白藜芦醇抑制Sonic hedgehog信号并减轻大鼠肺纤维化的研究

Resveratrol inactivates sonic hedgehog signaling and alleviates lung fibrosis in rats

目的研究白藜芦醇对博莱霉素诱导大鼠肺纤维化的影响。方法完全随机分组法将40只SD雄性大鼠分为4组:对照组、模型组、25μmol白藜芦醇组和50μmol白藜芦醇组。模型组大鼠气管内滴注博莱霉素,25和50μmol白藜芦醇组大鼠气管内滴注博莱霉素后分别用25和50μmol白藜芦醇灌胃,对照组大鼠气管内滴注生理盐水。处理30 d后,观察各处理组大鼠肺组织病理变化并检测大鼠肺组织羟脯氨酸(HYP)和Ⅰ型胶原蛋白含量。分离各组大鼠肺成纤维细胞,并利用实时荧光定量聚合酶链反应(q RT-PCR)和Western blot检测细胞中SHH(Sonic hedgehog,SHH)、Smo、Gli-1 m RNA和蛋白的表达,同时检测细胞增殖和凋亡。结果模型组大鼠肺泡结构严重破坏并伴有胶原纤维沉淀,白藜芦醇处理可减轻纤维化病变。白藜芦醇可降低肺组织中博莱霉素诱导的HYP和Ⅰ型胶原蛋白含量。博莱霉素能显著上调成纤维细胞中SHH、Smo、Gli-1m RNA和蛋白的表达,而白藜芦醇则可抑制SHH、Smo和Gli-1的表达。博莱霉素促进成纤维细胞增殖并减少凋亡,白藜芦醇抑制细胞增殖并促进细胞凋亡。结论白藜芦醇可抑制博莱霉素诱导的SHH信号活化并减轻大鼠肺纤维化。

Objective To investigate the effect of resveratrol on lung fibrosis in rats. Methods Forty SD male rats were randomly allocated to four groups： control, model, 25-μmol resveratrol and 50-μmol resveratrol groups. Rats in the model group were intratracheally administrated with Bleomycin. Rats in the 25-μmol resveratrol and 50-μmol resveratrol groups were administrated with Bleomycin before intragastric administration of resveratrol. Rats in the control group were administrated with normal saline. After 30 d pathological changes of the lungs in each group were observed and the levels of hydroxyproline（HYP） and type Ⅰcollagen were determined. Lung fibroblasts in the rats of each group were isolated and the expression of SHH,Smo and Gli-1 were analyzed by q RT-PCR and Western blot, along with the evaluation of proliferation and apoptosis in these cells. Results The pulmonary alveoli structures of model rats were damaged seriously with the deposition of collagen, while resveratrol attenuated the progression of lung fibrosis. Resveratrol reduced HYP content and type Ⅰ collagen expression induced by Bleomycin in the lung tissue. Moreover, Bleomycin significantly upregulated the expressions of Sonic hedgehog（SHH）, Smo and Gli-1 m RNAs and proteins,which were inhibited by resveratrol. In addition, Bleomycin enhanced the proliferation and reduced apoptosis of fibroblasts, while resveratrol inhibited fibroblst proliferation and promoted apoptosis. Conclusions Resveratrol might impede Bleomycin-induced SHH signaling and contribute to the alleviation of lung fibrosis in rats.