Acute liver injury Coagulation Platelets Thrombosis von Willebrand factor
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摘要

BACKGROUND & AIM:Acetaminophen (APAP)-induced acute liver failure is associated with substantial alterations in the hemostatic system. In mice, platelets accumulate in the liver after APAP overdose and appear to promote liver injury. Interestingly, patients with acute liver injury have highly elevated levels of the platelet-adhesive protein von Willebrand factor (VWF), but a mechanistic connection between VWF and progression of liver injury has not been established. We tested the hypothesis that VWF contributes directly to experimental APAP-induced acute liver injury.
METHODS:Wild-type mice and VWF-deficient (Vwf-/-) mice were given a hepatotoxic dose of APAP (300 mg/kg, i.p.) or vehicle (saline). VWF plasma levels were measured by ELISA, and liver necrosis or hepatocyte proliferation was measured by immunohistochemistry. Platelet and VWF deposition were measured by immunofluorescence.
RESULTS:In wild-type mice, VWF plasma levels, high molecular weight (HMW) VWF multimers, and VWF activity decreased 24 h after APAP challenge. These changes coupled to robust hepatic VWF and platelet deposition, although VWF deficiency had minimal effect on peak hepatic platelet accumulation or liver injury. VWF plasma levels were elevated 48 h after APAP challenge, but with relative reductions in HMW multimers and VWF activity. Whereas hepatic platelet aggregates persisted in livers of APAP-challenged wild-type mice, platelets were nearly absent in Vwf-/- mice 48 h after APAP challenge. The absence of platelet aggregates was linked to dramatically accelerated repair of the injured liver. Complementing observations in Vwf-/- mice, blocking VWF or the platelet integrin αIIbβ3 during development of injury significantly reduced hepatic platelet aggregation and accelerated liver repair in APAP-challenged wild-type mice.
CONCLUSION:These studies are the first to suggest a mechanistic link between VWF, hepatic platelet accumulation, and liver repair. Targeting VWF might provide a novel therapeutic approach to improve repair of the APAP-injured liver.
LAY SUMMARY:Patients with acute liver injury due to acetaminophen overdose have highly elevated levels of the platelet-adhesive protein von Willebrand factor. It is not known whether von Willebrand factor plays a direct role in the progression of acute liver injury. We discovered that von Willebrand factor delays repair of the acetaminophen-injured liver in mice and that targeting von Willebrand factor, even in mice with established liver injury, accelerates liver repair.

译文

背景与目的: 对乙酰氨基酚 (APAP) 诱导的急性肝衰竭与止血系统的实质性改变有关。在小鼠中,APAP 过量后,血小板在肝脏中积累,并似乎促进肝损伤。有趣的是,急性肝损伤患者的血小板粘附蛋白血管性血友病因子 (VWF) 水平高度升高,但 VWF 与肝损伤进展之间的机制联系尚未建立。我们验证了 VWF 直接导致实验性 APAP 诱导的急性肝损伤的假设。
方法: 给野生型小鼠和 VWF 缺陷 (Vwf-/-) 小鼠注射肝毒性剂量的 APAP (300 毫克/千克,i p.) 或车辆 (盐水)。用 ELISA 法测定血浆 VWF 水平,用免疫组织化学法测定肝坏死或肝细胞增殖。通过免疫荧光测定血小板和 VWF 沉积。
结果: 在野生型小鼠中,APAP 激发后 24 h,VWF 血浆水平、高分子量 (HMW) VWF 多聚体和 VWF 活性降低。这些变化与强健的肝脏 VWF 和血小板沉积相结合,尽管 VWF 缺乏对肝脏血小板峰值积累或肝损伤的影响最小。VWF 血浆水平在 APAP 激发后 48  h 升高,但 HMW 多聚体和 VWF 活性相对降低。而肝血小板聚集体在 APAP 激发野生型小鼠的肝脏中持续存在,在 APAP 激发后 48-h,Vwf-/-小鼠的血小板几乎不存在。血小板聚集体的缺乏与受损肝脏的快速修复有关。补充 Vwf-/-小鼠的观察,在损伤发展过程中阻断 VWF 或血小板整合素 α iib β3 可显著降低 APAP 激发野生型小鼠的肝脏血小板聚集和加速肝脏修复。
结论: 这些研究首次表明 VWF 、肝脏血小板聚集和肝脏修复之间存在机制联系。靶向 VWF 可能提供一种新的治疗方法来改善 APAP 损伤肝脏的修复。
总结: 对乙酰氨基酚过量导致急性肝损伤的患者血小板粘附蛋白血管性血友病因子水平升高。尚不清楚血管性血友病因子是否在急性肝损伤的进展中起直接作用。我们发现血管性血友病因子延迟了小鼠对乙酰氨基酚损伤肝脏的修复,并且靶向血管性血友病因子,甚至在已确定肝损伤的小鼠中,也加速了肝脏的修复。

Acetaminophen

呼吸 解热镇痛、非甾体抗炎药 药物
概述  :  

药物概述对乙酰氨基酚可解热止痛,用于缓解各种关节疼痛、神经痛、肌肉痛、痛经及牙痛等,尤其可用于对肠溶阿司匹林过敏或对阿司匹林不能耐受的消化道炎症或溃疡者。 药动学本品口服后吸收迅速而完全,进食富含碳水化合物的食物后再服用本品,其吸收减少。口服后达到血药浓度峰值的时间为0.5~2h。在体内有90%~95%于肝内被代谢,主要与葡萄醛酸、硫酸结合,其次是与半胱氨酸、硫醚氨酸氧化代谢。代谢物均经肾脏排泄,当超量服用时其主要代谢途径饱和后,则有一部分中间产物产生肝肾毒性。 作用机制本品

Acetaminophen   /əˌsiːtəˈmɪnəfen/ 

释    义   n. 对乙酰氨基酚;[药] 醋氨酚;退热净;扑热息痛(一种替代阿司匹林的解热镇痛药)

同根词   acetamide n. [有化] 乙酰胺

               acetanilide n.[药] 乙酰苯胺;退热冰,退热剂

例    句   There have been no reports of interactions between this product and ibuprofen or acetaminophen. 没有报告显示本品和布洛芬或是退热净产品有相互作用。

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