汉防己甲素对矽肺大鼠治疗作用及肝肾毒性

Therapeutic effect of tetrandrine on silicosis rats and its toxic effect on liver and kidney function

目的探讨汉防己甲素(TET)对矽肺模型大鼠的治疗作用及其对肝肾功能的影响。方法将无特定病原体级Wistar健康雄性大鼠随机分为对照组、模型组和TET组,每组14只。采用非暴露式气管注入法,模型组和TET组大鼠一次性予气管灌注1 mL质量浓度为50 g/L的二氧化硅混悬液制作矽肺大鼠模型,对照组大鼠一次性予气管灌注1 mL 0.9%氯化钠溶液;于造模后第2天,TET组大鼠予剂量为30 mg/kg体质量TET溶液灌胃,另2组大鼠予等体积0.9%氯化钠溶液灌胃,1次/d, 6次/周。每组大鼠分别于造模后第28和56天各处死7只。观察各组大鼠肺脏、肝脏和肾脏组织形态学变化;采用酶联免疫吸附实验检测各组大鼠肺组织肿瘤坏死因子-α(TNF-α)、转化生长因子-β1(TGF-β1)、白细胞介素(IL)-1β和IL-6水平;采用全自动生化分析仪检测各组大鼠血清中谷氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)活力和尿素氮、肌酐水平。结果 TET组大鼠第28和56天的肺脏脏器系数均低于模型组(P值均<0.05);TET组大鼠第56天的肺脏脏器系数高于同组第28天(P<0.05)。对照组大鼠肺组织结构正常;模型组大鼠肺组织于造模后第28、56天出现不同程度的肺泡结构破坏、炎性细胞浸润及纤维化等病理改变;TET组大鼠肺组织病变程度较模型组减轻。模型组大鼠肺组织中TNF-α、TGF-β1、 IL-1β和IL-6水平均高于对照组(P值均<0.01);TET组大鼠肺组织中TNF-α、TGF-β1、 IL-1β和IL-6水平均低于模型组(P值均<0.01),但与对照组比较,差异均无统计学意义(P值均>0.05)。TET组大鼠血清中ALT和AST活力均高于模型组和对照组(P值均<0.01)。TET组大鼠血清中尿素氮水平高于对照组(P<0.01),但与模型组比较,差异无统计学意义(P>0.05)。各组大鼠血清中肌酐水平比较,差异无统计学意义(P>0.05)。各组大鼠不同时间点肝和肾组织均未见异常病理改变。结论 TET可降低矽肺大鼠的炎症反应,改善肺部组织纤维化;但该治疗剂量下可能对矽肺大鼠有一定的肝、肾毒性。

Objective To explore the therapeutic effect of tetrandrine(TET) on silicosis model rats and its toxic effect on liver and kidney function. Methods The specific pathogen free healthy male Wistar rats were randomly divided into the control group, the model group and the TET group, with 14 rats in each group. By un-exposure tracheal injection method, the rats in the model and TET groups were given one-time tracheal infusion of free silicon dioxide suspension with a mass concentration of 50 g/L to establish the rat model of silicosis. Rats in the control group were infused with 1 mL of 0.9% sodium chloride solution with the same method. On the second day after the model was established, the TET group was given 30 mg/kg body mass of TET solution by gavage. The other two groups were given the same amount of 0.9% sodium chloride solution. The treatment was once per day, six times per week. Seven rats in each group were sacrificed on the 28 th and 56 th days after modeling. The morphological change of the lung, liver and kidney tissues of each group was observed. The enzyme-linked immunosorbent assay was used to detect the level of tumor necrosis factor-α(TNF-α), transforming growth factor-β1(TGF-β1), interleukin(IL)-1β and IL-6, in the lung tissues of rats in each group. The activities of aminotransferase(ALT), aspartate aminotransferase(AST) and the levels blood urea nitrogen(BUN), creatinine(CRE) were detected by automatic biochemical analyzer. Results The lung organ coefficients of rats in the TET group were lower than those of the model group on the 28 th and 56 th days(all P<0.05). The lung organ coefficient of the rats in the TET group on the 56 th day was higher than that in the same group on the 28 th day(P<0.05). The lung tissue structure of the control group was normal. After modeling, the lung tissues of rats in model group showed different degrees of pathological changes such as alveolar structure destruction, inflammatory cell infiltration, and fibrosis on the 28 th and 56 th days. The degree of pathological changes in TET group was less than that of the model group. In the lung tissues of rats in the model group, the levels of TNF-α, TGF-β1, IL-1β and IL-6 were higher than those of the control group(all P<0.01). The levels of TNF-α, TGF-β1, IL-1β and IL-6 in the lung tissues of rats in the TET group were lower than that of the model group(all P<0.01), but there was no statistically significant difference when compared with the control group(all P>0.05). The activities of ALT and AST in the TET group were higher than those in the model group and the control group(all P<0.01). The level of serum BUN in TET group was higher than that in control group(P<0.01), but it showed no statistical difference when compared with the control group(P>0.05). The level of serum CRE in each group showed no significant difference(P>0.05). There were no abnormal pathological changes found in the liver and kidney tissues of rats in each group at different times. Conclusion TET can reduce the inflammatory response in silicosis rats and improve lung tissue fibrosis;however, the therapeutic dose may have certain toxicity to the liver and kidney of the silicosis rats.