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Neutrophil extracellular traps induce intrahepatic thrombotic tendency and liver damage in cholestatic liver disease.
Yu, Muxin; Li, Xiaowen; Xu, Long; Zheng, Chuwei; Pan, Weiwei; Chen, Hui; Liu, Xiaoyu; Zhang, Xianshan; Zhang, Jinming.
Afiliação
  • Yu M; Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China.
  • Li X; Department of Pathology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
  • Xu L; Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China.
  • Zheng C; Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
  • Pan W; Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China.
  • Chen H; Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China.
  • Liu X; Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China.
  • Zhang X; Department of Clinical Medical Sciences, College of Medicine, Jiaxing University, Jiaxing, China.
  • Zhang J; Department of Gastroenterology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
Hepatol Commun ; 8(8)2024 08 01.
Article em En | MEDLINE | ID: mdl-39101776
ABSTRACT

BACKGROUND:

Cholestatic liver diseases induce local and systemic hypercoagulation, with neutrophil extracellular traps (NETs) serving as major drivers. These NETs have been linked to decreased liver function in patients with obstructive jaundice. However, the impact of NETs on liver hypercoagulation in cholestatic liver disease remains unknown.

METHODS:

We utilized bile duct ligation to create experimental mice and analyzed NETs formation in the liver. Fibrin deposition, tissue factor expression, and inflammation in the liver were visualized through western blot and immunohistochemical techniques. LSECs were incubated with isolated NETs, and we detected endothelial procoagulant activity using coagulation protein production assays and measuring endothelial permeability. In both in vivo and in vitro settings, DNase I was applied to clarify the effect of NETs on intrahepatic hypercoagulability, hepatotoxicity, LSEC, and macrophage activation or injury.

RESULTS:

Bile duct ligation mice exhibited significantly increased levels of NETs in liver tissue, accompanied by neutrophil infiltration, tissue necrosis, fibrin deposition, and thrombophilia compared to sham mice. Notably, NETs resulted in phosphatidylserine and tissue factor exposure on LSEC, enhancing coagulation Factor Xa and thrombin production. The enhanced procoagulant activity could be reversed by degrading NETs with DNase I. Additionally, NETs-induced permeability changes in LSECs, characterized by increased VE-cadherin expression and F-actin retraction, which could be rescued by DNase I. Meanwhile, NET formation is associated with KC activation and the formation of inflammatory factors.

CONCLUSIONS:

NETs promote intrahepatic activation of coagulation and inflammation, leading to liver tissue injury. Strategies targeting NET formation may offer a potential therapeutic approach for treating cholestatic liver disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose / Armadilhas Extracelulares / Fígado Limite: Animals / Humans / Male Idioma: En Revista: Hepatol Commun Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose / Armadilhas Extracelulares / Fígado Limite: Animals / Humans / Male Idioma: En Revista: Hepatol Commun Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Estados Unidos