Identification of new molecular targets and the study for the mechanism of bile ducts-and hepatocyte-destruction in primary biliary cirrhosis

原发性胆汁性肝硬化新分子靶点的鉴定及胆管和肝细胞破坏的机制研究

• 批准号: 17590696
• 负责人: NAKAMURA Minoru
• 金额: $ 2.24万
• 依托单位: National Hospital Organization(NHO) Nagasaki Medical Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590696/
• 关键词: primary biliary cirrhosis; anti-gp210 antibodies; anti-centromere antibodies; predictive autoantibodies; NHOSLJ; anti-mitochondrial antibodies; anti-nuclear antibodies; 分子標的; gp210; centromere; TLR3; 胆管上皮細胞; 自然免疫

The predictive role of anti-nuclear antibodies (ANAs) remains elusive in the long-term outcome of primary biliary cirrhosis (PBC). The aim of this study is to clarify the significance of ANAs in the progression of PBC.The associations between ANAs and the progression of PBC were evaluated using step-wise Cox proportional hazard regression and an unconditional step-wise logistic regression model based on the data of 276 biopsy-proven, definite PBC patients who have been registered to National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). Serum antibodies to nuclear antigens including gp210, centromere, sp100 and chromatin were measured by ELISA over periods extending from 1 to 292 (median 60.5) months of observation. A total of 91 PBC liver biopsy specimens were also assessed for histological variables in relation to ANAs.When death of hepatic failure/liver transplantation (LT) was defined as an end-point in all PBC patients, positive anti-gp210 antibodies (Haza … More rd ratio (HR)=6.742, 95% confidence interval (CI) : 2.408, 18.877), the late stage (Scheuer's stage 3, 4) (HR=4.285, 95% CI : 1.682,10.913) and male sex (HR=3.266, 95% CI : 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e. hepatic failure type-progression) or to the development of esophageal varices or hepatocelluar carcinoma without developing jaundice (T.bilirubin<1.5mg/dl) (i.e. non-hepatic failure type-progression) was defined as an end-point in the early stage (Scheuer's stage 1, 2) PBC patients, positive anti-gp210 antibodies was, a significant risk factor for hepatic failure type-progression (odds ratio (OR)=33.777, 95% CI : 5.930, 636.745), whereas positive anti-centromere antibodies was a significant risk factor for non-hepatic failure type-progression (OR=4.202, 95% CI : 1.307, 14.763). Histologically, positive anti-gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, while positive anti-centromere antibodies was most significantly associated with more severe ductular reaction These results indicate that there are two different progression-types in PBC, hepatic failure type-and non-hepatic failure type-progression, which may be represented by positive-anti-gp210 and-anti-centromere antibodies, respectively. Less

抗核抗体（ANA）对原发性胆汁性肝硬化（PBC）长期结果的预测作用仍然难以捉摸。本研究的目的是阐明 ANA 在 PBC 进展中的重要性。使用逐步 Cox 比例风险回归和无条件逐步 Logistic 回归模型评估 ANA 与 PBC 进展之间的关联，该模型基于 276 名已在日本国家医院组织肝病研究组 (NHOSLJ) 注册的经活检证实的明确 PBC 患者的数据。通过 ELISA 在 1 至 292（中位数 60.5）个月的观察期内测量针对核抗原（包括 gp210、着丝粒、sp100 和染色质）的血清抗体。还对总共 91 份 PBC 肝活检标本进行了与 ANA 相关的组织学变量评估。当所有 PBC 患者将肝衰竭/肝移植 (LT) 死亡定义为终点时，抗 gp210 抗体阳性（Haza … 更多 rd 比 (HR)=6.742，95% 置信区间 (CI)：2.408， 初次肝活检时，晚期（Scheuer 分期 3、4）（HR=4.285，95% CI：1.682,10.913）和男性（HR=3.266，95% CI：1.321,8.075）是显着危险因素。当临床进展至肝衰竭/LT死亡（即肝衰竭类型进展）或发展为食管静脉曲张或肝细胞癌但无黄疸（T.胆红素<1.5mg/dl）（即非肝衰竭类型进展）被定义为早期（Scheuer's 1、2期）PBC患者的终点时，阳性 抗gp210抗体是肝衰竭类型进展的显着危险因素（比值比（OR）= 33.777，95％CI：5.930，636.745），而抗着丝粒抗体阳性是非肝衰竭类型进展的显着危险因素（OR=4.202，95％CI：1.307， 14.763）。组织学上，抗gp210抗体阳性与更严重的界面性肝炎和小叶炎症最显着相关，而抗着丝粒抗体阳性与更严重的导管反应最显着相关。这些结果表明PBC有两种不同的进展类型，肝衰竭型进展和非肝衰竭型进展，这可能以抗gp210阳性为代表。 和抗着丝粒抗体。较少的

项目成果

IgA class antibodies to 2-oxo-acid dehydrogenase complex are not predictive markers of histopathological progression in primary biliary cirrhosis.

2-含氧酸脱氢酶复合物的 IgA 类抗体不是原发性胆汁性肝硬化组织病理学进展的预测标志物。

• 发表时间: 2006
• 期刊: Autoimmunity 39(2)
• 作者: Omagari K;Kadokawa Y;Nakamura M;Akazawa S;Ohba K;Ohnita K;Mizuta Y;Daikoku M;Yatsuhashi H;Ishibashi H;Kohno S.
• 通讯作者: Kohno S.

コランジオサイトのセルサイクルとその制御-コランジオサイト研究の最近の展開-

colangiosite的细胞周期及其控制 - colangiosite研究的最新进展 -

• 发表时间: 2006
• 期刊: 肝胆膵 53
• 作者: 小森敦正;瀧井康;石橋大海;中村 稔
• 通讯作者: 中村 稔

Feasibility study of ambulatory continuous infusion of 5-fluorouracil followed by cisplatin through hepatic artery for metastatic colorectal cancer.

经肝动脉门诊持续输注5-氟尿嘧啶随后顺铂治疗转移性结直肠癌的可行性研究。

• 发表时间: 2006
• 期刊: Cancer Chemother Pharmacol. 57(1)
• 作者: Qin B;Kato K;Mitsugi K;Nakamura M;Tanaka R;Baba E;Ariyama H;Kuroiwa T;Harada M;Nakano S.
• 通讯作者: Nakano S.

Immunosuppressive FK506 inhibits matrix metalloproteinase-9 induction in TNF-alpha-stimulated human hepatic stellate cells.

免疫抑制性 FK506 可抑制 TNF-α 刺激的人肝星状细胞中基质金属蛋白酶 9 的诱导。

• 发表时间: 2006
• 期刊: Life Sci. 78(21)
• 作者: Migita K;Maeda Y;Abiru S;Nakamura M;Komori A;Yokoyama T;Takii Y;Mod T;Yatsuhashi H;Eguchi K;Ishibashi H.
• 通讯作者: Ishibashi H.

Relationship between serum resistin concentrations and inflammatory markers in patients with type 2 diabetes mellitus

• DOI: 10.1016/j.metabol.2006.08.008
• 发表时间: 2006-12-01
• 期刊: METABOLISM-CLINICAL AND EXPERIMENTAL
• 影响因子: 9.8
• 作者: Huang Hui-bing;Migita, Kiyoshi;Kimura, Hironori
• 通讯作者: Kimura, Hironori