4-苯基丁酸对博来霉素诱导小鼠肺纤维化的保护作用及机制探讨

Research on the protective effect and mechanisms of 4-phenylbutyric acid on bleomycin-induced pulmonary fibrosis in mice

目的 以博来霉素(bleomycin,BLM)诱导的肺纤维化小鼠为模型,探讨4-苯基丁酸(4-phenylbutyric acid,4-PBA)在肺纤维化中的作用及其机制。方法 C57BL/6小鼠气管内注射BLM建立小鼠肺纤维化模型。将120只小鼠随机分为三组:BLM组、BLM+4-PBA组和对照组。对小鼠肺组织进行病理分析,比较小鼠存活率,检测内质网应激标志物感受器活化转录因子6(activating transcription factor 6,ATF6)和C/EBP同源蛋白(C/EBP homologous protein,CHOP)在小鼠肺组织中的表达水平。结果 BLM诱导的肺纤维化小鼠肺组织中胶原沉积明显,给予4-PBA后减轻了肺组织胶原沉积。与BLM组相比,在肺纤维化形成期维持2周的4-PBA治疗可明显改善小鼠肺功能,提高生存率。同时,4-PBA治疗显著降低了小鼠肺组织中ATF6和CHOP的mRNA及蛋白表达水平。结论 4-PBA可抑制内质网应激,从而减轻BLM诱导的小鼠肺纤维化。

Objective To explore the effects of 4-phenylbutyric acid(4-PBA)on idiopathic pulmonary fibrosis(IPF)using a murine model of bleomycin(BLM)-induced pulmonary fibrosis.Methods Pulmonary fibrosis was induced in C57BL/6 mice by intratracheal injection of BLM.A total of 120 mice were randomly allocated into three groups:BLM group,BLM+4-PBA group,and control group.Pathology of lung tissue was analyzed to evaluate the degree of pulmonary fibrosis,and the survival of the mice was noted.The expression levels of the endoplasmic reticulum stress markers,activating transcription factor 6(ATF6)and C/EBP homologous protein(CHOP),were analyzed in lung tissues from mice.Results BLM induced significant collagen deposition in the lungs of the mice,which was alleviated by 4-PBA.4-PBA also dramatically improved the pulmonary function and increased the survival rate in the BLM+4-PBA group compared with that in the BLM group.Both the mRNA and protein expression levels of ATF6 and CHOP were significantly reduced in mouse lung tissue after 2 weeks of 4-PBA treatment.Conclusions 4-PBA treatment could alleviate BLM-induced pulmonary fibrosis in mice via the attenuation of endoplasmic reticulum stress.