis, which contrasts the obstructive physiology and pathological foci in small airways in conventional bronchiolitis obliterans syndrome. Among patients with bronchiolitis obliterans syndrome, there is a subpopulation that responds relatively well to azithromycin. Because these patients show airway neutrophilia, this subtype of chronic lung allograft dysfunction was named neutrophilic reversible allograft dysfunction. Conversely, patients with bronchiolitis obliterans syndrome unresponsive to azithromycin show airway fibrosis with less inflammation (fibrous bronchiolitis obliterans syndrome). In general, restrictive allograft syndrome shows poorer survival than does bronchiolitis obliterans syndrome, and early-onset bronchiolitis obliterans syndrome (within 2 years) shows a worse prognosis than does late-onset bronchiolitis obliterans syndrome. Until preventive and therapeutic options are refined, chronic lung allograft dysfunction will remain a major life-limiting factor. It has significant psychological, physical, social, and economic impacts. Early introduction of palliative care is another important strategy to improve patients' quality of life.

Microvascular loss may be an unappreciated root cause of chronic rejection for all solid organ transplants. As the only solid organ transplant that does not undergo primary systemic arterial revascularization at the time of surgery, lung transplants rely on the establishment of a microcirculation and are especially vulnerable to the effects of microvascular loss. Microangiopathy, with its attendant ischemia, can lead to tissue infarction and airway fibrosis. Maintaining healthy vasculature in lung allografts may be critical for preventing terminal airway fibrosis, also known as the bronchiolitis obliterans syndrome (BOS). BOS is the major obstacle to lung transplant success and affects up to 60% of patients surviving 5 years. The role of complement in causing acute microvascular loss and ischemia during rejection has recently been examined using the mouse orthotopic tracheal transplantation; this is an ideal model for parsing the role of airway vasculature in rejection. Prior to the development of airway fibrosis in rejecting tracheal allografts, C3 deposits on the vascular endothelium just as tissue hypoxia is first detected. With the eventual destruction of vessels, microvascular blood flow to the graft stops altogether for several days. Complement deficiency and complement inhibition lead to markedly improved tissue oxygenation in transplants, diminished airway remodeling, and accelerated vascular repair. CD4+ T cells and antibody-dependent complement activity independently mediate vascular destruction and sustained tissue ischemia during acute rejection. Consequently, interceding against complement-mediated microvascular injury with adjunctive therapy during acute rejection episodes, in addition to standard immunosuppression which targets CD4+ T cells, may help prevent the subsequent development of chronic rejection.

Smoking, both by donors and by recipients, has a major impact on outcomes after organ transplantation. Recipients of smokers' organs are at greater risk of death (lungs hazard ratio [HR], 1.36; heart HR, 1.8; and liver HR, 1.25), extended intensive care stays, and greater need for ventilation. Kidney function is significantly worse at 1 year after transplantation in recipients of grafts from smokers compared with nonsmokers. Clinicians must balance the use of such higher-risk organs with the consequences on waiting list mortality if the donor pool is reduced further by exclusion of such donors. Smoking by kidney transplant recipients significantly increases the risk of cardiovascular events (29.2% vs. 15.4%), renal fibrosis, rejection, and malignancy (HR, 2.56). Furthermore, liver recipients who smoke have higher rates of hepatic artery thrombosis, biliary complications, and malignancy (13% vs. 2%). Heart recipients with a smoking history have increased risk of developing coronary atherosclerosis (21.2% vs. 12.3%), graft dysfunction, and loss after transplantation. Self-reporting of smoking is commonplace but unreliable, which limits its use as a tool for selection of transplant candidates. Despite effective counseling and pharmacotherapy, recidivism rates after transplantation remain high (10-40%). Transplant services need to be more proactive in educating and implementing effective smoking cessation strategies to reduce rates of recidivism and the posttransplantation complications associated with smoking. The adverse impact of smoking by the recipient supports the requirement for a 6-month period of abstinence in lung recipients and cessation before other solid organs.

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.

Objectives: Many centres avoid using cardiopulmonary bypass (CPB) for lung transplant due to concerns over aggravated lung reperfusion injury and excessive blood loss. We reviewed our 23-years' experience of single lung transplantation., Methods: A retrospective review of single lung transplants at our institution (1987-2010), examining differences in allograft function and postoperative complications between CPB and non-bypass (non-CPB) cases., Results: Two hundred and fifty-nine single lung transplants were undertaken. Fifty-three (20.5%) with CPB. There was no difference demographically between the two groups. No difference existed in preoperative PO(2)/FiO(2). At 1 and 24 h, the postoperative PO(2)/FiO(2) ratio was no different (mean 2.95 and 3.24 in non-CPB cases; 3.53 and 3.75 in CPB patients, P = 0.18 and P = 0.34, respectively). Extubation time was not influenced by the use of CPB. Postoperative blood loss was greater in the CPB group. The usage of fresh frozen plasma and platelets was similar (P = 0.64 and 0.41, respectively). More blood was transfused during postoperative care of CPB patients (P = 0.02)., Conclusions: Fears of poor postoperative lung function after CPB appear unfounded. We could detect no difference in function or extubation time. Although the use of CPB increases postoperative bleeding and the need for transfusion, it may be used safely to facilitate lung transplantation.

The inferiority of organs from brain dead donors is reflected by impaired graft survival and patient outcome. Brain death effects hemodynamic stability, hormonal changes, and neuroimmunologic effects and unleashes a cascade of inflammatory events. Despite considerable efforts in experimental and clinical research, most of the mechanisms linked to brain death are only appreciated on a descriptive level. This overview presents our current understanding of the pathophysiology and consequences of brain death on organ injury and summarizes available therapeutic interventions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Primary graft dysfunction (PGD) occurs in 10-25% of cases and remains responsible for significant morbidity and mortality after lung transplantation. Our goal was to explore donor and recipient variables and procedure factors that could be related to early graft failure in cystic fibrosis patients receiving bilateral lung transplantation, the PGD grade being derived from the PaO(2)/FiO(2) ratio measured at the sixth post-operative hour., Methods: Data from 122 cystic fibrosis patients having undergone lung transplantation in six transplant centres in France were retrospectively analysed. Donor and recipient variables, procedure characteristics and anaesthesia management items were recorded and analysed with regard to the PaO(2)/FiO(2) ratio at the sixth post-operative hour. Recipients were divided into three groups according to this ratio: Grade I PGD, when PaO(2)/FiO(2) >300 mmHg or extubated patients, Grade II, when PaO(2)/FiO(2) = 200-300 mmHg, and Grade III, when PaO(2)/FiO(2) <200 mmHg or extracorporeal membrane oxygenation still required., Results: Forty-eight patients were Grade I, 32 patients Grade II and 42 patients Grade III PGD. Oto's donor score, recipient variables and procedure characteristics were not statistically linked to PaO(2)/FiO(2) at the sixth post-operative hour. Ischaemic time of the last implanted graft and the lactate level at the end of the procedure are the only factors related to Grade III PGD in this group., Conclusions: Hyperlactataemia most probably reflects the severity of early PGD, which leaves graft ischaemic time as the only factor predicting early PGD in a multicentre population of cystic fibrosis lung graft recipients.

Objectives: Acute allograft rejection is one of the significant complications occurring in lung transplant recipients. Early growth response-1 (Egr-1), zinc-finger-type transcription factor, is known as a master switch regulator of diverse chemical mediators. We used an orthotopic mouse model of left lung transplant to elucidate the function of Egr-1 in acute pulmonary rejection., Methods: Left lung grafts retrieved from C57BL/6 wild mice or C57BL/6 Egr-1-null mice were orthotopically transplanted into BALB/c mice; the lungs were harvested at day 1, 3, 5 or 7 after lung transplantation. The grade of acute rejection was histopathologically evaluated. The intragraft gene expression levels of Egr-1 and downstream target mediators were quantitatively measured by real-time polymerase chain reaction. Immunohistochemical analysis was used to determine the location and distribution of the Egr-1 protein in the pulmonary graft., Results: Severe acute rejection was observed in allografts from wild-type mice at 5 days after transplantation. Only minimal rejection was seen in the lung graft from Egr-1-null donor mice at 5 days after transplantation. Strong upregulation of Egr-1 mRNA transcripts was observed at day 1, which then decreased during the next 5 days. The mRNA of Egr-1 target mediators [interleukin-1-beta (IL-1β), monocyte chemotactic protein-1 (MCP-1) and plasminogen activator inhibitor-1] reached maximal levels at day 5. Egr-1-null allografts exhibited significantly lower expressions of IL-1β and MCP-1 mRNA (P < 0.05)., Conclusions: Our study showed that deletion of Egr-1 in lung allografts ameliorates severe acute rejection with the reduction of expression levels of chemical mediators, implying a new possible strategy for treating acute pulmonary allograft rejection.

Purposes: Outcomes following lung transplantation are limited by bronchiolitis obliterans syndrome (BOS). As the number of circulating regulatory T cells (Treg) is lower in lung recipients with BOS than in stable lung recipients, we hypothesized that Treg is also correlated with lung function in the early post-transplantation period., Methods: This prospective study included 18 consecutive patients whose lung function parameters were recorded 3 weeks and 3 months after transplantation, between February and July 2007. Peripheral blood mononuclear cells were stained with anti-CD3, -CD4, -CD8, -CD19, -CD25, -CD28, -CD45RA, -CD45RO, -CD69, -CD127, -CTLA4, and -Foxp3 antibodies and FACS assays were performed. In addition, intracellular cytokines were stained for FACS., Results: Treg-specific markers (Foxp3, CD127(lo), and CTLA4) in the CD25+ CD4+ population were correlated with both forced expiratory volume in 1 s and forced vital capacity. Th1-cytokine secretion was more dominant in CD4+ CD25+ T cells than in CD4+ CD25- T cells. In contrast, Th2 and Treg cytokine secretion was the dominant response in stable recipients., Conclusions: The frequency of Treg cells was positively correlated with good lung function in the early period after lung transplantation.

Lung transplantation has become the standard of care for particular individuals with advanced lung disease. However, this surgical procedure involves interruption of the lower vagal nerve fibers which leads to loss of the protective cough reflex. Injury of the neural pathways involved with the sensory limb of the cough reflex is associated with an increased risk of complications involving the allograft. While loss of the cough reflex was once considered permanent, recent evidence indicates functional and structural restoration is a time-dependent process that occurs 6-12 months after lung transplantation. The implication that the cough reflex may be reestablished in lung transplant recipients provides insight into the dynamic response to airway neural injury that may lead to improvements in allograft tissue repair.

Background: An obstructive pattern in pulmonary function test is common after lung transplantation (LTx) and may be caused by multiple disorders. In this study, the impact and outcome of an obstructive spirometric pattern identified in transplant recipients early posttransplantation were investigated., Methods: Analyzing all patients undergoing double LTx between September 1, 2007, and October 1, 2009, we separated patients with an obstructive (forced expiratory volume in 1 sec [FEV(1)]: vital capacity [VC] <0.7) and a nonobstructive pattern (FEV(1):VC ≥0.7) in pulmonary function tests 3 months after transplantation. Pulmonary function measurement, bronchoscopy, laboratory parameter, computed tomography morphology, mortality, and bronchiolitis obliterans syndrome (BOS)-free survival were analyzed up to 36 months after transplantation. In addition, information about donor lungs were collected (age, smoking history, and blood gas before lung harvesting)., Results: From 122 recipients included, 17 (14%) exhibited an obstructive pattern. Recipients with an early obstructive pattern were older at transplantation, had significantly decreased FEV(1), increased total lung capacity, and donor organ with lower pO(2) when ventilated with 100% oxygen before retrieval. Obstructive patients developed their best FEV(1) earlier after LTx and demonstrated a significant increase in BOS development (47% vs. 14%)., Conclusions: An obstructive lung function pattern early after LTx was associated with earlier development of BOS and may have negative impact on outcome after double LTx. Early obstructive pattern after transplantation might be an indication of structural donor lung injury.

Background: Vitamin D deficiency has been reported in different chronic pulmonary diseases like asthma and chronic obstructive pulmonary disease, but little is known in lung transplant recipients., Methods: Serum 25-hydroxyvitamin D (25-OHD) levels and pulmonary function (forced expiratory volume in 1 sec [FEV(1)] %predicted) were measured in 131 lung transplant patients during their yearly posttransplant check-up hospital stay, and the total number of infections and perivascular/peribronchiolar rejections were assessed from transplantation on., Results: Vitamin D deficiency (<30 ng/mL) occurred in 62 of 131 patients (47.3%), of whom 26 (19.8%) were severely deficient (<20 ng/mL). The FEV(1) was significantly lower in the deficient group compared with the group with normal levels (P=0.019). Moreover, we could find an association between FEV(1) and 25-OHD levels in univariate analysis (P=0.018), which remained significant in multivariate analysis (P=0.012). The same holds true for the association between 25-OHD levels and the peak postoperative FEV(1) (P=0.021 in multivariate analysis). We also identified significantly more patients with moderate to severe B-grade rejections in the deficient group (P=0.0038)., Conclusion: Vitamin D deficiency is present in 47% of our lung transplant patients and seems independently associated with a lower FEV(1) and more severe B-grade rejections. This study raises the potential need for additional vitamin D treatment in lung transplantation and clearly indicates the role of a randomized placebo-controlled trial with vitamin D supplementation, which is ongoing in our center.

Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50-75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25-50% of the mice from 4-12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV(0.1), TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options.

Study Objectives: To compare the pharmacokinetics (PK) of tobramycin in patients with cystic fibrosis (CF) before and after bilateral lung transplantation, in order to evaluate optimal dosing practices post transplant., Design: Retrospective, single-center, chart review study, in which tobramycin concentrations from CF patients were used to calculate PK parameters, including elimination rate constant, half-life, volume of distribution (Vd), area under the curve (AUC), and clearance before and after lung transplantation., Setting: Medical school-affiliated teaching hospital., Patients: Eight patients with CF, who received a bilateral lung transplant from January 1, 2005 through August 1, 2009 (4 males, 4 females; mean age 26.3 years)., Interventions: None., Main Results: Sixty-nine sets of pre- (n=52) and post transplant (n=17) tobramycin concentrations were available. PK parameters were significantly altered post transplant. Elimination rate constant decreased 38% from 0.26±0.1 to 0.16±0.1 h(-1) (P<0.001), with a related increase of 200% in half-life from 2.8±0.8 to 8.4±8.7 h (P<0.001). Clearance decreased 25% post transplant from 67.3±32.3 to 50.2±15.9 mL/min (P=0.04). No statistically significant change occurred in AUC or Vd after transplant, although a trend was seen toward increased Vd. Dosage requirements after transplantation were significantly lower, 10.7±2.5 and 7.6±1.6 mg/kg/day, pre and post transplant, respectively (P<0.001). Concentrations were also evaluated in 2 time periods: 0-3 weeks and ≥6 weeks post transplant, based on available data. Clearance and Vd ≥6 weeks post transplant did not significantly differ from pre-transplant values (P=0.28 and 0.54, respectively), suggesting that these changes may be temporary., Conclusions: The results suggest that tobramycin PK are altered in patients with CF after bilateral lung transplantation, although no clear trend was seen owing to inter-patient variability. We propose that PK parameters should be reassessed during each treatment course post transplant., (© 2011 John Wiley & Sons A/S.)

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted., (©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The strong association between gastroesophageal reflux disease (GERD) and the development and progression of pulmonary diseases has been suggested, and GERD has been focused on as a potential cause and thus a target for prevention and/or therapy. Because GERD is curable, the proper diagnosis and management of underlying GERD would theoretically improve the outcomes. This article reviews the existing literature and discusses the strategy to manage GERD in patients with end-stage pulmonary diseases before and after lung transplantation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: This publication attempted to evaluate the frequency of mold colonization and infection and the procalcitonin serum concentrations (PCT) among lung transplant recipients., Methods and Materials: We included 49 patients (36 males and 13 females) of mean age at transplantation of 47.1±13.6 years. Molds were isolated using routine microbiologic methods. PCT (ng/mL) was measured using an immunoluminescence assay with values below 0.5 showing no probability of infection, 0.5 to 2.0, a moderate infection risk; 2.0 to 10, a high infection risk; and above 10 high sepsis risk., Results: Twenty-four (49%) patients revealed the presence of molds in material from the lower respiratory tract (sputum, tracheal, or tracheobronchial aspirate), mini-bronchoalveolar lavage. Aspergillus species was isolated in 14 (28.6%) patients, Penicillium in 7 (14.3%) patients, and Zygomycetes fungi in 9 (18.4%) patients. The average PCT value from 61 examinations of PCT during fungal isolation was 0.5±0.7 ng/mL. However, when the studied group was categorized according to the PCT range, the rates for the groups were no infection (n=30; 49.2%), moderate (n=20; 32.8%), high (n=9; 14.8%) and high sepsis risk (n=2; 3.3%)., Conclusions: The mold colonization of transplanted lung is a frequent complication and should be considered even in the case of proper prophylaxis. Procalcitonin might be the marker helpful in mold infection diagnosis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: Ex vivo lung evaluation (ex vivo) has been developed as a useful method by which to assess lungs from donation-after-cardiac death (DCD) donors prior to transplant. However, the safety of the ex vivo circulation itself with respect to grafts has not been fully investigated. The aim of this study is to evaluate the effects of the ex vivo circuit using a swine lung transplant model., Methods: Lungs with or without 2-h warm ischemia were used. To assess post-transplant graft function, the left lung was transplanted after 2-h ex vivo or cold preservation; blood gas analysis of the left pulmonary vein (partial pressure of oxygen, PO(2)) was performed during the 6-h post-transplant follow-up period. Data were compared between the ex vivo (+) and ex vivo (-) groups., Results: Partial pressure of oxygen/ inspired oxygen fraction (PO(2)/FiO(2)) in the ex vivo (-) group was significantly greater than that in the ex vivo (+) group until 3h after transplant. The PO(2)/FiO(2) levels in both groups then increased and became similar at 6 h after transplant, regardless of whether ischemic or non-ischemic lungs (p<0.001 and p=0.004, respectively) were used., Conclusions: Negative effects of the ex vivo system were limited and seen only in the immediate post-transplant period. Therefore, in DCD swine lung transplantation, the ex vivo system appears to be safe., (Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Adult cystic fibrosis (CF) patients experience significant increases in serum vitamin A and E levels after lung transplantation. It is unclear whether this finding is specific to the CF population or inherent to the lung transplantation process., Methods: The objectives of this study were to assess pre- and postlung transplantation serum vitamin A and E levels in subjects with end-stage lung disease secondary to all causes. The study population consisted of adults who received a lung transplant at the Toronto Lung Transplant Program between 2004 and 2009. The mean change in serum vitamin A and E levels pre- and postlung transplant was evaluated using a paired t test, while differences in vitamin A and E levels between CF and non-CF subjects were determined using a Student's t test., Results: Thirty-two CF and 21 non-CF subjects who underwent lung transplantation were included in the study. Mean serum vitamin A and vitamin E levels increased significantly after transplant, from 1.2 to 3.5 μmol/L (P<0.0001) and from 21.9 to 33.2 μmol/L (P<0.0001), respectively. The proportion of individuals with serum levels above the upper limit of normal increased from 7.6% to 88.7% (P<0.0001) and from 11.3% to 24.5% (P=0.02) for vitamin A and vitamin E, respectively. The dosage of vitamin supplementation did not increase after transplant., Conclusions: Significant increases in serum vitamin A and E levels were seen in both CF and non-CF subjects after lung transplantation. Further research is needed to understand the cause and clinical implications of these findings.

Lung transplantation has become an accepted option for many patients with end-stage pulmonary diseases. Anesthesia and surgery following lung transplantation may be required for various diseases that may affect both systemic organs and the transplanted graft. When a patient with a lung transplant undergoes surgery, there is the potential for interference with lung function, depending on the type of intervention and its anatomical site. Accurate preoperative evaluation, an understanding of the physiology of the transplanted lung, proper airway instrumentation, individualized management of intraoperative ventilation, and fluid balance are essential for a positive perioperative outcome., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: More than 11 million Americans live with chronic lung disease; in search for an alternative to donor organs, we attempted to regenerate lungs based on perfusion decellularized lung scaffolds that can be transplanted similar to a donor organ., Methods: Cadaveric rat lungs were decellularized by detergent perfusion. Resulting scaffolds were mounted in bioreactors and seeded with endothelial and fetal lung cells. Biomimetic organ culture was maintained for 7 days. Resulting bioartificial left lungs were transplanted in orthotopic position after left pneumonectomy in rats. Cadaveric left lung transplants and pneumonectomies served as controls. Blood gas analyses, compliance testing, and fluoroscopies were performed on postoperative days 1, 7, and 14. Lungs were removed for final analysis on day 14., Results: Perfusion decellularization of cadaveric lungs yielded acellular scaffolds with intact architecture and matrix composition. Alveolar volumes, number, and size were comparable in bioartificial and native lungs, as were gas exchange, vital capacity and compliance in vitro. After using improved graft preservation and postoperative weaning protocols, animals could be fully recovered, and bioartificial lung constructs provided oxygenation as long as 7 days at levels comparable to cadaveric lung transplants. Compliance, gas exchange, and radiographic appearance gradually declined over the subsequent 7 days owing to progressive graft consolidation and inflammation., Conclusions: Perfusion decellularization of cadaveric lungs yields intact scaffolds that can be seeded with cells to generate bioartificial lung grafts. After orthotopic transplantation, grafts are perfused by the recipient's circulation, ventilated through the recipient's airway and provide gas exchange in vivo for 7 days., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To present a model of prostaglandin I2 (PGI2) administration (inhaled vs. parenteral) and to assess the functional performance of the lungs in an ex vivo lung perfusion system., Methods: Forty Wistar rats were anesthetized and placed on mechanical ventilation followed by median sterno-laparotomy and anticoagulation. The main pulmonary artery was cannulated. All animals were maintained on mechanical ventilation and were randomized into four groups (10 rats/group): inhaled saline (IS); parenteral saline (PS); inhaled PGI2 (IPGI2); and parenteral PGI2 (PPGI2). The dose of PGI2 used in the IPGI2 and PPGI2 groups was 20 and 10 µg/kg, respectively. The heart-lung blocks were submitted to antegrade perfusion with a low potassium and dextran solution via the pulmonary artery, followed by en bloc extraction and storage at 4ºC for 6 h. The heart-lung blocks were then ventilated and perfused in an ex vivo lung perfusion system for 50 min. Respiratory mechanics, hemodynamics, and gas exchange were assessed., Results: Mean pulmonary artery pressure following nebulization decreased in all groups (p < 0.001), with no significant differences among the groups. During the ex vivo perfusion, respiratory mechanics did not differ among the groups, although relative oxygenation capacity decreased significantly in the IS and PS groups (p = 0.04), whereas mean pulmonary artery pressure increased significantly in the IS group., Conclusions: The experimental model of inhaled PGI2 administration during lung extraction is feasible and reliable. During reperfusion, hemodynamics and gas exchange trended toward better performance with the use of PGI2 than that with the use of saline.

Background: Donation after cardiac death (DCD) to overcome the donor organ shortage is now moving into the clinical setting, but the medium-term outcome after DCD lung transplantation (LTx) remains largely unknown., Methods: In this retrospective study, DCD LTx recipients (n = 21) were compared with a cohort of donation-after-brain-death (DBD) LTx recipients (n = 154) transplanted between February 2007 and July 2010. Immediate (post)operative outcome was evaluated by assessing need for peri-operative extracorporeal membrane oxygenation (ECMO), time to extubation, hospital discharge and primary graft dysfunction (PGD) within the first 48 hours. Survival, incidence of bronchiolitis obliterans syndrome (BOS), acute rejection (AR) and inflammatory markers in blood and in bronchoalveolar lavage (BAL) were assessed and compared over a median follow-up of 327 days for DCD and 531 days for DBD, showing no statistically significant difference (NS)., Results: There were no differences between groups with regard to patient characteristics except for a higher number of patients transplanted for obliterative bronchiolitis in the DCD group (4 of 21 vs 7 of 154; p < 0.05). In the DCD group, 2 of 21 patients died, vs 23 of 154 patients in the DBD group (NS). Actuarial survival rates at 6 months, 1 year and 3 years are 95%, 95% and 71% for the DCD group and 96%, 91% and 75% for the DBD group (NS). Three patients (14%) in the DCD group developed BOS vs 15 patients (10%) in the DBD group (NS). Survival and freedom from BOS were not different between the groups. AR, inflammatory markers and immediate (post)operative outcome also did not differ., Conclusions: In our experience, both early- and medium-term outcome in DCD lung recipients is comparable to that of DBD lung recipients. Use of lungs recovered from controlled donors after cardiac death is a safe option for expansion of the donor pool., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: To determine whether the hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin has a graft-protective effect, we retrospectively analyzed 502 patients who had undergone lung transplantation in Hannover., Methods: Propensity scores have been calculated for each patient and compared between two groups. Cox Hazard analyses were performed for different parameters (e.g., basic parameters of patients, underlying diagnoses, different operations, and important organ functions after lung transplantation). Lung function after transplantation was monitored using repeated measurement analyses. Additionally, conditional Kaplan-Meier survival analyses were used to explore the impact of different diagnoses, the severity of bronchiolitis obliterans, the type of transplantation, and different immunosuppressant regimes on patient survival., Results: The results indicate a strong association between the postoperative administration of statins and the improvement of survival, maintenance of graft (lung) function, and slowing of the onset of bronchiolitis obliterans., Conclusion: These findings suggest a new postoperative therapeutic focus for maintaining graft function.

Background: Donor organ shortage represents a major problem in lung transplantation. Donation after cardiac death could help to expand the pool of organs, but the additional period of warm ischemia after cardiac arrest aggravates primary graft dysfunction. The pulmonary endothelium of the graft constitutes an important source and target of reactive oxygen species generated during ischemia and reperfusion. Targeted protection of graft pulmonary endothelial cells by the antioxidant enzyme catalase, conjugated with a platelet/endothelial cell adhesion molecule-1 (PECAM-1) antibody to nanosized particles (anti-PECAM/catalase conjugates), might improve outcome in lung transplantation using donors after cardiac death and prolonged hypothermic preservation., Methods: Left lung transplantation was performed in 18 pigs. Before cardiac arrest, donors received anti-PECAM/catalase, unconjugated component mixture or vehicle solution. After 90-min warm and 18-hr hypothermic ischemia, lungs were transplanted, and function was assessed during 6 hr after reperfusion. Samples of bronchoalveolar lavage fluid and lung tissue were taken thereafter. Six sham-operated animals served as controls., Results: During 6-hr reperfusion, anti-PECAM/catalase significantly ameliorated graft function, evidenced by major improvements of gas exchange and reduced intrapulmonary shunt fraction. Furthermore, lipid peroxidation, alveolar leakage, and edema formation were reduced in protected grafts. Similarly moderate lung pathology was seen after transplantation., Conclusions: Augmentation of the antioxidant capacity of graft pulmonary endothelial cells with anti-PECAM/catalase nanoparticles represents a straightforward approach to enable a safe transplantation of prolonged preserved donation after cardiac death lungs. Anti-PECAM/catalase protection alleviated oxidative stress and allowed immediate reconstitution of normal gas exchange and pulmonary microcirculation, a prerequisite for improved graft and patient outcome.

Background: The purpose of this study was to examine the effect of an inpatient rehabilitation program on health-related quality of life (HRQOL) and exercise capacity (EC) in long-term (>1 year after lung transplantation) survivors (LTSs) in comparison to a control group (CG)., Methods: Sixty LTSs, 4.5 ± 3.2 years after lung transplantation (LTx), were randomly assigned to two equally sized groups that were stratified for gender and underlying disease. Thirty LTSs (age 49 ± 13 years, 13 male and 17 females, 19 double LTxs, 7 BOS Stage ≥ 1) attended an inpatient rehabilitation program (intervention group, IG) for 23 ± 5 days. The CG (age 50 ± 12 years, 13 males and 17 females, 20 double LTxs, 2 BOS Stage ≥ 1) received medical standard therapy (physiotherapy). Patients were evaluated by cardiopulmonary exercise testing, 6-minute walk test (6MWT), SF-36, SGRQ and the Quality of Life Profile for Chronic Diseases questionnaire before and after (18 ± 3 days) the program., Results: The groups were statistically indistinguishable in terms of clinical data. Each treatment group significantly improved their sub-maximal EC (6MWT: IG, 493 ± 90 m vs 538 ± 90 m, p < 0.001; CG, 490 ± 88 m vs 514 ± 89 m, p < 0.001) and maximal EC (VO(2peak): IG, 17.0 vs 18.5 ml/min/kg, p = 0.039; CG, 18.0 vs 19.5 ml/min/kg, p = 0.005), without reaching statistical significance between the groups. In both study groups, patients HRQOL tended to improve. Significant correlations were found between EC parameters and HRQOL scales., Conclusions: Our data suggest that structured physical training may improve exercise tolerance in LTS. Our study results did not demonstrate a significant benefit of an inpatient over an outpatient exercise program., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Lung transplantation (LTx) is established as a life-saving treatment in end-stage lung disease. However, long-term survival is hampered by the development of chronic rejection, almost synonymous with bronchiolitis obliterans syndrome (BOS). The rejection is characterized by deposition of extracellular matrix in small airways. Fibroblasts/myofibroblasts are the main producers of extracellular matrix molecules such as proteoglycans. This study compared fibroblast phenotype and activity in the wound healing process at different points after LTx in patients who later did, or did not, develop BOS., Methods: Distally derived fibroblasts from patients 6 and 12 months after LTx and from healthy controls were analyzed for production of the proteoglycans versican, perlecan, biglycan, and decorin, with and without transforming growth factor (TGF)-β(1). Fibroblast migration and proliferation were also studied., Results: At 6 and 12 months after LTx, versican production was higher in fibroblasts from LTx patients (p < 0.01 p < 0.01) than from controls. Fibroblasts from patients who later developed BOS were more responsive to TGF-β(1)-induced synthesis of versican and biglycan than patients without signs of rejection (p < 0.05). Production of perlecan and decorin was negatively correlated with fibroblast proliferation in fibroblasts at 6 months after LTx. In a more detailed case study of 2 patients, one with and one without BOS, the altered proteoglycan profile was associated with impaired lung function., Conclusions: LTx changes the phenotype of fibroblasts to a non-proliferative but extracellular matrix-producing cell due to wound healing involving TGF-β(1). If not controlled, this may lead to development of BOS., (Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Bronchiolitis obliterans syndrome (BOS) has an incidence of 57% at 5 years after lung transplantation, accounts for 30% of all deaths 3 years posttransplant and because treatment options are extremely limited, it constitutes a significant health care problem. Adult mesenchymal stem cells (MSCs) play a role in lung turnover; however, their role in BOS remains unknown., Methods: MSCs were isolated from bronchoalveolar lavage (BAL) in 101 lung allograft recipients. BAL was screened by protein array and MSCs were analyzed by real-time polymerase chain reaction, proliferation, migration, and enzyme linked immunosorbent assays., Results: Multipotent MSCs were isolated from BAL of lung recipients independent of BOS presence. However, MSCs from BOS patients proliferated at higher rates (P<0.001) and were associated with higher α-smooth muscle actin (P = 0.03) but lower surfactant protein B (P = 0.02) compared with those from no-BOS patients. Histological analysis revealed that MSCs are abundant in lung tissue of BOS patients. MSCs from BOS patients produced higher endothelin-1 (ET-1) amounts (P<0.001) compared with those from no-BOS; and ET-1 stimulated whereas ET-1 blockade suppressed MSC proliferation, migration, and differentiation., Conclusions: These results indicate that MSCs are associated with BOS and are governed by ET-1. Targeting MSCs by ET-1 blockade might be useful in BOS treatment.

Chronic lung allograft rejection, known as obliterative bronchiolitis (OB), is the leading cause of death in lung transplant patients. Although OB pathogenesis is not fully understood, in this issue of the JCI, Jiang and colleagues report that tissue hypoxia resulting in dysfunctional airway microvasculature precedes the airway fibrosis characteristic of OB. In addition, a relative deficiency of allograft endothelial cell-derived HIF-1α contributes to this process. Data showing that overexpressing HIF-1α restores the microvascular airway normoxia and prevents airway fibrosis highlight a novel role for vascular biology in OB pathogenesis.

Objective: The use of non-heart-beating (NHB) lung donors has been propagated as an alternative besides heart-beating (HB) lung donors to overcome organ shortage. We evaluated the effectiveness of NHB lung transplantation., Methods: The donor and recipient data of all 35 NHB category III lung transplantations (LTx) between January 2005 and December 2009 were reviewed. For comparison, we collected recipient and donor data of a cohort of 77 HB lung transplantations. In both groups, we assessed survival, primary graft dysfunction (PGD), forced expiratory volume in 1s (FEV(1)), acute rejection, and bronchiolitis obliterans syndrome (BOS)., Results: Thirty-five NHB lung transplantations were performed, five single LTx and 30 bilateral LTx in 12 male and 23 female patients. The donor oxygenation capacity was 61 kPa (interquartile range (IQR), 56-64). Warm ischemia time in the donor was 29 min (IQR, 24-30). Cold ischemic time of the last implanted lung was 458 min (IQR, 392-522). Cardiopulmonary bypass was used 13 times. PGD (1-3) was observed in 45% of the patients at T0, in 42% at T24, in 53% at T48, and in 50% at T72. PGD 3 decreased from 24% at T0 to 6% at T72. The use of nitric oxide (NO) within 24h after transplantation was necessary in three patients with successful weaning in all. There was no significant difference for donor and recipient characteristics between NHB and HB lung transplantations. Survival, occurrence of PGD, and acute rejection was equal to the HB cohort. The incidence of BOS was lower in the NHB group. The measured FEV(1) tended to be better in the NHB group., Conclusion: Lungs from nonheparinized category III NHB donors are well suited for transplantation and can safely increase the donor pool., (Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Biomarkers in exhaled breath condensate (EBC) and fractional exhaled nitric oxide (FeNO) have been widely evaluated in respiratory research as non-invasive methods of sampling the lungs. These methods are particularly attractive in lung transplantation (LTx) as they are simple, repeatable and sensitive. Chronic rejection, manifest by progressive airflow limitation and bronchiolitis obliterans syndrome (BOS), is currently the major limiting factor to long-term survival in LTx. Early detection of BOS and initiation of appropriate treatment could significantly improve survival. Exhaled breath biomarkers could allow early diagnosis of factors associated with chronic rejection. FeNO is elevated in LTx patients with infections and chronic rejection prior to clinical presentation, and several EBC biomarkers and volatile organic compound patterns also show promise in these areas. This review summarizes information on exhaled breath biomarkers in LTx and discusses their potential role in the management of LTx patients.

Background: Mannose-binding lectin (MBL) is a key molecule of the innate immune system and, in addition to the classical and alternative pathways, a principle driver of complement activation. Genetic mutations of MBL are common, result in low serum levels of MBL, and are associated with increased infection risk in solid-organ transplant recipients., Methods: We performed a retrospective study of MBL2 genotype and plasma and bronchoalveolar lavage (BAL) MBL levels in 37 lung transplant recipients (LTR). Plasma MBL levels were measured pretransplant and both plasma and BAL MBL levels were measured at 3, 6, and 12 months after lung transplantation. MBL2 genotyping was performed on recipient and donor peripheral blood mononuclear cells. Clinical variables analyzed included primary graft dysfunction, intensive care unit stay, acute allograft rejection, infection, bronchiolitis obliterans syndrome (BOS), and mortality., Results: Plasma MBL levels posttransplant were predicted by recipient, and not donor MBL2 genotype. Compared with pretransplant levels, plasma MBL was significantly increased at 3, 6, and 12 months posttransplant (P<0.05). LTR who developed BOS or died during the study period had higher plasma MBL levels at 6 and 12 months posttransplant (P ≤ 0.05) compared with LTR with stable graft function. MBL was not routinely detected in the lung allograft; however if present in the BAL at 3 and 6 months posttransplant, it was associated with the later development of BOS (P<0.05)., Conclusions: Plasma MBL levels increase after lung transplantation and persistently increased MBL levels are associated with poor long-term outcomes.

Objective: Lung transplantation is a standard treatment option for patients with end-stage lung disease. Lung transplantation in the elderly is controversial due to concerns over anticipated increased surgical risks, inferior long-term outcomes and proper stewardship in allocating limited donor organs. With demographic trends showing an increasing proportion of patients over 60 years old, we evaluated our outcomes with lung transplantation in this older cohort., Methods: Between January 1990 and July 2009, 142 patients underwent lung transplantation at our institution. A total of 15 patients receiving heart/lung transplantation and one patient declining research participation were excluded. As many as 126 patients were analyzed in two groups: <60 and ≥ 60 years old., Results: There were 65 females (52%) and 61 males (48%). A total of 53 patients (42%) underwent bilateral sequential lung transplantation and 73 patients single-lung transplantation (58%). Median age at transplantation was 55.3 years (range, 21.6-73.1 years) with 94 patients <60 years (75%) and 32 patients ≥ 60 years (25%). Median follow-up was 4.3 years (range, 0-17.8 years). Overall survival at 30 days was 93.7% with no difference between age groups (p=0.95). There was no difference between the groups for in-hospital, postoperative complications (p=0.86), or unplanned readmission rates within 90 days of the hospitalization (p=0.26). Postoperative pulmonary function (forced expiratory volume in 1s (FEV1) % predicted) at transplant, 4 weeks, 3 months, and 6 months after transplantation was not different between groups (p=0.93). No difference in long-term survival was observed (p=0.59), with 5-year survival of 52.2% for patients <60 years and 47.3% for patients ≥ 60 years. Overall, 20 patients developed bronchiolitis obliterans syndrome and 13 posttransplant lymphoproliferative disease, which was not statistically different between age groups (p=0.87, p=0.37, respectively)., Conclusion: Increased age of 60 years and greater, in highly selected patients, does not appear to have a significant impact on the short- or long-term outcome in patients undergoing lung transplantation. Judicious selection of older patients, who are otherwise excellent candidates for lung transplantation, remains a reasonable option., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Galactosyl transferase gene knock-out (GalTKO) swine offer a unique tool to evaluate the role of the Gal antigen in xenogenic lung hyperacute rejection., Methods: We perfused GalTKO miniature swine lungs with human blood. Results were compared with those from previous studies using wild-type and human decay-accelerating factor-transgenic (hDAF(+/+) ) pig lungs., Results: GalTKO lungs survived 132 ± 52 min compared to 10 ± 9 min for wild-type lungs (P = 0.001) and 45 ± 60 min for hDAF(+/+) lungs (P = 0.18). GalTKO lungs displayed stable physiologic flow and pulmonary vascular resistance (PVR) until shortly before graft demise, similar to autologous perfusion, and unlike wild-type or hDAF(+/+) lungs. Early (15 and 60 min) complement (C3a) and platelet activation and intrapulmonary platelet deposition were significantly diminished in GalTKO lungs relative to wild-type or hDAF(+/+) lungs. However, GalTKO lungs adsorbed cytotoxic anti-non-Gal antibody and elaborated high levels of thrombin; their demise was associated with increased PVR, capillary congestion, intravascular thrombi and strong CD41 deposition not seen at earlier time points., Conclusions: In summary, GalTKO lungs are substantially protected from injury but, in addition to anti-non-Gal antibody and complement, platelet adhesion and non-physiologic intravascular coagulation contribute to Gal-independent lung injury mechanisms., (© 2011 John Wiley & Sons A/S.)

Azithromycin (AZM) improved bronchiolitis obliterans syndrome (BOS) and reduced aspiration in lung transplant (LTx) recipients. We hypothesize that AZM could improve graft and overall survival more efficiently in LTx patients with BOS who have bile acid (BA) aspiration by protecting against the aspiration-induced progression of BOS. The goal was to compare FEV(1) (% baseline), BOS progression and overall survival in LTx recipients treated with AZM for BOS, both with versus without BA aspiration. Therefore, LTx recipients treated with AZM for BOS were recruited and broncho-alveolar lavage (BAL) samples were analyzed for the presence of BA and neutrophilia before the start of AZM treatment. Short-term effect of AZM on FEV(1) and BAL neutrophilia was assessed, progression of BOS and survival were followed-up for 3 years and results were compared between patients with/without BA aspiration. 19/37 LTx patients had BA in BAL. BA aspiration predisposed to a significantly worse outcome, in terms of decline in FEV(1) , progression of BOS ≥ 1 and survival. AZM does not seem to protect against the long-term allograft dysfunction caused by gastroesophageal reflux (GER) and aspiration and an additional treatment targeting aspiration may be indicated in those LTx patients., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: The limited number of available grafts is one of the major obstacles of lung transplantation. Size-reduced lung transplantation allows the use of oversized grafts for small recipients. Optimal lung size matching is vital to achieve best functional outcome and avoid potential problems when using oversized grafts. We hypothesise that donor-predicted postoperative forced expiratory volume in 1s (ppoFEV1) correlates with the recipient best FEV1 after size-reduced lung transplant, being useful for the estimation of function outcome., Methods: All patients undergoing size-reduced or standard bilateral lung transplantation were included (1992-2007). Donor ppoFEV1 was calculated and corrected with respect to size reduction and correlated with recipient measured best FEV1 post-transplant. In addition, pre- and postoperative clinical data including surgical complications and outcome of all size-reduced lung transplant recipients were compared with standard lung transplant recipients., Results: A total of 61 size-reduced lung transplant recipients (lobar transplants, n=20; anatomic or non-anatomic resection, n=41) were included and compared to 145 standard transplants. The mean donor-recipient height difference was statistically significant between the two groups (p=0.0001). The mean donor ppoFEV1 was comparable with recipient best FEV1 (2.7±0.6 vs 2.6±0.7 l). There was a statistically significant correlation between donor ppoFEV1 and recipient best FEV1 (p=0.01, r=0.688). The 30-day mortality rate and 3-month, 1- and 5-year survival rates were comparable between the two groups., Conclusions: In size-reduced lung transplantation, postoperative recipient best FEV1 could be predicted from donor-calculated and corrected FEV1 with respect to its size reduction. Compared to standard lung transplantation, equivalent morbidity, mortality and functional results could be obtained after size-reduced lung transplantation., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Granulocytes are pivotal regulators of tissue injury. However, the transcriptional mechanisms that regulate granulopoiesis under inflammatory conditions are poorly understood. Here we show that the transcriptional coregulator B cell leukemia/lymphoma 3 (Bcl3) limits granulopoiesis under emergency (i.e., inflammatory) conditions, but not homeostatic conditions. Treatment of mouse myeloid progenitors with G-CSF--serum concentrations of which rise under inflammatory conditions--rapidly increased Bcl3 transcript accumulation in a STAT3-dependent manner. Bcl3-deficient myeloid progenitors demonstrated an enhanced capacity to proliferate and differentiate into granulocytes following G-CSF stimulation, whereas the accumulation of Bcl3 protein attenuated granulopoiesis in an NF-κB p50-dependent manner. In a clinically relevant model of transplant-mediated lung ischemia reperfusion injury, expression of Bcl3 in recipients inhibited emergency granulopoiesis and limited acute graft damage. These data demonstrate a critical role for Bcl3 in regulating emergency granulopoiesis and suggest that targeting the differentiation of myeloid progenitors may be a therapeutic strategy for preventing inflammatory lung injury.

Rationale: flow volume loops (FVL) in some bilateral lung transplant (BLT) and heart-lung transplant (HLT) patients suggest variable extrathoracic obstruction in the absence of identifiable causes. These FVLs usually have supranormal expiratory and normal inspiratory flow rates (SUPRA pattern)., Objectives: characterize the relationship of the SUPRA pattern to predicted donor and recipient lung volumes, airway size, and survival., Methods: we performed a retrospective review of adult BLT/HLT patients. We defined the SUPRA FVL pattern as: (1) mid-vital capacity expiratory to inspiratory flow ratio (Ve50:Vi50) > 1.0, (2) absence of identifiable causes of extrathoracic obstruction, and (3) Ve50/FVC ≥ 1.5 s(-1). We calculated predicted total lung capacity (pTLC) ratio by dividing the donor pTLC by the recipient pTLC. We measured airway luminal areas on thoracic computer tomographic scans. We compared survival in patients with and without the SUPRA pattern., Measurements and Main Results: the SUPRA FVL pattern occurred in 56% of the 89 patients who qualified for the analysis. The pTLC ratio of SUPRA and non-SUPRA patients was 1.11 and 0.99, respectively (P = 0.004). A higher pTLC ratio was correlated with increased probability of the SUPRA pattern (P = 0.0072). Airway luminal areas were larger in SUPRA patients (P = 0.009). Survival was better in the SUPRA cohort (P = 0.009)., Conclusions: the SUPRA FVL pattern was frequent in BLT/HLT patients. High expiratory flows in SUPRA patients could result from increased lung elastic recoil or reduced airway resistance, both of which could be caused by the pTLC mismatch. Improved survival in the SUPRA cohort suggests potential therapeutic approaches to improve outcomes in BLT/HLT patients.

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.)