Contribution of transforming growth factor-a to thr development of hepatic fibrosis in alcoholic liver diseases

转化生长因子-a对酒精性肝病肝纤维化发展的贡献

• 批准号: 09670560
• 负责人: KATO Junji
• 金额: $ 1.92万
• 依托单位: SAPPORO MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670560/
• 关键词: Alcoholic liver fibrosis; TGF-alpha; ethanol; Ito cells; HepG2 cells; IMR-90 cells; procollagen peptide C; collagen

Although it is well known that hepatic fibrosis develops in alcoholic liver diseases (ALD) without accompanying inflammation, the underlying mechanism is unclear. Using ethanol-exposed human HepG2 hepatoblastoma cells as a model for ALD, we previously found that ethanol exposure causes HepG2 cells to secrete a polypeptide factor which stimulates collagen synthesis in human IMR-90 fibroblasis. The aim of this study was to characterize and identify this factor.Collagen stimulating activity in conditioned media (CM) from ethanol-exposed HepG2 cells was assessed by its ability to stimulate synthesis of type I procollagen peptide (PIC) in IMR-90 cells. The identity of the factor was tested by the ability of antibodies to various cytokines to deplete collagen stimulating activity from CM.Transforming growth factor (TGF)-alpha in the CM of ethanol-treated HepG2 and serum TGF-alpha levels in patients with ALD were determined using an enzyme-linked immunosorbent assay. The collagen stimulating activity in CM could be depleted by antibody to TGF-alpha. Consistent with this, TGF-alpha in the CM of ethanol-treated HepG2 increased in a time-and dose-dependent manner. Suggesting that TGF-alpha may play a role in ALD, serum TGF-alpha levels in patients with ALD liver fibrosis were significantly higher than in patients with chronic viral hepatitis and viral cirrhosis. In conclusion, TGF-alpha may contribute to the development of hepatic fibrosis in ALD.

虽然众所周知，酒精性肝病（ALD）发生肝纤维化而不伴有炎症，但其潜在机制尚不清楚。利用乙醇暴露的人HepG2肝母细胞瘤细胞作为ALD的模型，我们之前发现乙醇暴露导致HepG2细胞分泌一种多肽因子，刺激人IMR-90纤维母细胞瘤的胶原合成。本研究的目的是表征和确定这一因素。通过刺激IMR-90细胞中I型前胶原肽（PIC）合成的能力，评估了乙醇暴露的HepG2细胞在条件培养基（CM）中的胶原刺激活性。通过对各种细胞因子的抗体的能力来测试该因子的身份，以消耗CM的胶原刺激活性。采用酶联免疫吸附法测定乙醇处理HepG2细胞CM中转化生长因子(TGF)- α和ALD患者血清TGF- α水平。tgf - α抗体可使CM的胶原刺激活性降低。与此一致的是，乙醇处理HepG2的CM中tgf - α呈时间和剂量依赖性增加。ALD肝纤维化患者血清tgf - α水平明显高于慢性病毒性肝炎和病毒性肝硬化患者，提示tgf - α可能在ALD中发挥作用。总之，tgf - α可能参与ALD患者肝纤维化的发生。

项目成果

Niitsu Y, Kato J, et al.: "A proof of glutathione S-transferase-pi-related multidrug resistance by transfer of antisense gene to cancer cells and sense gene to bone marrow stem cell." Chemico-Biological Interactions.111-112. 325-332 (1998)

Niitsu Y、Kato J 等人：“通过将反义基因转移到癌细胞并将有义基因转移到骨髓干细胞，证明谷胱甘肽 S-转移酶-pi 相关的多药耐药性。”

Hirayama Y, Kato J, et al.: "Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stro

Hirayama Y、Kato J 等人：“正常受试者和特发性血小板减少性紫癜、再生障碍性贫血和原发性血小板增多症患者骨髓中血小板生成素的浓度与其骨髓基质的 mRNA 表达相关。

Takayama T., Kato J., et al: "Aberrant crypt foci of the colon as precursors of adenoma and cancer."New England Journal of Medicine. 339. 1277-1284 (1998)

Takayama T.、Kato J. 等人：“结肠的异常隐窝灶是腺瘤和癌症的前兆。”新英格兰医学杂志。

Kato J, Mogi Y, Kohgo Y, st al.: "Suppressive effect of ethanol on the expression of hepatic asialoglycoprotein receptors augmented by interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha" J Gastroenterol. 33. 855-859 (1998)

Kato J、Mogi Y、Kohgo Y 等人：“乙醇对白细胞介素 1 β、白细胞介素 6 和肿瘤坏死因子 α 增强的肝脏脱唾液酸糖蛋白受体表达的抑制作用”J Gastroenterol。

Sakamaki S,Kato J,et al: "Long-term survival and differentiation of human peripheral blood CD34+cells in SCID mice." International Journal of Hematology. 65. 375-384 (1997)

Sakamaki S、Kato J 等人：“SCID 小鼠中人外周血 CD34 细胞的长期存活和分化。”