Losartan对高氧致慢性肺疾病新生大鼠肺纤维化的干预作用

The Effect of Losartan on Lung Fibrosis of Hyperoxia Induced Newborn Rat CLD

目的研究血管紧张素Ⅱ1型受体(AT1R)拮抗剂losartan对高氧致慢性肺疾病(CLD)大鼠模型的影响,从而探讨CLD可能的发病机制。方法将Wistar新生大鼠生后24h内随机分为空气组(组Ⅰ)、高氧组(组Ⅱ)、高氧+注射用水组(组Ⅲ)和高氧+losartan组(组Ⅳ)。组Ⅱ～组Ⅳ吸入氧浓度为85%～90%,组Ⅲ和组Ⅳ自生后6d每日分别用注射用水和losartan(5mg/kg)灌胃至实验结束。各组大鼠分别于生后1、3、7、14和21d处死。HE、Masson染色观察肺组织病理学、胶原纤维沉积的变化。ELISA和逆转录聚合酶链反应检测肺组织Ⅰ型胶原(ColⅠ)蛋白和mRNA的表达。结果组Ⅱ新生大鼠肺组织病理学改变为肺泡简单化,肺泡数目减少,终末气腔扩张,次级隔数目减少,肺泡间隔显著增厚。组Ⅳ肺泡间隔变薄,但肺泡腔没有明显缩小,且肺泡次级隔仍较少。在生后14和21d,与组Ⅰ比较,组Ⅱ蓝色胶原纤维所占比例明显增加。组Ⅳ蓝色胶原纤维所占比例较组Ⅱ减少且排列比较疏松,但仍明显高于组Ⅰ。组Ⅱ～组ⅣColⅠ蛋白和mRNA的含量均随日龄增加逐渐增加(P<0.01)。组Ⅳ在14d时ColⅠ蛋白和mRNA的含量较组Ⅱ略有下降(P>0.05),21d时显著下降(P<0.01),但仍高于组Ⅰ(P<0.05)。结论 losartan可以抑制高氧致CLD新生大鼠肺胶原的沉积,但是并不能逆转高氧诱导的新生大鼠肺发育阻滞。losartan不能阻止高氧诱导的CLD的发生。

Objective To evaluate the influence of losartan,angiotensin II type 1 receptor（AT1R）antagonists,in a mouse model of hyperoxia-exposed newborn rats induced chronic lung disease（CLD）.Methods Within 24 hours after birth,neonatal Wistar rats were divided randomly into four groups：air group（Ⅰ）,O2 exposed group（Ⅱ）,O2 exposed ＋ aqua（Ⅲ）,O2 exposed ＋ losartan（Ⅳ）.Except group Ⅰ,neonatal Wistar rats were exposed to about 85%～90% oxygen;from the 6 d after birth to the end of experiment,the pups in group Ⅲ and Ⅳ received aqua and losartan（5 mg/kg）by intragastric administration daily.Pups in each group were sacrificed on 1,3,7,14 and 21 d after the birth.Lung histological changes and degree of collagen fiber in the lungs were evaluated by Hematoxylin eosin and Masson stain.The protein and mRNA level of collagen Ⅰ assayed by ELISA and RT-PCR.Results Neonatal rats exposed to hyperoxia environment resulted in the quantity of alveolar reduced,enlarged terminal air space,secondary septum decreased,and alveolar septa was thicker;alveolar septum was thinner in group Ⅳ comparing with group Ⅱ,but alveolar space was not deflate obviously,and the sum of secondary septum is still less.Neonatal rats exposed to hyperoxia environment caused blue fibres deposition increased markedly.In group Ⅳ,the ratio of blue fibres is decreased and rarefied relatively compare with group Ⅱ,but it is more than group Ⅰ.In group Ⅱ～Ⅳ,collagenⅠprotein and mRNA levels were gradually increased with increasing age（P〈0.01）,on 21 day up to the peak level.Group Ⅳ decreased slightly on 14 day compared with group Ⅱ,and on 21 day decreased significantly（P〈0.01）,but still higher than the groupⅠ（P〈0.05）.Conclusion Losartan attenuated lung collagen deposition of hyperoxia induced newborn rats with CLD,but it does not reverse the hyperoxia-induced neonatal rat lung development block.Losartan does not prevent the occurrence of hyperoxia-induced CLD.