RESUMEN
BACKGROUND: Although sevoflurane (Sevo) had been shown to ameliorate posttransplant injury in various organs, data available are inconsistent, particularly in the context of lung transplantation (Tx). We here investigated if preconditioning by Sevo can protect from posttransplant injury regarding both, primary graft dysfunction (PGD) and acute rejection (AR) after experimental lung Tx, thereby focusing on two important clinical outcome parameters. MATERIALS AND METHODS: Three experimental approaches were used: (1) BALB/c mice were preconditioned for 2 h with Sevo or a fentanyl cocktail (Control; n = 10); (2) syngeneic (Syn) mouse lung Tx (C57BL/6) with a Sevo-preconditioned graft followed by 18 h storage to mimic PGD (Syn-Tx, n = 12) versus controls (fentanyl cocktail); and (3) allogeneic (Allo) Tx (BALB/c, donor; C57BL/6, recipient) to mimic AR (Allo-Tx, n = 12) versus controls (fentanyl cocktail). Syn-Tx grafts were harvested on Day 1, Allo-Tx grafts on Day 3 and analyzed for histology, immunohistochemistry, blood gas analysis, and inflammatory cytokines (enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction). RESULTS: Evaluating the preconditioning effect of Sevo only showed significantly better oxygenation (P = 0.03) and a tendency toward lower levels of lung tissue messenger RNA for tumor necrosis factor-α. In Syn-Tx recipients, the Sevo group had histologically a tendency toward an attenuation of PGD and showed significantly lower levels of interleukin 6 (P = 0.01) in plasma, but higher levels of interleukin 10 (P < 0.01) in lungs. Allo-Tx grafts in Sevo Tx recipients showed attenuated AR with histologically significantly lower rejection scores (P = 0.03), fewer classical macrophages (F4/80+; P < 0.01), but more anti-inflammatory activated macrophages (M2, CD206+; P < 0.01). Functionally, the Sevo group had a tendency toward improved oxygenation. CONCLUSIONS: We demonstrated that Sevo preconditioning has protective effects on lung transplants in both, PGD and AR. The observed amelioration may be attributed to suppressed inflammatory cytokines during PGD and the induction of alternatively activated macrophages during AR. These promising data could set the base for using Sevo preconditioning in donor lungs for a human trial.
Asunto(s)
Rechazo de Injerto/prevención & control , Trasplante de Pulmón , Éteres Metílicos/uso terapéutico , Cuidados Preoperatorios/métodos , Disfunción Primaria del Injerto/prevención & control , Sustancias Protectoras/uso terapéutico , Animales , Esquema de Medicación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Sevoflurano , Resultado del TratamientoRESUMEN
Chest-wall invading malignancies usually necessitate the resection of the respective part of the thoracic wall. Gore-Tex® is the material of choice that is traditionally used to repair thoracic defects. This material is well accepted by the recipient; however, though not rejected, it is an inert material and behaves like a 'foreign body' within the thoracic wall. By contrast, there are materials that have the potential to physiologically integrate into the host, and these materials are currently under in vitro and also in vivo investigation. These materials offer a gradual but complete biodegradation over time, and severe adverse inflammatory responses can be avoided. Here, we present a novel material that is a biodegradable nanocomposite based on poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles in comparison to the traditionally employed Gore-Tex® being the standard for chest-wall replacement. On a mouse model of thoracic wall resection, that resembles the technique and localization applied in humans, poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles and Gore-Tex® were implanted subcutaneously and additionally tested in a separate series as a chest-wall graft. After 1, 2, 4 and 8 weeks cell infiltration into the respective materials, inflammatory reactions as well as neo-vascularization (endothelial cells) were determined in six different zones. While Gore-Tex® allowed for cell infiltration only at the outer surface, electrospun poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles were completely penetrated by infiltrating cells. These cells were composed mainly by macrophages, with only 4% of giant cells and lymphocytes. Total macrophage count increased by time while the number of IL1-ß-expressing macrophages decreased, indicating a protective state towards the graft. As such, poly-lactic-co-glycolic acid and amorphous calcium phosphate nanoparticles seem to develop ideal characteristics as a material for chest-wall replacement by (a) having the advantage of full biodegradation, (b) displaying stable chest-wall structures and (c) adapting a physiological and integrating graft compared to Gore-Tex®.