Intrahepatic neutrophil accumulation and extracellular trap formation are associated with posthepatectomy liver failure.
Intrahepatic neutrophil accumulation and extracellular trap formation are associated with posthepatectomy liver failure.
复制标题
DOI：
10.1097/hc9.0000000000000348
复制
发表时间：
2024-01-01
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
--
作者：
术后肝功能衰竭(PHLF)是一种危及生命的并发症，治疗选择有限。中性粒细胞在再生过程中发挥着重要的、动态的作用，但对其在人类肝脏再生中的作用尚不完全清楚，尤其是在大多数患者中可检测到的潜在肝病，严重影响肝脏再生。在这里，我们研究了PHLF患者的中性粒细胞在肝内的堆积和中性粒细胞细胞外陷阱(NETS)，并在小鼠部分肝切除(PHX)模型中验证了NETS的功能相关性。我们用荧光显微镜观察了35例肝切除患者(10例PHLF)在肝再生开始前后中性粒细胞、巨噬细胞、嗜酸性粒细胞和肥大细胞的流入及其细胞外陷阱的存在。此外，对99例(24例PHLF)患者在手术前和术后5天进行了血浆分析，证实了Net形成和中性粒细胞的激活。此外，在代谢性肝病小鼠的小鼠PHX模型中，我们通过DNase I抑制了Nets。我们检测到中性粒细胞在肝内迅速聚集，髓过氧化物酶释放水平升高，并在再生的人肝中形成网状结构，在PHLF患者中，浸润性中性粒细胞和网状细胞的数量显著增加。中性粒细胞激活的循环标志物，包括弹性酶、髓过氧化物酶和瓜氨酸组蛋白H3，与肝损伤的标志物相关。在小鼠PHX模型中，我们发现Net的抑制加速了肝细胞的增殖和肝再生。PHLF患者表现为肝内中性粒细胞加速浸润和网状形成，与肝损害有关。此外，我们将术后髓过氧化物酶水平确定为不良结果的预测标记物，并观察到在小鼠PHX模型中阻断Net可加速组织再生。
Posthepatectomy liver failure (PHLF) represents a life-threatening complication with limited therapeutic options. Neutrophils play a critical and dynamic role during regeneratory processes, but their role in human liver regeneration is incompletely understood, especially as underlying liver disease, detectable in the majority of patients, critically affects hepatic regeneration. Here we explored intrahepatic neutrophil accumulation and neutrophil extracellular traps (NETs) in patients with PHLF and validated the functional relevance of NETs in a murine partial hepatectomy (PHx) model. We investigated the influx of neutrophils, macrophages, eosinophils, and mast cells and the presence of their respective extracellular traps in liver biopsies of 35 patients undergoing hepatectomy (10 patients with PHLF) before and after the initiation of liver regeneration by fluorescence microscopy. In addition, NET formation and neutrophil activation were confirmed by plasma analysis of 99 patients (24 patients with PHLF) before and up to 5 days after surgery. Furthermore, we inhibited NETs via DNase I in a murine PHx model of mice with metabolically induced liver disease. We detected rapid intrahepatic neutrophil accumulation, elevated levels of myeloperoxidase release, and NET formation in regenerating human livers, with a significantly higher increase of infiltrating neutrophils and NETs in patients with PHLF. Circulating markers of neutrophil activation, including elastase, myeloperoxidase, and citrullinated histone H3, correlated with markers of liver injury. In a murine PHx model, we showed that the inhibition of NET accelerated hepatocyte proliferation and liver regeneration. Patients with PHLF showed accelerated intrahepatic neutrophil infiltration and NET formation, which were associated with liver damage. Further, we identified postsurgical myeloperoxidase levels as predictive markers for adverse outcomes and observed that blocking NETs in a murine PHx model accelerated tissue regeneration.