洛沙坦对高氧致新生大鼠慢性肺疾病的保护作用

Protective effect of Losartan in hyperoxia-induced chronic lung disease in newborn rats

目的研究血管紧张素II1型受体拮抗剂洛沙坦对高氧致新生大鼠慢性肺疾病（CLD）肺组织的影响,探讨肺组织局部肾素血管紧张素系统（RAS）在CLD发病中的可能机制。方法将Wistar新生大鼠生后24h内随机分为空气组（Ⅰ）、高氧组（Ⅱ）、高氧＋注射用水组（Ⅲ）和高氧＋洛沙坦组（Ⅳ）,Ⅱ~Ⅳ组氧浓度为85%~90%,Ⅲ、Ⅳ组在生后6 d每天用注射用水和洛沙坦（5 mg/kg）灌胃至实验结束,在实验的1、3、7、14和21 d处死,HE染色和放射性肺泡计数（RAC）观察肺组织病理改变,免疫组织化学检测α-SMA蛋白表达;生化检测羟脯氨酸（HYP）的含量。结果Ⅱ和Ⅲ组肺组织肺泡间隔显著增厚,肺泡数目减少,终末气腔扩张,RAC较Ⅰ组显著下降（P〈0.01）。Ⅳ组肺泡间隔变薄,但肺泡腔没有明显缩小,RAC仍明显低于Ⅰ组。高氧暴露后α-SMA在肺泡间隔和肺泡表面表达显著增强,呈条索状分布;Ⅱ和Ⅲ组7d后较Ⅰ组α-SMA表达显著增强（P〈0.01）;Ⅳ组α-SMA表达较Ⅱ组明显减弱,14 d较Ⅱ组明显下降（P〈0.05）,21 d时则显著下降（P〈0.01）,但仍高于Ⅰ组（P〈0.01）。高氧后14 d和21 d新生大鼠肺组织HYP含量显著增加（P〈0.01）,洛沙坦干预后能明显减轻肺纤维化的程度。结论肺局部RAS系统参与高氧CLD的发生,洛沙坦只能抑制CLD新生大鼠肺纤维化的进展,但并不能逆转高氧诱导的新生大鼠肺发育阻滞。

【Objective】To investigate the effect of Losartan,an angiotensin II type 1 receptor antagonist,on newborn rats with hyperoxia-induced chronic lung disease（CLD） and Speculate the role of local renin an-giotensin systems（RAS） in the lung tissue in the pathogenesis of CLD and possible mechanisms.【Methods】 Within 24 hours after birth,neonatal Wistar rats were divided randomly into four groups： air group（I）,O2 ex-posed group（II）,O2 exposed ＋ aqua group（Ⅲ）,O2 exposed ＋ Losartan group（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,thepups in group Ⅲ and Ⅳ received aqua and Losartan（5 mg/kg） by intragastric administration daily.Pups ineach group were sacrificed on 1,3,7,14 and 21 d after the birth.Lung histological changes were evaluatedby Hematoxylin eosin and radical alveolar counts（RAC）,alpha-SMA proteins were detected by immunohisto-chemistry.Hydroxyproline in lung tissues were determined by spectroscopy.【Results】Hyperoxia-exposed re-sulted in secondary septum decreased,enlarged terminal air space,and alveolar septa was thicker.RAC ingroup Ⅱ and Ⅲ decreased significantly compared to Ⅰ（P 0.01）.Alveolar septum was thinner in Ⅳ com-paring with group Ⅱ,but alveolar cavity was not deflate obviously,RAC was still lower significantly than thatin group Ⅰ.Neonatal rats exposed to hyperoxia enviorment caused alpha-SMA expression increased markedly in alveolar septa and the surface of alveolar on 14 and 21 d.After 7 d,alpha-SMA expression in group Ⅱand Ⅲ was significantly increased than in group Ⅰ（P 0.01）.Alpha-SMA in group Ⅳ decreased comparedwith group Ⅱ on 14 d（P 0.05）,on 21 d decreased significantly（P 0.01）,but still higher than group Ⅰ（P 0.01）.In group Ⅱ~Ⅲ,hydroxyproline contents in lung tissue were increased significantly on 14 and 21 days（P 0.01）.Losartan attenuated slightly the degree of lung fibrosis on 14 and apparently on 21 days.【Conclu-sions】Pulmonary local RAS system may be involved in the occurrence of hyperoxia induced newborn ratsCLD,Losartan can inhibit the progress of pulmonary fibrosis in neonatal rats with CLD,but it does not re-verse lung development block of high oxygen-induced neonatal rats.