Thrombomodulin-mediated Inhibition of Neutrophil Extracellular Trap Formation Alleviates Hepatic Ischemia-reperfusion Injury by Blocking TLR4 in Rats Subjected to Liver Transplantation
Thrombomodulin-mediated Inhibition of Neutrophil Extracellular Trap Formation Alleviates Hepatic Ischemia-reperfusion Injury by Blocking TLR4 in Rats Subjected to Liver Transplantation
复制标题
血栓调节蛋白介导的中性粒细胞胞外陷阱形成抑制作用通过阻断肝移植大鼠的 TLR4 减轻肝脏缺血再灌注损伤
DOI：
10.1097/tp.0000000000003954
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发表时间：
2022-02-01
期刊：
影响因子：
6.2
通讯作者：
Wu, Zhongjun
中科院分区：
文献类型：
--
作者：
Liu, Yanyao;Lei, Zilun;Wu, Zhongjun
背景。肝缺血再灌注损伤（IRI）是肝移植不可避免的结果，其中中性粒细胞胞外陷阱（NET）可能在IRI诱导的炎症免疫反应中发挥关键作用。本研究的目的是鉴定重组人血栓调节蛋白（rTM）在缓解肝移植后肝脏IRI中的作用并阐明其具体机制。方法。在肝移植患者和肝移植后大鼠的血清中检测到NET形成（NETosis）。使用苏木精-伊红染色、末端脱氧核苷酸转移酶2'-脱氧尿苷、5'-三磷酸缺口末端标记染色、免疫组织化学和免疫荧光来评估rTM对体外和体内NETosis的影响。结果。我们发现rTM显着抑制NETs中的中性粒细胞形成，减少肝细胞凋亡，减轻大鼠肝脏IRI并改善肝功能。在体外，rTM 抑制 NET 中的中性粒细胞形成，脂多糖（Toll 样受体 4 激动剂）逆转 rTM 对 NETosisN 的抑制作用。 rTM 阻断 Toll 样受体 4 和下游细胞外信号调节激酶/c-Jun NH2 末端激酶和烟酰胺腺嘌呤二核苷酸磷酸 (NADPH)/活性氧/肽基精氨酸脱亚氨酶 4 信号通路，以预防肝脏 IRI 并抑制 NETosis。此外，我们证明 rTM 和 NADPH 氧化抑制剂联合治疗比单独治疗具有更好的效果。结论。 NETs 是肝脏 IRI 的潜在治疗靶点，rTM 可用于预防 IR 引起的肝损伤。此外，共同靶向 NETosis 相关信号通路可能是治疗肝脏 IRI 的一种新的治疗策略。
Background. Hepatic ischemia-reperfusion injury (IRI) is an unavoidable outcome of liver transplantation, during which neutrophil extracellular traps (NETs) may play a critical role in the IRI-induced immune response to inflammation. The purpose of this study was to identify the function of recombinant human thrombomodulin (rTM) in the remission of hepatic IRI after liver transplantation and elucidate the specific mechanism. Methods. NET formation (NETosis) was detected in the serum of liver transplantation patients and rats following liver transplantation. Hematoxylin–eosin staining, terminal deoxynucleotidyl transferase 2´-deoxyuridine, 5´-triphosphate nick-end labeling staining, immunohistochemistry, and immunofluorescence were used to assess the effect of rTM on NETosis in vitro and in vivo. Results. We found that rTM markedly inhibited neutrophil formation in NETs, reduced apoptosis in hepatocytes, alleviated rat hepatic IRI, and improved liver function. In vitro, rTM inhibited neutrophil formation in NETs, and lipopolysaccharide (a Toll-like receptor 4 agonist) reversed the inhibitory effect of rTM on NETosisN. rTM blocked a Toll-like receptor 4 and the downstream extracellular signal-regulated kinase/c-Jun NH2 terminal kinase and nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species/peptidylarginine deiminase 4 signaling pathways to protect against hepatic IRI and inhibit NETosis. In addition, we demonstrated that combined treatment with rTM and an NADPH oxidative inhibitor had a better effect than either treatment alone. Conclusions. NETs are a potential therapeutic target in hepatic IRI, and rTM could be used to prevent IR-induced hepatic injury. In addition, cotargeting NETosis-related signaling pathways might be a novel therapeutic strategy for hepatic IRI treatment.