血管内皮生长因子抑制剂对小鼠左肺全切手术后肺功能的影响

Effects of vascular endothelial growth factor inhibitor on lung function in mice after unilateral pneumonectomy

目的观察不同剂量血管内皮生长因子(VEGF)抑制剂对小鼠左肺全切手术后肺功能的影响。方法45只行左侧全肺切除术C57BL/6雄性小鼠,根据VEGF受体1注射剂量分为0μg/kg(对照组)、5μg/kg组、20μg/kg组、60μg/kg组、180μg/kg组,每组9只。各组每天给药剂量分别为0、5、20、60、180μg/kg,饲养4 d后,比较各组肺体积、肺容量、肺顺应性,进一步比较VEGF的表达,并分析缺氧诱导因子(HIF)及其相关基因的表达。结果VEGF受体1药代模型拟合为二室模型:C=A1 e(-Ke t)+A2 e(-Kαt)+A3 e(-Kβt)。VEGF受体1的半衰期[t1/2(K)]为25.997 h;术后4 d观测,20μg/kg组的肺体积数值最大[(64.8±5.1)μl/g]。与对照组(0μg/kg)比较,5μg/kg组小鼠的右肺体积明显降低(t=7.982,P<0.05),而60μg/kg组和80μg/kg组小鼠的右肺体积没有明显变化。术后4 d,20μg/kg组小鼠的右肺体积、总容量、顺应性均显著高于对照组(t=6.568、11.436、9.391,P<0.05);与对照组比较,20μg/kg VEGFr1组小鼠的VEGFr2和VEGF mRNA的表达均明显提升(t=7.425、9.391,P<0.05);20μg/kg VEGFr1组小鼠的肺部和血浆中的VEGF含量明显高于对照组(t=23.764、6.972,P<0.05);(6)20μg/kg组小鼠的HIF-2α表达、以及HIF相关基因PH、VHL、CXCR4、HK、PDK、PDGFα的表达,均显著高于对照组(t=6.486、12.283、12.283、5.134、12.671、8.870,P<0.05)。结论VEGF抑制剂通过刺激HIF的途径在20μg/kg的浓度可有效提升小鼠左肺全切术后右肺的生长,改善其功能。

Objective To investigate the effect of vascular endothelial growth factor(VEGF)inhibitor on lung function in mice after unilateral pneumonectomy.Methods 45 male C57BL/6 mice undergoing left pneumonectomy were divided into 0μg/kg(control group),5.0μg/kg group,20μg/kg group,60μg/kg group and 180μg/kg group according to the injection dose of VEGF receptor 1.The daily dosage of each group were 0,5.0,20,60,180μg/kg,After 4 days of feeding,the lung volume,lung volume and lung compliance were compared,and the expression of VEGF was further compared,and the expression of hypoxia-inducible factor(HIF)and its related genes were analyzed.Results The VEGF receptor 1 pharmacokinetic model was fitted to a two-compartment model:C=A1 e(-Ke t)+A2 e(-Kαt)+A3 e(-Kβt).The half-life of VEGF receptor 1[t1/2(K)]is 25.997 h;Observed 4 days after surgery,the lung volume value of the 20μg/kg group was the largest[(64.8±5.1)μl/g].Compared with the control group(0μg/kg),the right lung volume of the mice in the 5μg/kg groups was significantly lower(P<0.05),while the right lung volume in the 60μg/kg group and the 80μg/kg group did not obvious change.The right lung volume,total volume and compliance of the mice in the 20μg/kg group were significantly higher than those in the control group(t=6.568,11.436,9.391,P<0.05).Compared with the control group,the expression of VEGFr2 and VEGF mRNA in the 20μg/kg VEGFr1 group was significantly increased(t=7.425,9.391,P<0.05).The VEGF content in the lung and plasma of 20μg/kg VEGFr1 mice was significantly higher than that of the control group(t=23.764,6.972,P<0.05);(6)The expression of HIF-2αand the expression of HIF-related genes PH,VHL,CXCR4,HK,PDK and PDGFαin the 20μg/kg group were significantly higher than those in the control group(t=6.486,12.283,12.283,5.134,12.671,8.870,P<0.05).Conclusion VEGF inhibitor can effectively promote the growth of right lung after left lung resection in mice by stimulating HIF at a concentration of 20μg/kg.