新型磷酸二酯酶5抑制剂CPD1对百草枯诱导的肺纤维化大鼠治疗作用

Effect of a novel phosphodiesterase type 5 inhibitor,CPD1,on paraquat-induced lung fibrosis in rats

目的探讨新型磷酸二酯酶5抑制剂CPD1对百草枯(paraquat,PQ)诱导的肺纤维化大鼠肺组织病理结构损伤和上皮-间质转化(epithelial-mesenchymal transition,EMT)的影响。方法模型组和治疗组大鼠腹腔注射PQ(30 mg·kg^(-1)),2 h后分别灌胃CPD1(5 mg·kg^(-1)·d^(-1))、尼达尼布(50 mg·kg^(-1)·d^(-1)),持续4周。观察CPD1治疗对肺纤维化大鼠肺组织病理结构损伤、胶原沉积及EMT标志物α平滑肌肌动蛋白(α-SMA)和E-钙黏蛋白(E-cadherin)表达的影响。结果模型组大鼠肺组织指数明显增大,肺泡塌陷和扩张弥漫性分布,肺泡壁及肺泡间隔均增厚,肺间质胶原沉积增多,E-cadherin表达降低,而α-SMA和纤维连接蛋白表达增加(P<0.01);CPD1治疗可明显减轻模型大鼠肺组织病理结构损伤程度,减少肺泡塌陷和扩张,减轻胶原纤维的沉积,上调E-cadherin表达,降低α-SMA和fibronectin的表达(P<0.01)。结论CPD1可能通过抑制EMT和炎症,减少肺组织间质胶原纤维的产生,减缓PQ引起的肺纤维化进展。

Aim To investigate the effects of CPD1,a novel phosphodiesterase 5 inhibitor,on lung pathological phenotype and epithelial-mesenchymal transition of alveolar epithelial cells in lung fibrosis model rats caused by paraquat(PQ).Methods Lung fibrosis model was constructed by a single intraperitoneal injection of PQ(30 mg·kg^(-1)).Two hours after PQ injection,the rats were treated with CPD1(5 mg·kg^(-1)·d^(-1)),or nintedanib(50 mg·kg^(-1)·d^(-1))by intragastric administration,respectively,for four weeks.The distribution of lung tissue structural lesions and fibrosis,as well as the expressions of E-cadherin,α-smooth muscle actin(α-SMA)and fibronectin were observed.Results Compared with the control group,the lung tissue structure was seriously damaged in PQ group,and with many inflammatory cell infiltrations.The pulmonary index(PI)of wet lung-to-body weight ratio was markedly raised,and the diffuse alveolar collapsed and was dilatated in PQ group.Collagen deposition markedly increased in the thickened alveolar walls and alveolar spaces in the PQ group.Moreover,the expressions ofα-SMA and fibronectin increased significantly in PQ group,but the E-cadherin expression was reduced(P<0.01).Compared to PQ group,the lung tissue damage was significantly improved in CPD1 group rats;most notably,5 mg·kg-1 CPD1 had a better curative effect than nintedanib.Furthermore,CPD1 inhibited the expression ofα-SMA and collagen markedly(P<0.01).Conclusions Phosphodiesterase 5 inhibitor CPD1 strongly alleviates PQ-induced pulmonary damage by inhibiting the epithelial-mesenchymal transition of alveolar epithelial cells,minimizing the inflammatory cell infiltration and expression of collagen fibers.