洛伐他丁对肝星状细胞增殖及细胞外基质分泌的影响

目的 观察洛伐他丁对肝星状细胞增殖及细胞外基质分泌的影响,并探讨其作用机制。方法 用不同浓度的洛伐他丁和胆固醇合成过程中产生的非脂性中间产物香叶基香叶基焦磷酸处理大鼠肝星状细胞株;用MTT法检测细胞增殖,流式细胞仪检测细胞周期,ELISA检测细胞外基质IV型胶原和层粘连蛋白,免疫细胞化学结合计算机图文分析系统检测c—jun、c-fos基因表达。结果 洛伐他丁可剂量依赖性地抑制肝星状细胞增殖（对照组A值24 h和48 h分别为0.736±0.090和0.972±0.097,洛伐他丁浓度在10μmol/L时24h和48h分别为0.602±0.049和0.785±0.028,两组比较差异有显著性）,影响其细胞周期,使G0/G1期细胞增多,S期细胞减少,并明显抑制c-jun、c—fos表达（洛伐他丁浓度在 50μmol/L时分别较对照组降低51.5％和 54.5％）,抑制IV型胶原和层粘连蛋白分泌（P<0.01）。而香叶基香叶基焦磷酸可部分拮抗洛伐他丁的上述抑制作用。结论 洛伐他丁可显著抑制肝星状细胞增殖及细胞外基质分泌,其机制可能与抑制香叶基香叶基焦磷酸产生而阻止信号转导有关。

Effect of lovastatin on proliferation and extracellular matrix secretion of rat hepatic stellate cells in vitro

OBJECTIVE: To investigate the effect of lovastatin on proliferation and extracellular matrix secretion of hepatic stellate cells in vitro. METHODS: Rat hepatic stellate cells were incubated with different concentration of lovastatin and geranyl geranypyrophosphate. Cell proliferation was assessed by MTT colorimetric assay. Cell cycle was analysed by flow cytometry. Type IV collagen and laminin were determined by ELISA, and c-jun and c-fos expression by immunocytochemistry and computer video text analysis system. RESULTS: Addition of 0.1 to 50 micromol/L lovastatin into culture medium had no toxicity to hepatic stellate cells, but could significantly inhibit hepatic stellate cell proliferation and provoke G0/G1 phase arrest in dose-dependent manner, and could also markedly inhibit the c-jun and c-fos expression and type IV collagen and laminin secretion, which could partly be antagonized by geranyl geranypyrophosphate. CONCLUSIONS: Lovastatin can significantly inhibit hepatic stellate cell proliferation and type IV collagen and laminin secretion, which might be partly related to its inhibitory effect on geranyl geranypyrophosphate formation.