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Deficiency of neutrophil gelatinase-associated lipocalin elicits a hemophilia-like bleeding and clotting disorder in mice
Blood ( IF 21.0 ) Pub Date : 2024-12-20 , DOI: 10.1182/blood.2024026476
Min Xue, Shaoying Wang, Changjiang Li, Yuewei Wang, Ming Liu, Xiaoshan Huang, Gan Wang, Qikai Yin, Dandan Xiao, Shuo Yang, Musan Yan, Liyuan Niu, Muhammad Awais, Chuanbin Shen, Jianxun Wang, Ren Lai, Heyu Ni, Xiaopeng Tang
Blood ( IF 21.0 ) Pub Date : 2024-12-20 , DOI: 10.1182/blood.2024026476
Min Xue, Shaoying Wang, Changjiang Li, Yuewei Wang, Ming Liu, Xiaoshan Huang, Gan Wang, Qikai Yin, Dandan Xiao, Shuo Yang, Musan Yan, Liyuan Niu, Muhammad Awais, Chuanbin Shen, Jianxun Wang, Ren Lai, Heyu Ni, Xiaopeng Tang
Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in patients with thrombosis. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, factor XIa (FXIa), and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or IV administration promoted coagulation and hemostasis and aggravated thrombosis, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 minutes, respectively, resembling uncontrollable bleeding and clotting disorder seen in hemophilic mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in inflammation-induced thrombosis models. Collectively, these findings unveil a previously unidentified role of NGAL in the processes of coagulation, hemostasis, and thrombosis, as well as the cross talk between innate immunity, inflammation, and coagulation. Thus, modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.
中文翻译:
中性粒细胞明胶酶相关脂质运载蛋白的缺乏会在小鼠中引发血友病样出血和凝血障碍
凝血与炎症有关,但关键途径,尤其是先天免疫系统和凝血调节,尚不清楚,需要进一步探索。在这里,我们证明了中性粒细胞明胶酶相关脂质运载蛋白 (NGAL) 是一种先天免疫炎症介质,在血栓形成患者中上调。此外,它有助于凝血、止血和血栓形成的启动和放大。这是通过增强细胞表面的组织因子表达,增强凝血酶、激肽释放酶、因子 XIa (FXIa) 和 FVIIa 等各种凝血因子,促进凝血酶诱导的血小板聚集,以及抑制抗凝血酶来实现的。在血栓弹力图分析中,NGAL 敲除导致凝块反应时间和动力学时间显著延长,血栓发生角度减小,血栓最大振幅降低,这与活化部分凝血活酶时间和凝血酶原时间显著延长一致。在几种小鼠止血和血栓形成模型中,NGAL 过表达或静脉给药促进凝血止血并加重血栓形成,而 NGAL 敲除或抗 NGAL 单克隆抗体治疗显着延长出血时间并减轻血栓形成。值得注意的是,NGAL 敲除将小鼠尾部出血时间或动脉闭塞时间分别延长至 40 或 60 分钟以上,类似于血友病小鼠中无法控制的出血和凝血障碍。此外,抗 NGAL 单克隆抗体治疗显着减少了炎症诱导血栓形成模型中血栓的形成。 总的来说,这些发现揭示了 NGAL 在凝血、止血和血栓形成过程中以前未被确定的作用,以及先天免疫、炎症和凝血之间的串扰。因此,调节 NGAL 水平可能有助于平衡血栓形成和出血风险。
更新日期:2024-12-20
中文翻译:
中性粒细胞明胶酶相关脂质运载蛋白的缺乏会在小鼠中引发血友病样出血和凝血障碍
凝血与炎症有关,但关键途径,尤其是先天免疫系统和凝血调节,尚不清楚,需要进一步探索。在这里,我们证明了中性粒细胞明胶酶相关脂质运载蛋白 (NGAL) 是一种先天免疫炎症介质,在血栓形成患者中上调。此外,它有助于凝血、止血和血栓形成的启动和放大。这是通过增强细胞表面的组织因子表达,增强凝血酶、激肽释放酶、因子 XIa (FXIa) 和 FVIIa 等各种凝血因子,促进凝血酶诱导的血小板聚集,以及抑制抗凝血酶来实现的。在血栓弹力图分析中,NGAL 敲除导致凝块反应时间和动力学时间显著延长,血栓发生角度减小,血栓最大振幅降低,这与活化部分凝血活酶时间和凝血酶原时间显著延长一致。在几种小鼠止血和血栓形成模型中,NGAL 过表达或静脉给药促进凝血止血并加重血栓形成,而 NGAL 敲除或抗 NGAL 单克隆抗体治疗显着延长出血时间并减轻血栓形成。值得注意的是,NGAL 敲除将小鼠尾部出血时间或动脉闭塞时间分别延长至 40 或 60 分钟以上,类似于血友病小鼠中无法控制的出血和凝血障碍。此外,抗 NGAL 单克隆抗体治疗显着减少了炎症诱导血栓形成模型中血栓的形成。 总的来说,这些发现揭示了 NGAL 在凝血、止血和血栓形成过程中以前未被确定的作用,以及先天免疫、炎症和凝血之间的串扰。因此,调节 NGAL 水平可能有助于平衡血栓形成和出血风险。