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目的研究不同时间段给予全反式维甲酸(ATRA)对肺气肿模型大鼠的干预作用及其机制。方法60只SD大鼠随机分为6组:生理盐水组(N组)、模型组(P组)、棉籽油组(C组)、早期干预组(R1组)、中期干预组(R2组)和后期干预组(R3组),每组10只。N组大鼠气管滴注生理盐水1mL·kg-1,其余5组气管滴注5%木瓜蛋白酶1mL·kg-1建立肺气肿模型。R1、R2和R3组分别于造模后15～30d、30～45d和45～60d给予ATRA500μg·kg-1腹腔注射,C组给予棉籽油腹腔注射。观察各组支气管肺泡灌洗液(BALF)中血管内皮生长因子(VEGF)含量和细胞数,肺组织病理学改变及肺组织血管内皮生长因子受体2(VEGFR-2)、基质金属蛋白酶1(MMP-1)的表达水平。结果与N组比较,P组BALF中细胞总数明显升高(P<0.01),其中以巨噬细胞和中性粒细胞为主。R1、R2和R3组与P组比较细胞总数降低(P<0.01),此3组之间无显著差异。与N组比较,其余5组平均肺泡面积和内衬间隔增大,每个视野内肺泡数减少(P<0.01);与P组相比,R1、R2和R3组肺泡数增加、平均肺泡面积减小(P<0.01),以R1组最为明显。与N组相比,P组VEGF和VEGFR-2表达降低,MMP-1表达增高(P<0.01);与P组相比,R1、R2和R3组VEGF和VEGFR-2表达增高,MMP-1表达降低(P<0.05),R1、R2和R3组之间无显著差异。结论ATRA可以促进肺泡再生,早期干预效果较佳,这种作用可能与调节VEGF、VEGFR-2、MMP-1有关。
Objective To investigate the effects of all-trans retinoic acid (ATRA) on rats with emphysema induced by different periods of time and its mechanism. Methods Sixty SD rats were randomly divided into six groups: normal saline group (N group), model group (P group), cottonseed oil group (C group), early intervention group (R1 group), medium term intervention group (R2 group) And late intervention group (R3 group), 10 in each group. Rats in group N were infused with saline 1 mL · kg-1 intratracheally, and the other 5 groups were infused with 5 mL papain 1 mL · kg-1 to establish model of emphysema. The rabbits in group R1, R2 and R3 were intraperitoneally injected with ATRA 500μg · kg-1 at 15-30 days, 30-45 days and 45-60 days respectively. The rats in group C were injected intraperitoneally with cottonseed oil. The contents of vascular endothelial growth factor (VEGF) and the number of cells in the bronchoalveolar lavage fluid (BALF), the pathological changes of the lung tissue and the expressions of vascular endothelial growth factor receptor 2 (VEGFR-2), matrix metalloproteinase 1 MMP-1) expression levels. Results Compared with group N, the total number of cells in BALF in group P was significantly increased (P <0.01), especially in macrophages and neutrophils. The total number of cells in R1, R2 and R3 groups was lower than that in P group (P <0.01), and there was no significant difference between these three groups. Compared with group N, the average alveolar area and inner lining interval of the remaining five groups increased, and the number of alveoli in each field decreased (P <0.01). Compared with group P, the number of alveoli in group R1, R2 and R3 increased, the average alveolar area (P <0.01), the most obvious in group R1. Compared with the N group, VEGF and VEGFR-2 expressions were decreased and the expression of MMP-1 was increased in the P group (P <0.01). Compared with the P group, the expressions of VEGF and VEGFR- (P <0.05). There was no significant difference between R1, R2 and R3 groups. Conclusions ATRA can promote alveolar regeneration, and the effect of early intervention is better. This effect may be related to the regulation of VEGF, VEGFR-2 and MMP-1.