曲古抑菌素A对博莱霉素致肺纤维化小鼠新生血管的影响

Effect of trichostatin A on lung angiogenesis in mice with bleomycin-induced pulmonary fibrosis

目的探讨组蛋白脱乙酰基转移酶抑制剂曲古抑菌素A（trichostatinA，TSA）对博莱霉素诱导肺纤维化小鼠的新生血管的影响。方法120只雄性C57BL／6小鼠随机分为控制对照组（CG）、肺纤维化模型组（MG）、TSA早期处理组（EG）和TSA晚期处理组（LG）。MG、EG、LG予以博莱霉素溶液10mg／kg气管内注射建立小鼠肺纤维化模型，CG予以等体积019％氯化钠溶液注射。TSA处理组在造模后分两个阶段（早期：第1～14天；晚期：第15～28天）予以TSA溶液40mg／kg腹腔内注射，每周2次；CG和MG则予以等体积二甲基亚砜（Dmso）腹腔注射。各组于造模后第7、14、28天分三批处死，观察肺组织大体，行HE和Masson染色，Szapiel评分，测定羟脯氨酸（HYP）含量，免疫组化检测血管内皮生长因子（vascularendothelialgrothfactor，VEGFo结果小鼠造模均成功：CG小鼠未见蓝色胶原沉积；MG小鼠可见蓝色胶原沉积明显；并随着小鼠生存时间延长，蓝色胶原沉积加重，EG小鼠可见蓝色胶原沉积介于CG组与MG组之间；LG组蓝色胶原沉积较EG更重。与CG组比较，其他各组各时点HYP含量及VEGF的tOD值均发生显著变化（均P〈0．01）；与MG组比较，EG组第7、14、28天HYP含量均显著降低（均P〈001）；与EG组比较．LG组第7、14、28天HYP含量均显著升高（均P〈0．01）与MG组比较，EG组第7、14、28天VEGF的IOD值均发生显著变化（均P〈001）；与EG组比较，LG组第7、14、28天VEGF的IOD值均显著升高（均P〈0．01o结论早期予以TSA可以抑制博莱霉素致肺纤维化小鼠新生血管形成，减轻肺问质纤维化，晚期干预则没有明显作用。

Objective TO investigate the effects of histone deacetylase inhibitor （HDACI）trichostatin A （TSA） on lung an- giogenesis in mice with bleomycin-induced pulmonary fibrosis. Methods One hundred and twenty C57BL/6 mice were ran- domly divided into four groups（n=30 in each group）. Pulmonary fibrosis was induced by intratracheal injection of bleomycin 10mg in MG, EG and LG groups. Intraparitoneal injection of TSA was given 2/w to mice in EG （（：11-d14） and LG （d15-28） groups; and same volume of dimethyl sulfoxide （DMSO） was given to mice in CG and MG groups. Mice were sacrificed in batches at d7, 14 and 28, the lung tissue specimens were stained with HE and Masson method and the fibrosis was evaluated with Szapiel score. The hydroxyproline （HYP） level was measured and VEGF was detected by immunohistochemistry. Results The HYP contents and the expression of VEGF in MG and LG were significant higher than those in CG; while the HYP level and the VEGF expression in EG were lower than those in MG and LG. Conclusion Results indicate that early administration of TSA in mice with bleomycin induction can attenuate the pulmonary fibrosis via inhibiting angiogenesis, however, delayed administration of TSA has no signifi- cant effect.