Van Zanden Judith E, 't Hart Nils A, Ottens Petra J, Liu Bo, Rebolledo Rolando A, Erasmus Michiel E, Leuvenink Henri G D
Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Front Pharmacol. 2021 Feb 22;12:587003. doi: 10.3389/fphar.2021.587003. eCollection 2021.
The process of brain death (BD) leads to a pro-inflammatory state of the donor lung, which deteriorates its quality. In an attempt to preserve lung quality, methylprednisolone is widely recommended in donor lung management. However, clinical treatment doses vary and the dose-effect relation of methylprednisolone on BD-induced lung inflammation remains unknown. The aim of this study was to investigate the effect of three different doses methylprednisolone on the BD-induced inflammatory response. BD was induced in rats by inflation of a Fogarty balloon catheter in the epidural space. After 60 min of BD, saline or methylprednisolone (low dose (5 mg/kg), intermediate dose (12.5 mg/kg) or high dose (22.5 mg/kg)) was administered intravenously. The lungs were procured and processed after 4 h of BD. Inflammatory gene expressions were analyzed by RT-qPCR and influx of neutrophils and macrophages were quantified with immunohistochemical staining. Methylprednisolone treatment reduced neutrophil chemotaxis as demonstrated by lower IL-8-like CINC-1 and E-selectin levels, which was most evident in rats treated with intermediate and high doses methylprednisolone. Macrophage chemotaxis was attenuated in all methylprednisolone treated rats, as corroborated by lower MCP-1 levels compared to saline treated rats. Thereby, all doses methylprednisolone reduced TNF-α, IL-6 and IL-1β tissue levels. In addition, intermediate and high doses methylprednisolone induced a protective anti-inflammatory response, as reflected by upregulated IL-10 expression when compared to saline treated brain-dead rats. We showed that intermediate and high doses methylprednisolone share most potential to target BD-induced lung inflammation in rats. Considering possible side effects of high doses methylprednisolone, we conclude from this study that an intermediate dose of 12.5 mg/kg methylprednisolone is the optimal treatment dose for BD-induced lung inflammation in rats, which reduces the pro-inflammatory state and additionally promotes a protective, anti-inflammatory response.
脑死亡（BD）过程会导致供体肺处于促炎状态，从而使其质量下降。为了试图保护肺质量，甲基强的松龙在供体肺管理中被广泛推荐。然而，临床治疗剂量各不相同，且甲基强的松龙对BD诱导的肺部炎症的剂量效应关系仍不清楚。本研究的目的是调查三种不同剂量的甲基强的松龙对BD诱导的炎症反应的影响。通过在硬膜外间隙插入Fogarty球囊导管使大鼠诱导脑死亡。BD诱导60分钟后，静脉注射生理盐水或甲基强的松龙（低剂量（5mg/kg）、中剂量（12.5mg/kg）或高剂量（22.5mg/kg））。BD诱导4小时后获取并处理肺组织。通过RT-qPCR分析炎症基因表达，并用免疫组织化学染色对中性粒细胞和巨噬细胞的流入进行定量。甲基强的松龙治疗降低了中性粒细胞趋化性，如较低的IL-8样CINC-1和E-选择素水平所示，这在接受中剂量和高剂量甲基强的松龙治疗的大鼠中最为明显。与生理盐水处理的大鼠相比，所有接受甲基强的松龙治疗的大鼠中巨噬细胞趋化性均减弱，这通过较低的MCP-1水平得到证实。因此，所有剂量的甲基强的松龙均降低了TNF-α、IL-6和IL-1β的组织水平。此外，与生理盐水处理的脑死亡大鼠相比，中剂量和高剂量的甲基强的松龙诱导了保护性抗炎反应，这通过上调的IL-10表达得以体现。我们表明，中剂量和高剂量的甲基强的松龙在靶向大鼠BD诱导的肺部炎症方面具有最大潜力。考虑到高剂量甲基强的松龙可能的副作用，我们从本研究得出结论，12.5mg/kg的中剂量甲基强的松龙是大鼠BD诱导的肺部炎症的最佳治疗剂量，它可降低促炎状态，并额外促进保护性抗炎反应。
