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Войти в исследования Journal of thrombosis and haemostasis : JTH · 2026
Carbon tetrachloride (CCl4)-induced liver injury activates hepatocyte-independent tissue factor-driven coagulation.
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Patel Amish K, Capece Gina E, Hazel Bianca, Roychowdhury Tayana, Mac Noah A, Hu Daniel, Baker Kevin S, Fernandes-Fonseca Maria T, Wei Zimu, Sachetto Ana T A, Goedken Michael J, Luyendyk James P, Mackman Nigel, Poole Lauren G
Аннотация
BACKGROUND: Liver injury is associated with activation of the blood coagulation cascade. Hepatocytes express low levels of tissue factor (TF), the transmembrane receptor and cofactor for coagulation factor VIIa (FVIIa). The TF-FVIIa complex activates the extrinsic coagulation pathway and plays an essential role in hemostasis.
OBJECTIVES: This study tested the hypothesis that hepatocyte TF drives coagulation activation after toxicant-induced liver injury.
METHODS: Wild-type mice, mice with whole-body TF deficiency (LowTF), and mice lacking TF specifically in hepatocytes (HPCΔTF) were challenged once with carbon tetrachloride (CCl4, 1 mL/kg, intraperitoneally). Liver injury and coagulation parameters were evaluated 2 to 96 hours after challenge. In separate studies, mice were challenged twice weekly for 4 to 6 weeks, and samples were collected 24 to 72 hours after the final challenge.
RESULTS: Acute CCl4 challenge caused hepatic injury and robust coagulation activation. Whole-body TF deficiency significantly reduced coagulation activation and attenuated peak hepatocellular necrosis, whereas hepatocyte TF deficiency had no effect on coagulation activation or acute liver injury. In situ hybridization identified cells in inflammatory foci expressing TF (F3) transcripts in the necrotic region of the CCl4-challenged liver. After chronic CCl4 challenge, whole-body TF deficiency significantly reduced coagulation activation and modestly decreased fibrosis by means of reduced hepatic stellate cell activation, but hepatocyte TF deficiency did not affect coagulation activation or liver fibrosis.
CONCLUSION: These data suggest that TF-expressing nonparenchymal cells mediate coagulation activation during CCl4-induced liver injury. Our findings provide the foundation for future work to identify TF-expressing cell types and their underlying contributions to liver injury pathogenesis.
OBJECTIVES: This study tested the hypothesis that hepatocyte TF drives coagulation activation after toxicant-induced liver injury.
METHODS: Wild-type mice, mice with whole-body TF deficiency (LowTF), and mice lacking TF specifically in hepatocytes (HPCΔTF) were challenged once with carbon tetrachloride (CCl4, 1 mL/kg, intraperitoneally). Liver injury and coagulation parameters were evaluated 2 to 96 hours after challenge. In separate studies, mice were challenged twice weekly for 4 to 6 weeks, and samples were collected 24 to 72 hours after the final challenge.
RESULTS: Acute CCl4 challenge caused hepatic injury and robust coagulation activation. Whole-body TF deficiency significantly reduced coagulation activation and attenuated peak hepatocellular necrosis, whereas hepatocyte TF deficiency had no effect on coagulation activation or acute liver injury. In situ hybridization identified cells in inflammatory foci expressing TF (F3) transcripts in the necrotic region of the CCl4-challenged liver. After chronic CCl4 challenge, whole-body TF deficiency significantly reduced coagulation activation and modestly decreased fibrosis by means of reduced hepatic stellate cell activation, but hepatocyte TF deficiency did not affect coagulation activation or liver fibrosis.
CONCLUSION: These data suggest that TF-expressing nonparenchymal cells mediate coagulation activation during CCl4-induced liver injury. Our findings provide the foundation for future work to identify TF-expressing cell types and their underlying contributions to liver injury pathogenesis.