Yamada Yoshito, Laube Isabelle, Jang Jae-Hwi, Bonvini John M, Inci Ilhan, Weder Walter, Beck Schimmer Beatrice, Jungraithmayr Wolfgang
Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland; Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
J Surg Res. 2017 Jun 15;214:270-277. doi: 10.1016/j.jss.2017.03.021. Epub 2017 Mar 31.
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.
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).
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.
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.
尽管已表明七氟醚（Sevo）可改善各种器官的移植后损伤，但现有数据并不一致，尤其是在肺移植（Tx）方面。我们在此研究了 Sevo 预处理是否能在实验性肺移植后保护免受原发性移植功能障碍（PGD）和急性排斥反应（AR）的移植后损伤，从而关注两个重要的临床结局参数。
采用了三种实验方法：（1）将 BALB/c 小鼠用 Sevo 或芬太尼混合物预处理 2 小时（对照组；n = 10）；（2）用 Sevo 预处理的移植物进行同基因（Syn）小鼠肺移植（C57BL/6），随后储存 18 小时以模拟 PGD（Syn-Tx，n = 12），与对照组（芬太尼混合物）比较；（3）进行异基因（Allo）移植（BALB/c 供体；C57BL/6 受体）以模拟 AR（Allo-Tx，n = 12），与对照组（芬太尼混合物）比较。Syn-Tx 移植物在第 1 天收获，Allo-Tx 移植物在第 3 天收获，并进行组织学、免疫组织化学、血气分析和炎性细胞因子分析（酶联免疫吸附测定或逆转录聚合酶链反应）。
评估 Sevo 的预处理效果仅显示氧合明显更好（P = 0.03），且肿瘤坏死因子-α 的肺组织信使核糖核酸水平有降低趋势。在 Syn-Tx 受体中，Sevo 组在组织学上有 PGD 减轻的趋势，血浆中白细胞介素 6 水平显著降低（P = 0.01），但肺中白细胞介素 10 水平较高（P < 0.01）。Sevo 处理的受体中的 Allo-Tx 移植物显示 AR 减轻，组织学上排斥评分显著降低（P = 0.03），经典巨噬细胞（F4/80+）较少（P < 0.01），但抗炎活化巨噬细胞（M2，CD206+）较多（P < 0.01）。在功能上，Sevo 组有氧合改善的趋势。
我们证明 Sevo 预处理对肺移植在 PGD 和 AR 方面均有保护作用。观察到的改善可能归因于 PGD 期间炎性细胞因子的抑制以及 AR 期间交替活化巨噬细胞的诱导。这些有前景的数据可为在供体肺中使用 Sevo 预处理进行人体试验奠定基础。
