Neurological Surgery Department, University of Sao Paulo School of Medicine, Av. Dr. Enéas Carvalho de Aguiar, 255, 5th Floor, São Paulo, CEP: 05402-000, Brazil.
Organ Procurement Organization Department, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.
Sci Rep. 2021 Sep 28;11(1):19221. doi: 10.1038/s41598-021-98538-z.
Brain death is characterized by a generalized inflammatory response that results in multiorgan damage. This process is mainly mediated through cytokines, which amplify graft immunogenicity. We investigated the immunological response in a brain death liver donor model and analysed the effects of thalidomide, a drug with powerful immunomodulatory properties. Brain death was induced in male Lewis rats. We studied three groups: Control (sham-operated rats in which trepanation was performed without inserting the balloon catheter), BD (rats subjected to brain death by increasing intracranial pressure) and BD + Thalid (BD rats receiving thalidomide after brain death). After 6 h, serum levels of AST, ALT, LDH, and ALP as well as systemic and hepatic levels of TNF-α, IL1-β, IL-6, and IL-10 were analysed. We also determined the mRNA expression of MHC Class I and Class II, NF-κB, and macrophage infiltration. NF-κB was also examined by electrophoretic mobility shift assay. Thalidomide treatment significantly reduced serum levels of hepatic enzymes and TNF-α, IL-1-β, and IL-6. These cytokines were evaluated at either the mRNA expression or protein level in liver tissue. In addition, thalidomide administration resulted in a significant reduction in macrophages, MHC Class I and Class II, and NF-κB activation. This study reveals that thalidomide significantly inhibited the immunologic response and graft immunogenicity, possibly through suppression of NF-κB activation.
脑死亡的特征是全身性炎症反应，导致多器官损伤。这个过程主要通过细胞因子介导，细胞因子会放大移植物的免疫原性。我们在脑死亡供肝模型中研究了免疫反应，并分析了沙利度胺（一种具有强大免疫调节特性的药物）的作用。我们诱导雄性 Lewis 大鼠发生脑死亡。我们研究了三组大鼠：对照组（假手术大鼠，仅行颅骨钻孔而不插入球囊导管）、BD 组（通过增加颅内压导致脑死亡的大鼠）和 BD+沙利度胺组（脑死亡后给予沙利度胺的 BD 大鼠）。6 小时后，分析血清中天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、乳酸脱氢酶（LDH）和碱性磷酸酶（ALP）水平，以及血清和肝脏中 TNF-α、IL1-β、IL-6 和 IL-10 的水平。我们还测定了 MHC Ⅰ类和Ⅱ类、NF-κB 和巨噬细胞浸润的 mRNA 表达。NF-κB 还通过电泳迁移率变动分析进行了检测。沙利度胺治疗显著降低了血清肝酶和 TNF-α、IL-1-β 和 IL-6 水平。这些细胞因子在肝组织中通过 mRNA 表达或蛋白水平进行了评估。此外，沙利度胺给药导致巨噬细胞、MHC Ⅰ类和Ⅱ类以及 NF-κB 激活显著减少。这项研究表明，沙利度胺可显著抑制免疫反应和移植物免疫原性，可能是通过抑制 NF-κB 激活。
