白藜芦醇通过TGF-β1/ADAMTS-1信号通路抑制肺纤维化

目的观察白藜芦醇(Res)对博莱霉素所致大鼠肺纤维化的影响,并探讨其是否通过转化生长因子-β1(TGF-β1)/含Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶(ADAMTS-1)信号通路起作用。方法 90只SD大鼠随机分为对照组(n=10)、模型组(n=40)和Res组(n=40),后两组经气管内注入博莱霉素建立大鼠肺纤维化模型,d 2起Res组大鼠予100 mg.kg-1Res灌胃,其余两组相同条件下给予生理盐水,模型组和Res组分别于d 7、d 14、d 28、d 56随机处死10只大鼠,而对照组于d 56全部处死作为总体对照,取出肺组织行HE染色和Masson染色,用荧光实时定量PCR和Western blot分别检测肺组织中TGF-β1、ADAMTS-1、Ⅰ型胶原(ColⅠ)、Ⅲ型胶原(ColⅢ)mRNA及蛋白表达,分离血清,并采用酶联免疫吸附法检测血清I型前胶原羧基端前肽(PICP)和Ⅲ型前胶原氨基端前肽(PⅢNP)浓度。结果 Res组大鼠肺泡炎症和肺纤维化程度明显轻于模型组(P<0.05)。与对照组比较,模型组肺组织ADAMTS-1 mRNA和蛋白表达量降低(P<0.05),而TGF-β1、ColⅠ、ColⅢmR-NA和蛋白表达量及血清PICP、PⅢNP浓度增加(P<0.05或0.01);相比于模型组同期,Res组各时间点ADAMTS-1mRNA和蛋白表达明显升高(P<0.05),而TGF-β1、ColⅠ、ColⅢmRNA和蛋白表达量及血清PICP、PⅢNP浓度则降低(P<0.05或0.01)。结论 Res通过TGF-β1/ADAMTS-1信号通路降解肺组织ColⅠ、ColⅢ发挥抗肺纤维化的作用。

Resveratrol inhibits pulmonary fibrosis through TGF-β1/ADAMTS-1 signaling pathway

Aim To observe the influence of resveratrol(Res) on bleomycin-induced pulmonary fibrosis in rats,and explore whether the effect is mediated by transforming growth factor-β1(TGF-β1) / a disintegrin-like and metalloproteinase with thrombospondin type 1 motif(ADAMTS-1) signaling pathway.Methods Ninety SD rats were randomly divided into control group(n=10),model group(n=40) and Res group(n=40).Rats in the latter 2 groups were intratracheally administered with bleomycin to produce pulmonary fibrosis.From the second day,rats in intervention group were intragastrically treated with 100 mg·kg-1 Res,whereas those of the other groups were treated with normal saline in the same condition.Ten rats in model and intervention groups were sacrificed on days 7,14,28 and 56 while all those of control group were killed on day 56 as total control.Then the pulmonary tissue was removed,and HE staining and Masson staining was performed.The mRNA and protein expressions of TGF-β1,ADAMTS-1,collagen type I(ColⅠ) and collagen type Ⅲ(ColⅢ) were detected by fluorescence real time quantitative PCR and Western blot,respectively.Serum was separated,and procollagen type 1carboxyterminal propeptide(PICP) and procollagen type Ⅲ aminoterminal propeptide(PⅢNP) were examined by ELISA.Results The pulmonary inflammation and fibrosis in intervention group was significantly improved,compared with that in model group(P<0.05).In comparison with control group,pulmonary ADAMTS-1 mRNA and protein expression was decreased(P<0.05) and the mRNA and protein expression of TGF-β1,ColⅠ and ColⅢ as well as serum PICP and PⅢNP concentrations were increased(P<0.05).After Res treatment,the mRNA and protein expression of ADAMTS-1 at every time point in intervention group was higher than that in model group(P<0.01),whereas the mRNA and protein expression of TGF-β1,ColⅠ and ColⅢ as well as serum PICP and PⅢNP concentrations were lower than those in model group(P<0.01).Conclusion Res exerts anti-pulmonary fibrosis effect through prompting degradation of pulmonary ColⅠ and ColⅢ via TGF-β1/ADAMTS-1 signaling pathway.