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.

大规模肝坏死（暴发性病毒肝炎的特征）是由于微循环障碍而引起的，这是由于库珀弗细胞和正弦曲线内皮细胞之间的凝结平衡引起的。与其他器官中的血管相比，由于没有或极低的组织因子因子因子途径抑制剂（TFPI）和内皮细胞上血栓瘤蛋白（TM）的表达，肝正正弦体的抗凝活性降低了。因此，TFPI和TM的替代可能是对这种肝损伤的有力疗法。当大鼠静脉内静脉内接受重组人TFPI时，TFPI在注射后迅速从循环中消失，并在正弦内皮细胞的表面和肝细胞的微绒毛表面被检测到，这表明TFPI可能在正弦壁上专门作为抗凝蛋白。 TM的设计是通过通过甘露糖受体作为靶向基因来表达其对正弦内皮细胞的作用。表面上包含甘露糖和FITC的杂种内注入的杂交在正弦壁的内壁上产生荧光产物。这些靶向肝弦乐壁的抗凝装置可能是暴发性病毒性肝炎的治疗候选者，其一般出血的不良影响最小。

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