Development of hepatic anti-fibrotic therapy targeted to angiotensin II receptor antagonist-soppression of collagen production in the Ito cell via TGF-β

开发针对血管紧张素 II 受体拮抗剂的肝抗纤维化疗法 - 通过 TGF-β 抑制 Ito 细胞中胶原蛋白的产生

• 批准号: 13557045
• 负责人: KAWATA Sumio
• 金额: $ 4.16万
• 依托单位: Yamagata University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557045/
• 关键词: Hepatic fibrosis; hepatic cirrhosis; chronic hepatitis C; Angiotensin II receptor; angiotensin II; 受容体阻害薬; アンギオテンシンII; アンギオテンシンII受容体; アンギオテンシン; アンギオテンシン受容体

Anti-fibrotic therapy is expcted to prevent hepatic cirrhosis.In 2001, we carried out a randomized controlled study on anti-fibrotic therapy for chronic hepatitis C without effect of interferon therapy. 30 consecutive patients with chronic hepatitis C were randomizedly divided into two groups. 15 patients were treated with losartan (50 mg/day), angiotensin II type 1 receptor antagonist, for 3 months. The other 15 patients were followed as controls. After the oral administration, plasma TGF-β1 concentrations, a marker of fibrosis, significantly decreased in the group of losartan whereas the concentrations did not change in the control group. Fibrosis area (%) in the losartan group was reduced with mild significance. This result suggested that blocking of angiotensin II signal leaded to suppression of heparic fibrosis.In 2002, angiotensin II type 1 receptor antagonist (CS-866) was administered to rat cirrhosis model. The treated rats showed significant decrease in hepatic TGF-β1 and hydroxyproline contents. Histological examination revealed that degree of hepatic fibrosis was much lower in the treated than the controls.

抗肝纤维化治疗有望预防肝硬化的发生，我们于2001年对干扰素治疗无效的慢性丙型肝炎患者进行了抗肝纤维化治疗的随机对照研究。将30例慢性丙型肝炎患者随机分为两组。15例患者用血管紧张素Ⅱ 1型受体拮抗剂氯沙坦（50 mg/d）治疗3个月。另15例患者作为对照组。口服给药后，氯沙坦组的血浆TGF-β1浓度（纤维化的标志物）显著降低，而对照组的浓度无变化。氯沙坦组纤维化面积（%）减少，但有轻度意义。2002年，在大鼠肝硬化模型中应用血管紧张素Ⅱ 1型受体拮抗剂（CS-866）。治疗组大鼠肝组织TGF-β1和羟脯氨酸含量明显降低。组织学检查显示，治疗组肝纤维化程度明显低于对照组。

项目成果

Saeki A, Tamura S, Kawata S, et al.: "Frequent impairment of the spindle assembly check point in hepatocellular carcinoma"Cancer. 94. 2047-2054 (2002)

Saeki A、Tamura S、Kawata S 等人：“肝细胞癌中纺锤体装配检查点的频繁损伤”癌症。

Saito T, Shinzawa H, Kawata S, et al.: "Lamivadine and rapid regeneration of the atrophic liver in decompensated cirrhosis due to HBV"Am. J. Gastroenterol. 97. 493-494 (2002)

Saito T、Shinzawa H、Kawata S 等人：“拉米伐定与 HBV 导致的失代偿性肝硬化中萎缩性肝脏的快速再生”Am。

Sakon M, Nagano H, Kawata S. et al.: "Combined intraarterial 5-FU and subcutanious IFN-α therapy for advanced hepatocellular carcinoma"Cancer. 94. 435-442 (2002)

Sakon M、Nagano H、Kawata S. 等人：“动脉内 5-FU 和皮下 IFN-α 联合疗法治疗晚期肝细胞癌”癌症。 94. 435-442 (2002)

Kitada T., Kawata S., et al.: "The addition of bisecting N-acetylglucosamine residues to E-cadherin down regulates phosphonylation of B-catenin"J.Biol.Chem. 276. 475-480 (2001)

Kitada T.、Kawata S. 等人：“将二等分的 N-乙酰葡糖胺残基添加到 E-钙粘蛋白上可下调 B-连环蛋白的磷酸化”J.Biol.Chem。

Aoki M, Saito T, Kawata S, et al.: "Clinical significance of a highly sensitive enzyme immunoassay of hepatitis B surface antigen"J. Med. Virol. 66. 166-170 (2002)

Aoki M，Saito T，Kawata S，等：“乙型肝炎表面抗原高灵敏酶免疫测定的临床意义”J。