Caspase Inhibition Reduces Hepatic Tissue Factor-Driven Coagulation In Vitro and In Vivo
| العنوان: | Caspase Inhibition Reduces Hepatic Tissue Factor-Driven Coagulation In Vitro and In Vivo |
|---|---|
| المؤلفون: | James P. Luyendyk, Anna K. Kopec, Patricia C. Contreras, Nigel Mackman, Alfred P. Spada |
| المصدر: | Toxicological Sciences. 162:396-405 |
| بيانات النشر: | Oxford University Press (OUP), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Primary Cell Culture, Caspase Inhibition and Hepatic Tissue Factor-Mediated Coagulation, Apoptosis, Caspase 3, 030204 cardiovascular system & hematology, Toxicology, Thromboplastin, 03 medical and health sciences, Tissue factor, 0302 clinical medicine, medicine, Animals, fas Receptor, Blood Coagulation, Caspase, Liver injury, biology, Chemistry, Microvesicle, medicine.disease, Caspase Inhibitors, Molecular biology, Microvesicles, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Liver, Hepatocyte, Microvessels, Hepatocytes, biology.protein |
| الوصف: | Tissue factor (TF) is the primary activator of the blood coagulation cascade. Liver parenchymal cells (ie, hepatocytes) express TF in a molecular state that lacks procoagulant activity. Hepatocyte apoptosis is an important feature of acute and chronic liver diseases, and Fas-induced apoptosis increases hepatocyte TF procoagulant activity in vitro. We determined the impact of a pan-caspase inhibitor, IDN-7314, on hepatocyte TF activity in vitro and TF-mediated coagulation in vivo. Treatment of primary mouse hepatocytes with the Fas death receptor ligand (Jo2, 0.5 μg/ml) for 8 h increased hepatocyte TF procoagulant activity and caused release of TF-positive microvesicles. Pretreatment with 100 nM IDN-7314 abolished Jo2-induced caspase-3/7 activity and significantly reduced hepatocyte TF procoagulant activity and release of TF-positive microvesicles. Treatment of wild-type C57BL/6 mice with a sublethal dose of Jo2 (0.35 mg/kg) for 4.5 h increased coagulation, measured by a significant increase in plasma thrombin-antithrombin and TF-positive microvesicles. Total plasma microvesicle-associated TF activity was reduced in mice lacking hepatocyte TF; suggesting TF-positive microvesicles are released from the apoptotic liver. Fibrin(ogen) deposition increased in livers of Jo2-treated wild-type mice and colocalized primarily with cleaved caspase-3-positive hepatocytes. Pretreatment with IDN-7314 reduced caspase-3 activation, prevented the procoagulant changes in Jo2-treated mice, and reduced hepatocellular injury. Overall, the results indicate a central role for caspase activity in TF-mediated activation of coagulation following apoptotic liver injury. Moreover, the results suggest that liver-selective caspase inhibition may be a putative strategy to limit procoagulant and prothrombotic changes in patients with chronic liver disease. |
| تدمد: | 1096-0929 1096-6080 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7628c69efaf4f462e63d4061351c3ce0 https://doi.org/10.1093/toxsci/kfx268 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....7628c69efaf4f462e63d4061351c3ce0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10960929 10966080 |
|---|