Immunosuppressive therapy in lung transplantation: state of the art

The coming of age of lung transplantation is accompanied by an immunosuppressive armamentarium that has been brought forward from other transplant indications. Widely employed on the basis of few small randomized studies, and mostly single-center experience or empirical expert knowledge, anti-rejection therapeutic strategies in pulmonary transplantation have hardly been rigorously evaluated in large-scale prospective international trials. This review compiles the available findings on the use of current immunosuppressants in clinical lung transplantation, accentuating high level-of-evidence study results. Reporting on recent meeting and registry data, and assembling ongoing relevant trials from international databases, this article serves as an update on the state of the art of immunosuppression in lung transplantatio

The influence of the rapamycin-derivate SDZ RAD on the healing of airway anastomoses

Objective: Among the many immunosuppressive effects of SDZ RAD (40-0(2-hydroxyethyl)-rapamycin), a rapamycin derivative, is the inhibition of fibroblast proliferation. Since the long-term success of lung transplantation is limited by the development of bronchiolitis obliterans, a fibroblast-associated progressive luminal obstruction of the terminal bronchioli, the use of SDZ RAD as immunosuppressive in pulmonary graft recipients may counteract this process. However, reduction of fibroblast activity, posttransplant, may impair the healing of the bronchial anastomoses. Materials and methods: The cervical trachea in pigs was denuded, divided and re-anastomosed with Prolene 4-0 single stitches. Control animals (group 1, n=4) were without, and study animals (group 2, n=6) were with SDZ RAD therapy (1.25 mg/kg/day, p.o., 14 days). After 14 days, the pigs were sacrificed. The anastomoses were examined histologically, and breaking strength of tracheal strips of 5-mm width was measured. Results: All animals survived without complications. Serum levels of SDZ RAD were 30.9±8.7 ng/ml (recommended level 20-40 ng/ml). All anastomoses healed macroscopically without difference between the two groups. Breaking strength was significantly lower in the treated animals (group 1 vs. group 2: 11.75±0.35 vs. 7.69±1.39 N, P=0.01). Histology did not show a significant change in histoarchitecture between the groups. Conclusions: Although SDZ RAD significantly reduced the breaking strength of the tracheal anastomosis, no obvious histological differences between treated and untreated animals could be detected. Since this model does not reflect the clinical situation, further investigations are necessary to reveal the effect of SDZ RAD on airway wound healing in concert with a contemporary clinically used multidrug immunosuppressive regimen in allograft recipient

Extended donor lungs: eleven years experience in a consecutive series

Objective: The aim of this study was to delineate the profile of extended donor lungs in comparison to ideal donor lungs and to analyse their outcome. Particular attention was given to donor lungs with a low PaO2 (≪250mmHg) before harvesting or with multiple extended criteria. Methods: Between 1993 and 2003, 148 patients (79 women, 69 men, mean age 39.9 years) underwent lung transplantation. Indications were cystic fibrosis in 35.8%, emphysema in 26.4%, pulmonary fibrosis in 12.2%, pulmonary hypertension in 9.5%, and others in 16.1%. Donor data and recipients medical files were reviewed. Criteria for donor lungs were considered extended if one or more of the following criteria were met: age ≫55 years, smoking ≫20 pack-years, PaO2 before harvesting ≪300mmHg, pathologic chest X-ray, and purulent secretion at bronchoscopy. A comparison between recipients from ideal and from extended donor lungs was performed with respect to the median duration of mechanical ventilation, the median length of stay at the intensive care unit, postoperative complications, the 30-day and the 1-year survival, and the 6-month follow-up spirometry. Results: Sixty-three (42.6%) donor lungs were considered extended and 20 (31.7%) met more than one criteria. Outcome comparison between recipients from ideal (I) and extended (II) donor lungs did not statistically differ in postoperative complications (18.8% (I) vs. 26.9% (II), P=0.32), mean duration of mechanical ventilation (d) (4.4±2.7 (I) vs. 2.6±2.1 (II), P=0.2), mean length of stay at the ICU (d) (11.5±8.8 (I) vs. 9.2±6.9 (II), P=0.4), 6-month pulmonary function (FEV1=83±23% of the predicted value (I) vs. 82±18% (II), P=0.81), 30-day survival (90.6% (I) vs. 93.7% (II), P=0.56), 1-year survival (83.5% (I) vs. 81% (II), P=0.83). Thirty-day survival was also comparable even in recipients from donor lungs with PaO2≪250mmHg (n=8) (90.6% (I) vs. 87.5%, P=0.57). The number of extended criteria had no impact on the outcome. The combination of PaO2≪300mmHg with purulent secretion at bronchoscopy seemed to influence the early outcome of recipients from extended donor lungs negatively. Conclusions: Our results suggest that the use of selected extended donor lungs does not compromise the outcome after transplantation. PaO2 ≪250mmHg before harvesting of the lungs is not an absolute contra-indication for transplantatio

Sildenafil extends survival and graft function in a large animal lung transplantation model

Objective: Restoring intracellular cGMP and inducing NO-synthesis attenuates ischemia-associated early pulmonary allograft dysfunction. Phosphodiesterase-5 (PDE), predominantly expressed in lung tissue, plays a pivotal role in modulating the cGMP/NO-synthase pathway in endothelial and epithelial cells. In this study, we evaluate the effect of employing sildenafil (Viagra®), a specific inhibitor of PDE-5, to counteract ischemia/reperfusion (I/R) injury in a single lung transplantation model of extended ischemia. Methods: Donor animals (weight matched outbred pigs, 28-35 kg) in the treatment group (I) (n = 5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex®, containing 0.7 mg sildenafil/l was used, and the graft stored at 1 °C in the perfusion solution. After 24 h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6 h. Except for the sildenafil application, the control group (II) (n = 4) was treated identically (PGE1 was injected into the PA). One hour after reperfusion, the right main bronchus (MB) and right PA were occluded. Over the next 5 h, cardiopulmonary parameters (systemic aterial, PA, central venous, left atrial pressure, pCO2, pO2) were measured, including extravascular lung water (EVLW). Thiobarbituric acid-reactive substance assay (TBARS) and myeloperoxidase (MPO) analysis from lung tissue were run. Results: All recipients of group I survived the 6-h reperfusion period; in contrast, all control animals died within 1-2 h after occlusion of the right side. In comparison to a marked rise in pulmonary vascular resistance (PVR) in group II (>1000 dyne s cm−5), PVR in group I remained stable, moderately elevated from baseline (baseline: 150-180 dyne s cm−5 vs endpoint: 1000 dyne s cm−5). EVLW in group I did not increase during reperfusion (baseline: 6.75 ± 1.4 mg/kg vs endpoint: 6.7 ± 1.0 mg/kg), in contrast to group II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7 ± 0.1 mg/kg vs group II: 6.48 ± 1.8 mg/kg). Tissue reactive free radicals at endpoint measurement in group I did not differ significantly from native tissue. Yet, when compared to specimen taken from group II at time of terminal graft failure, a significant increase in free radicals was noted (group I: 13.8 ± 1.6 pmol/g vs group II: 18.5 ± 3.0 pmol/g, p < 0.05). Conclusion: Sildenafil treatment prevents terminal early graft failure, allowing lung transplantation after 24-h ischemia time. Reperfusion edema was strikingly diminished, preserving pulmonary structural and functional integrity while prolonging graft ischemia time. Employing the established PDE-5 inhibitor sildenafil during lung perfusion, storage, and implantation, ischemic tolerance may be extended and early graft function improve

Tissue engineered cartilage generated from human trachea using DegraPol® scaffold

Objective: To date numerous attempts have been undertaken to conquer the challenging problem of reconstructing long segmental tracheal defects, as yet without lasting success. Recently, employing concepts of tissue engineering in animals, cartilage-like constructs were transplanted in vivo. However, both the feasibility of fabricating tracheal replacements and the use of human tracheal chondrocytes (HTC) for tissue engineering are still under investigation. In this study, we optimized isolation and cultivation techniques for human tracheal cartilage, assessing the feasibility of seeding these cells onto a novel, three-dimensional (3-D) polyester-urethane polymer (DegraPol®). Methods: Human tracheal cartilage was harvested from the trachea of lung donors, digested in 0.3% collagenase II, and the condrocytes serially passaged every 7-9 days. Cells were also cultivated over agar plate during the total 6-8 weeks expansion phase. Thereafter, chondrocytes were seeded onto DegraPol® (pore sizes 150-200 μm) with a seeding density of 2.4×107/ml, and chondrocyte-polymer constructs maintained during in vitro static culture. Results: HTC displayed stable proliferation kinetics in monolayer culture with positive expression of collagen type II. Following polymer seeding, both cellular proliferation and extracellular matrix (ECM) production, as measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and glycosaminoglycan assays, continued over extended culture. Active growth of HTC on DegraPol® was further demonstrated by Alcian blue staining, with the histomorphological appearance of the construct resembling that of native cartilage. Scanning electron microscopy showed chondrocyte growth and ECM synthesis both on the surface and inside the porous scaffold, with a dense cell layer on the surface of the scaffold and a lower cell distribution in the scaffold's interior. Conclusions: The harvested chondrocytes from human trachea cartilage expand well in vitro and possess the ability to form new cartilage-like tissue when seeded onto DegraPol® matrix. However, improved culture conditions are needed to permit cellular growth throughout cell-polymer construct

Prospective, Single-Arm, Longitudinal Study of Biomarkers in Real-World Patients with Severe Asthma

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Tissue engineered cartilage generated from human trachea using DegraPol (R) scaffold

ISSN:1010-794