摘要
目的探讨新型磷酸二酯酶5抑制剂CPD1对四氯化碳(carbon tetrachloride,CCl 4)诱导的肝纤维化小鼠肝组织结构损伤和肝星状细胞(hepatic stellate cells,HSCs)活化的影响。方法SPF级雄性C57BL/6 J小鼠随机分为正常对照组、模型组、CPD1治疗组、他达拉非治疗组,模型组和治疗组小鼠腹腔注射CCl 4(每周2次)。造模4周后治疗组分别给予CPD1(2 mg·kg^(-1)·d^(-1))、他达拉非(10 mg·kg^(-1)·d^(-1))灌胃治疗,持续4周。模型到期后,通过组织病理学染色、免疫荧光技术观察CPD1治疗对肝纤维化小鼠肝形态、组织结构损伤、胶原沉积及HSCs活化标志物α平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)、人肝星状细胞系LX-2细胞中纤维连接蛋白(fibronectin)表达和分布的影响。结果与正常组相比,模型组小鼠肝组织出现肝细胞坏死,炎症细胞浸润增加,肝小叶结构破坏,汇管区出现胶原沉积,α-SMA表达和分布明显增加;CPD1治疗可明显减轻模型小鼠肝组织损伤程度,减少肝细胞坏死和炎症细胞浸润,减轻胶原纤维的沉积,降低α-SMA的表达及分布,且治疗效果优于他达拉非;同时CPD1明显抑制LX-2细胞中转化生长因子-β1(TGF-β1)诱导的fibronectin和PAI-1蛋白的表达。结论磷酸二酯酶5抑制剂CPD1通过抑制HSCs的激活,减少肝组织中胶原纤维蛋白的产生,延缓肝纤维化的进展。
Aim To investigate the effects of CPD1,a novel phosphodiesterase 5 inhibitor,on liver pathological phenotype and hepatic stellate cells(HSCs)activation in hepatic fibrosis model mice caused by carbon tetrachloride(CCl 4).Methods Male C57BL/6 J mice were divided into four groups randomly(control group,CCl 4 group,CCl 4+CPD1 group and CCl 4+tadalafil group).Hepatic fibrosis model was constructed by intraperitoneal injection of CCl 4(twice a week).Four weeks after CCl 4 injection,the mice were treated with CPD1(2 mg·kg^(-1)·d^(-1)),or Tadalafil(10 mg·kg^(-1)·d^(-1))by intragastric administration,respectively,for four weeks.Hematoxylin-eosin staining and Sirius Red staining were used to observe the distribution of liver tissue structural lesions and fibrosis.Immunohistochemical staining was used to detect the expression ofα-smooth muscle actin(α-SMA)and fibronectin.Results Compared with control group,the liver tissue structure was seriously damaged in CCl 4 group with many hepatocytes necrosis and inflammatory cell infiltration,indicating that liver injury occurred in the CCl 4-induced hepatic fibrosis model mice.Moreover,the expressions ofα-SMA increased significantly in CCl 4 group.Compared to CCl 4 group,the liver tissue damage was significantly improved in PDE5 inhibitors group,most notably,CPD1 had a better curative effect than tadalafil did.Furthermore,CPD1 inhibited the expression ofα-SMA markedly and reduced the expression of ECM-related proteins induced by transforming growth factorβ1(TGF-β1)in Lieming Xu-2(LX-2)cells.Conclusions Phosphodiesterase 5 inhibitor CPD1 strongly alleviates CCl 4-induced hepatic damage by inhibiting the activation of HSCs and expression of collagen fibers.
作者
封文斌
杨建钦
陈心慧
谢中莲
张莹莹
陈颖禧
赵子建
穆云萍
李芳红
FENG Wen-bin;YANG Jian-qin;CHEN Xin-hui;XIE Zhong-lian;ZHANG Ying-ying;CHEN Ying-xi;ZHAO Zi-jian;MU Yun-ping;LI Fang-hong(School of Biomedical and Pharmaceutical Sciences,Guangdong University of Technology,Guangzhou 510006,China)
出处
《中国药理学通报》
CAS
CSCD
北大核心
2023年第3期470-476,共7页
Chinese Pharmacological Bulletin
基金
国家重点研发计划项目(No 2018YFA0800603)
广东省重点领域研发计划项目(No 2019B020201015)
广东省“珠江人才计划”项目(No 2016ZT06Y432)
广东省自然科学基金面上项目(No 2020A1515011302)
国家自然科学基金青年项目(No 82100064)。
关键词
磷酸二酯酶5抑制剂
CPD1
肝纤维化
肝星状细胞
四氯化碳
激活
phosphodiesterase type 5 inhibitors
CPD1
liver fibrosis
hepatic stellate cells
carbon tetrachloride
activation
