Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
Department of Anesthesiology and Intensive Care Medicine, University Hospital Leipzig, Liebigstraße 20, 04103, Leipzig, Germany.
Lung. 2019 Apr;197(2):217-226. doi: 10.1007/s00408-019-00197-5. Epub 2019 Feb 9.
Acute allograft rejection after lung transplantation remains an unsolved hurdle. The pathogenesis includes an inflammatory response during and after transplantation. Ropivacaine, an amide-linked local anesthetic, has been shown to attenuate lung injury due to its anti-inflammatory effects. We hypothesized that the drug would also be able to attenuate acute rejection (AR) after allogeneic lung transplantation.
Allogeneic, orthotopic, single left lung transplantation was performed between BALB/c (donors) and C57BL/6 (recipients) mice. Prior to explantation, lungs were flushed with normal saline with or without ropivacaine (final concentration 1 µM). Plasma levels of tumor necrosis factor-α and interleukins - 6 and - 10 were measured 3 h after transplantation by ELISA. Lung function was assessed on postoperative day five and transplanted lungs were analyzed using histology (AR), immunohistochemistry (infiltrating leukocytes) and Western blot (phosphorylation and expression of Src and caveolin-1).
Ropivacaine pre-treatment significantly reduced AR scores (median 3 [minimum-maximum 2-4] for control vs. 2 [1-2] for ropivacaine, p < 0.001) and plasma levels of tumor necrosis factor-α (p = 0.01) compared to control, whereas plasma concentrations of interleukin - 6 (p = 0.008) and - 10 (p < 0.001) were increased by ropivacaine. The number of T-lymphocytes infiltrating the transplanted lung was attenuated (p = 0.02), while no differences in macrophage or B-lymphocyte numbers could be observed after ropivacaine pre-treatment. Caveolin-1 phosphorylation in ropivacaine-treated lungs was diminished (p = 0.004).
Pre-treatment of donor lungs with the local anesthetic ropivacaine diminished histological signs of AR after orthotopic left lung transplantation in mice, most likely due to reduced infiltration of T-lymphocytes into the graft.
肺移植后急性移植物排斥反应仍然是一个未解决的难题。其发病机制包括移植期间和之后的炎症反应。罗哌卡因是一种酰胺类局部麻醉剂，由于其抗炎作用，已被证明可以减轻肺损伤。我们假设该药物也能够减轻同种异体肺移植后的急性排斥反应（AR）。
在 BALB/c（供体）和 C57BL/6（受体）小鼠之间进行同种异体、原位、单左肺移植。在取出前，用含有或不含有罗哌卡因（终浓度 1μM）的生理盐水冲洗肺。通过 ELISA 测量移植后 3 小时的血浆肿瘤坏死因子-α和白细胞介素 -6 和 -10 的水平。术后第 5 天评估肺功能，并通过组织学（AR）、免疫组织化学（浸润白细胞）和 Western blot（Src 和 caveolin-1 的磷酸化和表达）分析移植肺。
罗哌卡因预处理显著降低 AR 评分（对照组中位数为 3[最小值-最大值 2-4]，罗哌卡因组为 2[1-2]，p<0.001）和肿瘤坏死因子-α 的血浆水平（p=0.01），而白细胞介素 -6（p=0.008）和 -10（p<0.001）的血浆浓度增加。浸润移植肺的 T 淋巴细胞数量减少（p=0.02），但在罗哌卡因预处理后，巨噬细胞或 B 淋巴细胞数量没有差异。罗哌卡因处理的肺中的 caveolin-1 磷酸化减少（p=0.004）。
在小鼠原位左肺移植中，用局部麻醉剂罗哌卡因预处理供体肺可减轻 AR 的组织学迹象，这可能是由于移植物中 T 淋巴细胞浸润减少所致。
