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目的探讨组蛋白脱乙酰基转移酶抑制剂曲古抑菌素A(trichostatin A,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0.9%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Massorl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(vascular endothelial groth factor,VEGF)。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IOD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<0.01);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<0.01);与EG组比较,LG组第7、14、28天VEGF的IOD值均显著升高(均P<0.01)。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。减轻肺间质纤维化,晚期干预则没有明显作用。
Objective To investigate the effect of histone deacetylase inhibitor trichostatin A (TSA) on neovascularization in bleomycin-induced pulmonary fibrosis in mice. Methods 120 male C57BL / 6 mice were randomly divided into control group (CG), pulmonary fibrosis model group (MG), TSA early treatment group (EG) and TSA late treatment group (LG). MG, EG, LG to bleomycin solution 10mg / kg intratracheal injection of mouse model of pulmonary fibrosis. CG was injected into an equal volume of 0.9% sodium chloride solution. The TSA group was injected intraperitoneally with 40mg / kg TSA solution twice a week after modeling in two stages (early stage: first to fourteenth day and late stage: fifteenth to 28th day); CG and MG were given an equal volume Dimethyl sulfoxide (Dmso) intraperitoneal injection. Groups were sacrificed in three batches on the 7th, 14th and 28th days after the model establishment. The lung tissues were generally observed and stained with HE and Massorl. Szapiel score, the content of hydroxyproline (HYP), and the expression of vascular endothelial growth factor (VEGF) by immunohistochemistry. Results The mice were successfully established in model mice: no blue collagen deposition was observed in CG mice; blue collagen deposition was evident in MG mice; and as the survival time of mice increased, the accumulation of blue collagen increased. Blue collagen The deposition was between CG group and MG group; the blue collagen deposition in LG group was heavier than that of EG. Compared with the CG group, the levels of HYP and the IOD of VEGF were significantly changed at other time points (all P <0.01). Compared with the MG group, the HYP content of the EG group was significantly decreased on the 7th, 14th and 28th days P <0.01). Compared with EG group, HYP content in LG group was significantly increased on the 7th, 14th and 28th days (all P <0.01). Compared with the MG group, the IOD values of VEGF on the 7th, 14th and 28th day in EG group all changed significantly (all P <0.01); compared with the EG group, the IOD value of VEGF on the 7th, 14th and 28th day in the LG group increased significantly High (all P <0.01). Conclusions Early administration of TSA can inhibit neovascularization in bleomycin-induced pulmonary fibrosis in mice. Reduce pulmonary interstitial fibrosis, late intervention has no significant effect.