丙戊酸钠对博莱霉素致肺纤维化大鼠转化生长因子β1表达的调节

Valproate modulated expression of transforming growth factor-β1 in mice with bleomycin-induced pulmonary fibrosis

目的探讨组蛋白脱乙酰基转移酶抑制剂丙戊酸钠对博莱霉素诱导肺纤维化大鼠转化生长因子β1（TGF-β1）表达的调节。方法54只雄性SD大鼠随机分为控制对照组、肺纤维化模型组、丙戊酸钠干预组。肺纤维化模型组、丙戊酸钠干预组均给予博莱霉素溶液按5mg／kg气管内注入建立大鼠肺纤维化模型，控制对照组予以等体积生理盐水注射。丙戊酸钠干预组对肺纤维化大鼠予丙戊酸钠（200mg·kg^-1·d^-1）干预。各组随机于造模后第7、14和28天分3批处死，观察大鼠大体及HE变化和Masson染色，Szapiel评分，肺组织羟脯氨酸（HYP）检测及TGF-β1免疫组化检测。结果与控制对照组同时间点相比，肺纤维化模型组14d和28d肺组织TGF-β1及HYP含量显著增高（P〈0．01），丙戊酸钠干预后增高的Szapiel评分、TGF-β1及HYP受到明显抑制。结论予以VPA干预后肺组织Masson染色显示蓝色胶原沉积明显减少，能显著抑制博莱霉素诱导的大鼠肺纤维化的TGF-β1,VPA有抑制抗肺纤维化作用。

Objective To explore the effects of valproate, a histone deacetylase inhibitor on the expression of transforming growth factor-β1 （TGF-β1） in mice with bleomycin-induced pulmonary fibrosis. Methods Fifty-four SD rats were randomly divided into three groups （18 rats in each group） ： control group （CG）, bleomycin-induced pulmonary fibrosis model group （MG） and sodium valproate-treated group （VG） ,each group also divided into three batches：day 7,14 and 28. The rats in CG received a single intratracheal dose of 0.3 ml sterile physiological saline at day 0. The rats in MG and VG were induced by a single intratraeheal dose injection of bleomycin-A5 （5 mg/kg）with sterile physiological saline soultion. The rats in MG were intraperitoneally injected with sterile physiological saline （0.5 ml/d）and the rats in VG were intraperitoneally treated with sodium valproate （200 mg . kg ^-1 d^-1 ）. After treament 18 rats in each group were randomly killed on day 7,14 and 28. Their lungs were harvested for measurement of the pathological change in lung tissues. The sections of lungs were stained with HE for histopathology study to evaluate the severity of alveolitis and pulmonary fibrosis. Masson＇s triehrome was used to determine the content of hydroxyproline in lung samples. Collagen was assessed by the content of hydroxyproline in lung tissues. The expression of TGF-β1 in lung tissues was observed by histoimmunoehemical staining and these indexes were analyzed through SPSS 13.0 statistical software. Results It was founded that the hydroxyproline contents and Szapiel scores, the expression of TGF-β1 from the rats with bleomycin induced pulmonary fibrosis were greatly increased （ P〈0.01）. However,the hydroxyproline contents and Szapiel scores, the expression of TGF-β1 were greatly reduced in the mice treated by valproate and sacrificed on the day 14,28 compared with those induced with bleomycin alone. Conclusions This study indicates that administration of valproate to the mice suffered from pulmonary fibrosis induced bybleomycin attenuates the fibrosis via inhibiting the expression of TGF-β1 and reducing the Massonts trichrome in the lung.