Anti-monocyte Chemoattractant Protein-1 Gene Therapy Prevents Dimethylnitrosamine-induced Hepatic Fibrosis in Rats

抗单核细胞趋化蛋白-1基因治疗预防二甲基亚硝胺诱导的大鼠肝纤维化

• 批准号: 12670498
• 负责人: NAKAMUTA Makoto
• 金额: $ 1.92万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670498/
• 关键词: MCP1; 7ND; Hepatic fibrosis; Liver cirrhosis; chemokine; cytokine; gene therapy; hepatic stellate cell; 変異型MCP-1; 肝繊維化; サイトカイン; CCR2; コラーゲン

Background: Monocyte Chemoattractant Protein-1 (MCP-1) has been implicated in the process of hepatic inflammation, recruiting monocytes and lymphocytes during liver injury. MCP-1 also activates directly hepatic stellate cells, which play a major role in hepatic fibrosis. However, it remains unclear whether blockage of MCP-1 signaling could prevent hepatic fibrosis in vivo.Methods: We evaluated a strategy for anti-MCP-1 gene therapy against hepatic fibrosis by transfecting an amino-terminal deletion mutant, lacking the amino-terminal codons 2 to 8 of the human MCP-1 gene and designated 7ND, into skeletal muscle in a rat experimental model of dimethylnitrosamine (DMN) induced fibrosis.Results: Anti-MCP-1 gene therapy decreased significantly the occurrence of DMN-induced hepatic fibrosis evaluated by computed image analysis and by measurement of hydroxyproline contents of the liver, accompanied by a reduction in the expressions of α-smooth muscle actin. This treatment also caused a significant decrease in hepatic tissue levels of interleukin- (IL-) 12 (Th1 cytokine) and an increase in those of IL-10 (Th2 cytokine), indicating a change in the TH1/Th2 cytokine balance in the liver.Conclusions: Blockade of MCP-1 after intramuscular transfer of the 7ND gene suppressed hepatic fibrosis, and this strategy may be a useful and feasible gene therapy against hepatic fibrosis.

背景：单核细胞趋化蛋白-1(MCP-1)参与了肝脏炎症过程，在肝损伤过程中募集单核细胞和淋巴细胞。单核细胞趋化蛋白-1还可直接激活肝星状细胞，后者在肝纤维化中起主要作用。方法：在二甲基亚硝胺诱导的大鼠肝纤维化模型中，通过将缺失人单核细胞趋化蛋白-1基因氨基端密码子2~8的氨基端缺失突变体7ND导入骨骼肌，评价反义单核细胞趋化蛋白-1基因治疗肝纤维化的策略。结果：反义单核细胞趋化蛋白-1基因治疗明显减少二甲基亚硝胺诱导的大鼠肝纤维化的发生，通过计算机图像分析和测定肝组织羟脯氨酸含量来评价α-平滑肌肌动蛋白的表达。治疗后肝组织IL-12(Th1细胞因子)水平明显降低，IL-10(Th2细胞因子)水平明显升高，提示肝组织中TH1/Th2细胞因子平衡发生改变。结论：肌肉注射7ND基因后阻断MCP-1抑制肝纤维化，是一种有效可行的抗肝纤维化基因治疗策略。

项目成果

Nakamuta M, et al.: "Bisphenol A diglycidyl ether (BADGE) suppresses tumor necrosis factor-α production as a PPARγ agonist in the murine macrophage-like cell line"Cell Biology International. 26・3. 235-241 (2002)

Nakamuta M 等人：“双酚 A 二缩水甘油醚 (BADGE) 作为 PPARγ 激动剂在小鼠巨噬细胞样细胞系中抑制肿瘤坏死因子-α 的产生”Cell Biology International 26·3 (2002)。

Tada S, Nakamuta M, et al.: "Pirfenidone inhibits dimethylnitrosamine-induced hepatic fibrosis in rats"Clinical and Experimental Pharmacology and Physiology. 28. 522-527 (2001)

Tada S、Nakamuta M 等人：“吡非尼酮抑制二甲基亚硝胺诱导的大鼠肝纤维化”临床和实验药理学和生理学。

Uchimura K, Nakamuta M, et al.: "Activation of Retinoic X receptor and peroxisome proliferator-activated receptor-γ inhibits nitric oxide and tumor necrosis factor-α production"Hepatology. 33・1. 91-99 (2001)

Uchimura K、Nakamuta M等人：“视黄酸X受体和过氧化物酶体增殖物激活受体-γ的激活抑制一氧化氮和肿瘤坏死因子-α的产生”肝病学33・1。

Nakamuta M, et al.: "Dimethyl sulfoxide inhibits dimethylnitrosamine-induced hepatic fibrosis in rats"International Journal of Molecular Medicine. 8. 553-560 (2001)

Nakamuta M 等人：“二甲基亚砜抑制二甲基亚硝胺诱导的大鼠肝纤维化”国际分子医学杂志。

Nakamuta M, et al.: "Bisphenol A diglycidyl ether (BADGE) suppresses tumor necrosis factor-α production as a PPARγ agonist in murine macrophage-like cell line"Cell Biology International. 26・3. 235-241 (2002)

Nakamuta M 等人：“双酚 A 二缩水甘油醚 (BADGE) 作为 PPARγ 激动剂在小鼠巨噬细胞样细胞系中抑制肿瘤坏死因子-α 的产生”Cell Biology International 26·3 (2002)。