New devices in anticoagulant therapy for massive hepatic necrosis through sinusoidal fibrin deposition

通过肝窦纤维蛋白沉积抗凝治疗大面积肝坏死的新装置

• 批准号: 06454258
• 负责人: FUJIWARA Kenji
• 金额: $ 4.67万
• 依托单位: Saitama Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454258/
• 关键词: fulminant hepatitie; acute liver failure; sinusoidal fibrin doposition; Kupffer cells; sinusoidal endothetial cells; 肝移植; primary graft nonfunction; トロンボモジュリン; 組織因子; 肝マクロファージ; 肝類洞内皮細胞

Massive hepatic necrosis, characteristic of fulminant viral hepatitis, occurs as a result of microcirculatory disturbance due to deranged blood coagulation equilibrium between Kupffer cells and sinusoidal endothelial cells. Anticoagulant activity in the hepatic sinusoids was decreased compared to the vessels in other organs as a consequence of no or extremely reduced expressionof tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) on endothelial cells. Thus, the replacement of TFPI and TM might be a powerful therapy for such liver injury. When rats received recombinant human TFPI intravenously, TFPI disappeared from the circulation rapidly after the injection, and were detected on the surface of sinusoidal endothelial cells and microvilli of hepatocytes, suggesting that TFPI may act as an anticoagulant exclusively on the sinusoidal walls. TM was designed to exert its action enhanced on sinusoidal endothelial cells by expression as a targeting gene through mannose receptors. Intraportal injection of miscells containing mannose and FITC on the surface produced fluorescence products on the lining of sinusoidal walls. These anticoagulant devices targeting hepatic sinusoidal walls may be therapeutic candidates for fulminant viral hepatitis with minimal adverse effects of general bleeding.

大量肝坏死是暴发性病毒性肝炎的特征，是由于库普弗细胞和肝窦内皮细胞之间的凝血平衡紊乱导致微循环障碍而发生的。由于内皮细胞上组织因子途径抑制剂（TFPI）和血栓调节蛋白（TM）的表达没有或大大减少，因此与其他器官中的血管相比，肝窦中的抗凝活性降低。因此，替代 TFPI 和 TM 可能是治疗此类肝损伤的有效疗法。当大鼠静脉注射重组人TFPI时，TFPI在注射后迅速从循环中消失，并在肝窦内皮细胞和肝细胞微绒毛表面上检测到，表明TFPI可能仅在肝窦壁上充当抗凝剂。 TM 被设计为通过甘露糖受体作为靶向基因表达，从而增强对窦内皮细胞的作用。门静脉内注射表面含有甘露糖和 FITC 的混合细胞，在窦壁内壁产生荧光产物。这些针对肝窦壁的抗凝装置可能是暴发性病毒性肝炎的候选治疗药物，且一般出血的副作用最小。

项目成果

Fujiwara K,Mochida S,et al: "Exerpta Medica,International Congress Seier 1086 Proguer in Hepatology “Cellular and Molewla Biology"" Yamanaka M.et al(eds)Elsevier Science,BV,Amstedam, 141 (1995)

Fujiwara K、Mochida S 等人：“Exerpta Medica，国际大会 Seier 1086 Proguer in Hepatology “Cellular and Molewla Biology”” Yamanaka M.et al(eds)Elsevier Science,BV,Amsterdam, 141 (1995)

Ohno A.: "ICAM-1 Expresion in Hepatsaytes Following Dissoociation of Cell-to-cell Contact in Rats." Biochemical and Biophysical Research Comminication. 214. 1225-1231 (1995)

Ohno A.：“大鼠细胞间接触解离后 Hepatsaytes 中的 ICAM-1 表达。”

Fujiwara K,Mochida S,et al: "Use of Prostaglandin Is Analog in Treatment of Massive Hepatic Necrosi Asociated with Endottelial Cell Injuy and Diffune Fibrin Deposition" Digeative Dreaeis and Sciences. 40. 41-47 (1995)

Fujiwara K、Mochida S 等人：“前列腺素类似物在治疗与内皮细胞损伤和弥漫性纤维蛋白沉积相关的大面积肝坏死中的用途”消化研究与科学。

Ohno A,Mochida S,Arai M,Fujiwara K.: "ICAM-1 Expression in Hepatocytes Following Dissociation of Cell-to-cell Contact Rats." Biochem Biophys Res Commun. 214. 1225-1231 (1995)

Ohno A、Mochida S、Arai M、Fujiwara K.：“细胞与细胞接触大鼠解离后肝细胞中 ICAM-1 的表达”。

Fujiwara K,Mochida S,Ohno A,Arai M,Matsui A,Masaki N,Hirata K,Tomiya T,Yamaoka M,Nagoshi S,Ohta Y,Ogata I,Francavilla A,Van Thiel DH,Starzel TE.: "Use of Prostaglandin I_2 Analog in Treatment of Massive Hepatic Necrosis Associated with Endothelial Cell In

藤原 K、持田 S、大野 A、荒井 M、松井 A、正木 N、平田 K、富宫 T、山冈 M、名越 S、太田 Y、绪方 I、弗朗卡维拉 A、范蒂尔 DH、Starzel TE。：“使用