Endothelial damage and a thin intercellular fibrin network promote haemorrhage in acute promyelocytic leukaemia
| Autor: | Jin Zhou, Yingmiao Liu, Yueyue Li, Peng Zhou, Xiaojing Chen, Jinming Zhang, Lixiu Wang, Yue Zhang, Haijiao Jing, Jialan Shi, Chunxu Wang, Jingwen Du, Muxin Yu, Baorong Li, Shaohong Fang, Valerie A. Novakovic, Yufeng Wang, Yiming Feng, Zengxiang Dong |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Receptor expression Endothelial cells Cell Intracellular Space Fluorescent Antibody Technique lcsh:Medicine Cell Communication Mice 0302 clinical medicine Leukemia Promyelocytic Acute immune system diseases Receptor lcsh:R5-920 biology Chemistry General Medicine Middle Aged medicine.anatomical_structure 030220 oncology & carcinogenesis Female Disease Susceptibility lcsh:Medicine (General) Research Paper Adult Endothelium Hemorrhage Models Biological General Biochemistry Genetics and Molecular Biology Fibrin Permeability Cell Line Capillary Permeability 03 medical and health sciences In vivo medicine Cell Adhesion Animals Humans neoplasms Aged lcsh:R Acute promyelocytic leukaemia Disease Models Animal 030104 developmental biology Haemorrhage Cell culture biology.protein Cancer research Endothelium Vascular Ex vivo Biomarkers |
| Zdroj: | EBioMedicine, Vol 60, Iss, Pp 102992-(2020) EBioMedicine |
| ISSN: | 2352-3964 |
| Popis: | Background The role of vascular endothelium in acute promyelocytic leukaemia (APL) remains unknown. We aimed to investigate the mechanisms by which APL cells interact with endothelial cells (ECs) and to further explore how the endothelium affects bleeding as well as therapeutic interventions. Method APL cells and an original APL cell line, NB4 cells, were used for experiments. The effects of leukaemic cells on ECs were analyzed in vitro and in vivo. Moreover, the endothelial barrier function and procoagulant activity were detected. An APL mouse model was established for in vivo studies. Findings APL cells interacted with ECs via ICAM-1 and VCAM-1 receptors to disrupt endothelial integrity. This binding activated MLCK signaling, resulting in the trans-endothelial passage of protein and red blood cells (RBCs). Combined treatment with asiatic acid or anti-adhesion receptor antibody inhibited the response of ECs to APL cells, thereby preventing APL-associated haemorrhage in vitro and in vivo. Activated ECs exhibited a procoagulant phenotype after phosphatidylserine exposure. Plasma from APL patients formed a thin fibrin network between procoagulant ECs, and this intercellular fibrin decreased the passage of albumin and RBCs. Ex vivo addition of fibrinogen further enhanced this barrier function in a dose-dependent manner. Interpretation Endothelial damage induced by leukaemic cell adherence promotes haemorrhaging in APL. Stabilization of ECs, decreasing adhesion receptor expression, and increasing fibrinogen transfusion levels may be a new therapeutic avenue to alleviate this fatal bleeding complication. Funding National Science Foundation of China (81670128, 81873433). |
| Databáze: | OpenAIRE |
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