摘要
目的:探讨抑制聚ADP核糖多聚酶1(PARP1)活性对于博莱霉素导致的肺纤维化的改善作用,阐明抑制PARP1活化改善肺纤维化的作用机制。方法:48只雌性ICR小鼠随机分为对照组(腹腔注射生理盐水)和5、10、15mg·kg-1博莱霉素组(模型组)。3个模型组分别在第1、4、8、11、15、18、22和25天腹腔注射相应浓度的博莱霉素。60只雌性ICR小鼠随机分成对照组、10mg·kg-1博莱霉素模型组及不同剂量PARP1抑制剂PJ34治疗组(腹腔注射博来霉素20min前尾静脉注射1、5和10mg·kg-1 PJ34)。上述实验中,分别于第14、21和28天每组选取3只小鼠,处死后取肺。HE染色观察肺泡结构,Masson染色分析纤维化程度。肺上皮源性细胞A549用于博莱霉素刺激后,Real-time PCR法分析PJ34对上皮间充质转化(EMT)标志基因表达的影响。结果:与博莱霉素模型组比较,PJ34治疗组小鼠肺泡结构的破坏及胶原在肺间质中的沉积明显减轻;Realtime PCR法分析,与博莱霉素模型组比较,PJ34治疗组肺上皮细胞A549中E-cadherin mRNA表达水平升高(P<0.05),α-SMA和TGF-βmRNA表达水平下降(P<0.05或P<0.01)。结论:抑制PARP1活性可以影响EMT标志基因的表达及肺纤维化的产生,PARP1抑制剂可用于预防博来霉素治疗肿瘤过程中产生的肺纤维化。
Objective To determine the intervention effect of poly（ADP-ribose）polymerase 1（PARP1）inhibition on the bleomycin（BML）-induced pulmonary fibrosis in anti-tumor therapies,and to further elucidate the mechanisms of anti-fibrosis role of PARP1 inhibition.Methods Forty eight female ICR mice were randomly divided into normal control（peritoneal injection of saline）and BLM groups（model groups）with doses of 5,10and15mg·kg^-1,respectively.BLM was peritoneally injected at day 1,4,8,15,18,22 and 25.Sixty female ICR mice were randomly divided into normal control,10mg·kg^-1 BLM model group,and differeat doses（1,5and10mg·kg^-1）of PJ34-treated groups.BLM was administrated 20 min after intravenous injection of PARP1 inhibitor PJ34.In all above experiments,3mice were sacrificed at day 14,21 and 28,the lungs were removed for histochemical analysis. HE staining was performed to detect the alveolar damage and Masson staining was performed to detects the collagen deposition.Moreover,A549 cells were exposed to BLM,and the effects of PARP1 inhibition on the expression of EMT biomarkers were detected by Real-time PCR.Results Compared with BLM model group,the alveolar damage and collagen deposition in the lung tissue of the mice in PJ34-treated group were effectively decreased.Compared with BLM group,the E-cadherin mRNA expression levels in A549 cells of the mice in PJ34-treated group was increased（P〈0.05）,and the expression levels ofα-SMA and TGF-βmRNA were decreased（P〈0.05 or P〈0.01）.Conclusion PARP inhibition can affect the expressions of EMT marker genes,and alleviate the BLM-induced pulmonary fibrosis,suggesting PARP1 inhibitors can be utilized to prevent the pulmonary fibrosis in the process of cancer therapy.
出处
《吉林大学学报（医学版）》
CAS
CSCD
北大核心
2015年第3期442-447,I0001,I0002,共8页
Journal of Jilin University：Medicine Edition
基金
国家自然科学基金面上项目资助课题(31371293)
吉林省科技厅科技发展计划国际科技合作项目资助课题(20120728)
关键词
博莱霉素
肺纤维化
聚ADP核糖聚合酶1
上皮间质转化
bleomycin
pulmonary fibrosis
poly （ADP-ribose）polymerase 1
epithelial-mesenchymal transition
