隐丹参酮通过调节TGF⁃β/Smad通路改善高氧诱导肺损伤的纤维化过程
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R725.6

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江苏省卫生和健康委员会重点项目(ZDB2020005)


Cryptotanshinone ameliorates the fibrotic process in hyperoxia ⁃ induced lung injury by modulating the TGF⁃β/Smad pathway
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    摘要:

    目的:探讨隐丹参酮(cryptotanshinone,CTS)对高氧诱导的支气管肺发育不良(bronchopulmonary dysplasia,BPD)大鼠肺纤维化的影响及作用机制。方法:体内实验:将50只新生雄性SD大鼠随机分为空气组、高氧组、CTS低剂量组(7.5 mg/kg)、CTS 中剂量组(15.0 mg/kg)及CTS高剂量组(30.0 mg/kg)。高氧组及CTS干预组大鼠饲养于氧浓度95%的氧箱中,空气组饲养于空气中。CTS干预组大鼠生后每日给予CTS腹腔注射,空气组及高氧组每日腹腔注射同等体积DMSO。7 d后安乐死全部大鼠后取肺组织用于后续实验。应用HE染色观察肺泡病理改变;通过Masson染色观察肺组织纤维化程度;RT-qPCR法检测转化生长因子β1(transforming growth factor-β1,TGF-β1)及α平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)的mRNA 水平;Western blot检测细胞信号转导分子(small mother against decapentaplegic,Smad)2/3、p-Smad2/3的表达。体外实验:选用人胚肺成纤维细胞(human fetal lung fibroblast-1,HFL-1),按照培养条件分为空气组、高氧组及CTS干预组,空气组常规条件下培养,而高氧及干预组置于95%O2恒温培养箱中培养24 h,干预组加入CTS 10 μmol/L。CCK-8实验检测细胞活力;Western blot检测TGF-β1、 α-SMA、p-Smad2/3、Smad2/3蛋白表达变化。结果:与对照组相比,高氧组大鼠肺泡形态紊乱、间隔增宽,RAC值下降,纤维化评分上升(P<0.05);TGF-β1及α-SMA的mRNA水平升高(P<0.05);p-Smad2/3表达升高(P<0.05);不同剂量的CTS给药后可改善上述指标(P<0.05);同时,CTS还可以降低高氧后HFL-1细胞的TGF-β1、α-SMA、p-Smad2/3、Smad2/3表达(P<0.05)。结论:CTS 可通过TGF-β/Smad通路改善高氧诱导肺损伤的纤维化过程。

    Abstract:

    Objective:To investigate the effects and underlying mechanism of cryptotanshinone(CTS)on pulmonary fibrosis in rats with hyperoxia-induced bronchopulmonary dysplasia(BPD). Methods:50 newborn male Sprague-Dawley rats were randomly divided into air group,hyperoxia group,low-dose CTS(7.5 mg/kg)group,medium-dose CTS(15.0 mg/kg)group and high-dose CTS(30 mg/kg) group. Rats in hyperoxia and three CTS treatment groups were exposed to 95% oxygen(O2)for 7 d after birth,and the air group were exposed to a room environment(21% O2). 7 days later,all rats were euthanized. The alveolar morphology and lung fibrosis were evaluated using hematoxylin-eosin(HE)staining and Masson staining. The mRNA levels of transforming growth factor beta1(TGF-β1) and alpha-smooth muscle actin(α-SMA)were detected by RT-qPCR. The protein expression of cell signaling molecules small mother against decapentaplegic(Smad)2/3 and p -Smad2/3 was detected by Western blot. In vitro experiments:Human fetal lung fibroblasts (HFL-1)cells were selected and divided into air group,hyperoxia group and CTS intervention group according to the culture conditions. The air group was cultured under conventional conditions,while the hyperoxia and intervention groups were incubated in a 95% O2 incubator for 24 h. 10 μmol/L CTS was added to the intervention group. Cell viability was measured by CCK-8 assay,and protein expression of TGF-β1,α-SMA,p-Smad2/3 and Smad2/3 were detected by Western blot. Results:Compared with the control group,rats in the hyperoxia group had disorderd alveolar morphology,widened alveolar septa,decreased RAC values and increased fibrosis scores(P < 0.05);increased the mRNA levels of TGF-β1 and α-SMA(P < 0.05);and up-regulated p-Smad2/3 expression(P < 0.05). Different doses of CTS could improve the above indicators(P < 0.05). Meanwhile,CTS also reduced TGF-β1,α-SMA,p-Smad2/ 3,and Smad2/3 protein expression levels in HFL-1 cells after hyperoxia(P < 0.05). Conclusion:CTS ameliorates the fibrotic process of hyperoxia-induced lung injury via the TGF-β/Smad pathway.

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马萌萌,包天平,曹林霞,李靖燕,余冰睿,田兆方.隐丹参酮通过调节TGF⁃β/Smad通路改善高氧诱导肺损伤的纤维化过程[J].南京医科大学学报(自然科学版),2024,(2):178-184

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  • 收稿日期:2023-06-26
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  • 在线发布日期: 2024-02-05
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