Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Japan.
Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Japan,
Cell Physiol Biochem. 2020 Oct 15;54(5):1041-1053. doi: 10.33594/000000286.
BACKGROUND/AIMS: Although adhesion formation is a frequent adverse event following intraperitoneal surgery, efficient prophylactic interventions have not yet been established. We recently reported that blockade of interleukin (IL)-6 prevented postoperative adhesion after cecum cauterization. Intriguingly, this intervention dampened tumor necrosis factor (TNF) induction in the injured serosa. Herein, we addressed whether TNF might be a key target and, if so, how TNF blockade rescued adhesion formation.
Mice were administered an anti-TNF biologic (etanercept) on days -2 and -1 before and upon cecal cauterization. The adhesion scores were evaluated at day 7 postoperatively. Histological alterations were examined by immunochemistry/immunofluorescence studies. We incubated human neutrophils and mesothelial cell line cells with recombinant TNF in the presence of etanercept and measured transcript levels of cytokines and chemokines by quantitative reverse transcription-polymerase chain reaction (RT-qPCR).
Etanercept rescued mice from adhesion formation, accompanied by a robust reduction of neutrophilia in the injured serosa. Immunofluorescence revealed a substantial formation of neutrophil extracellular traps (NETs) with the potential to induce tissue damage and profibrotic responses. In contrast, the etanercept-treated mice lacked NET formation. In addition, etanercept inhibited TNF-induced IL-6, TNF, and neutrophil-recruiting chemokines in neutrophils and mesothelial cells, a major cellular source of myofibroblasts in the adhesion band.
Prophylactic administration of etanercept might be a potential strategy for preventing postoperative adhesion formation.
背景/目的：尽管粘连形成是腹腔内手术后常见的不良事件，但尚未建立有效的预防干预措施。我们最近报告称，阻断白细胞介素（IL）-6 可预防盲肠烧灼后的术后粘连。有趣的是，这种干预措施抑制了受伤浆膜中的肿瘤坏死因子（TNF）诱导。在此，我们研究了 TNF 是否可能是一个关键靶点，如果是这样，TNF 阻断如何挽救粘连形成。
在盲肠烧灼前 2 天和前 1 天以及手术后，给小鼠给予抗 TNF 生物制剂（依那西普）。术后第 7 天评估粘连评分。通过免疫化学/免疫荧光研究检查组织学改变。我们用重组 TNF 孵育人中性粒细胞和间皮细胞系细胞，并在存在依那西普的情况下测量细胞因子和趋化因子的转录水平。
依那西普可使小鼠免于粘连形成，同时受伤浆膜中的中性粒细胞增多得到了显著抑制。免疫荧光显示，大量形成了中性粒细胞胞外陷阱（NETs），有可能导致组织损伤和促纤维化反应。相比之下，依那西普治疗的小鼠缺乏 NET 形成。此外，依那西普抑制了 TNF 诱导的中性粒细胞和间皮细胞中 IL-6、TNF 和中性粒细胞募集趋化因子，这是粘连带中肌成纤维细胞的主要细胞来源。
预防性给予依那西普可能是预防术后粘连形成的一种潜在策略。
