IKKβ 抑制剂可减轻小鼠肝纤维化。
IκB kinase-beta inhibitor attenuates hepatic fibrosis in mice.
机构信息
Department of Gastroenterology, Shanghai Changning Central Hospital, Shanghai 200336, China.
出版信息
World J Gastroenterol. 2011 Dec 21;17(47):5203-13. doi: 10.3748/wjg.v17.i47.5203.
AIM
To investigate the anti-fibrosis effect of IκB kinase-beta inhibitor (IKK2 inhibitor IMD0354) in liver fibrosis.
METHODS
Twenty male C57BL6 mice were divided into four groups. Five high-fat fed mice were injected with lipopolysaccharide (LPS, 10 mg/kg) intraperitoneally and five high-fat fed mice were without LPS injection to build models of liver injury, and the intervention group (five mice) was injected intraperitoneally with IKK2 inhibitor (IMD 30 mg/kg for 14 d), while the remaining five mice received a normal diet as controls. Hepatic function, pathological evaluation and liver interleukin-6 (IL-6) expression were examined. Western blotting and real-time polymerase chain reaction were used to detect the expressions of nuclear factor-κB (NF-κB), alpha-smooth muscle actin (α-SMA), tumor growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α), typeIand type III collagen proteins and mRNA.
RESULTS
A mouse model of liver injury was successfully established, and IMD decreased nuclear translocation of NF-κB p65 in liver cells. In the IMD-treated group, the levels of alanine aminotransferase (103 ± 9.77 μ/L vs 62.4 ± 7.90 μ/L, P < 0.05) and aminotransferase (295.8 ± 38.56 μ/L vs 212 ± 25.10 μ/L, P < 0.05) were significantly decreased when compared with the model groups. The histological changes were significantly ameliorated. After treatment, the expressions of IL-6 (681 ± 45.96 vs 77 ± 7.79, P < 0.05), TGF-β1 (Western blotting 5.65% ± 0.017% vs 2.73% ± 0.005%, P < 0.05), TNF-α (11.58% ± 0.0063% vs 8.86% ± 0.0050%, P < 0.05), typeIcollagen (4.49% ± 0.014% vs 1.90% ± 0.0006%, P < 0.05) and type III collagen (3.46% ± 0.008% vs 2.29% ± 0.0035%, P < 0.05) as well as α-SMA (6.19 ± 0.0036 μ/L vs 2.16 ± 0.0023 μ/L, P < 0.05) protein and mRNA were downregulated in the IMD group compared to the fibrosis control groups (P < 0.05).
CONCLUSION
IKK2 inhibitor IMD markedly improved non-alcoholic fatty liver disease in mice by lowering NF-κB activation, which could become a remedial target for liver fibrosis.
目的
研究 IκB 激酶-β 抑制剂（IKK2 抑制剂 IMD0354）在肝纤维化中的抗纤维化作用。
方法
将 20 只雄性 C57BL6 小鼠分为四组。5 只高脂喂养的小鼠腹腔内注射脂多糖（LPS，10mg/kg）建立肝损伤模型，5 只高脂喂养的小鼠不注射 LPS 作为对照，干预组（5 只小鼠）腹腔内注射 IKK2 抑制剂（IMD30mg/kg，连续 14d），其余 5 只给予正常饮食作为对照。检测肝肾功能、病理评价和肝组织白细胞介素-6（IL-6）表达。Western blot 和实时聚合酶链反应检测核因子-κB（NF-κB）、α-平滑肌肌动蛋白（α-SMA）、转化生长因子-β1（TGF-β1）、肿瘤坏死因子-α（TNF-α）、I 型和 III 型胶原蛋白和 mRNA 的表达。
结果
成功建立了肝损伤小鼠模型，IMD 降低了肝细胞核内 NF-κB p65 的易位。在 IMD 治疗组，丙氨酸氨基转移酶（103±9.77μ/L 比 62.4±7.90μ/L，P<0.05）和天冬氨酸氨基转移酶（295.8±38.56μ/L 比 212±25.10μ/L，P<0.05）水平明显降低。组织学变化明显改善。治疗后，IL-6（Western blot 681±45.96 比 77±7.79，P<0.05）、TGF-β1（Western blot 5.65%±0.017% 比 2.73%±0.005%，P<0.05）、TNF-α（11.58%±0.0063% 比 8.86%±0.0050%，P<0.05）、I 型胶原（4.49%±0.014% 比 1.90%±0.0006%，P<0.05）和 III 型胶原（3.46%±0.008% 比 2.29%±0.0035%，P<0.05）以及α-SMA（6.19±0.0036μ/L 比 2.16±0.0023μ/L，P<0.05）蛋白和 mRNA 在 IMD 组均下调。
结论
IKK2 抑制剂 IMD 通过降低 NF-κB 的激活显著改善了非酒精性脂肪性肝病小鼠的肝纤维化，这可能成为肝纤维化的治疗靶点。
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