洛沙坦对高氧致慢性肺疾病新生大鼠肺纤维化的影响  

Effect of losartan on lung fibrosis in neonatal rats with hyperoxia-induced chronic lung disease

作　　者：陈宁[1] 李玖军[1] 薛辛东[1] 

机构地区：[1]中国医科大学盛京医院小儿内科,辽宁沈阳110004

出　　处：《中国当代儿科杂志》2007年第6期591-594,600,共5页Chinese Journal of Contemporary Pediatrics

基　　金：辽宁省科委资助项目(课题号:NO20022071)

摘　　要：目的血管紧张素Ⅱ除了调节血压，还参与肺纤维化的发生。研究血管紧张素Ⅱ1型受体拮抗剂洛沙坦对高氧致慢性肺疾病（CLD）新生大鼠肺组织的影响，探讨洛沙坦在抗纤维化的作用及可能的机制。方法将Waistar新生大鼠生后24h内随机分为：空气组、高氧组、高氧＋注射用水组、高氧＋洛沙坦组，高氧组氧浓度为85％-90％，高氧＋注射用水组、高氧＋洛沙坦组在生后6d每天用注射用水或洛沙坦（5mg／kg）灌胃至实验结束，于7，14，21d处死。观察病理组织学改变；生化检测肺组织超氧化物歧化酶活性（SOD）、丙二醛（MDA）和羟脯氨酸（HYP）的含量。结果高氧暴露后大鼠肺泡数目减少，终末气腔扩张，次级隔数目减少，肺泡间隔显著增厚，甚至出现肺出血和肺实变。洛沙坦干预后肺泡间隔变薄，但肺泡腔没有明显缩小，且肺泡次级隔仍较少。高氧后14和21d新生大鼠肺组织HYP含量较同期空气组显著增加（P〈0．01），洛沙坦治疗2周后肺组织HYP含量较高氧组明显下降（471.46±30．63μg／kg VS 545.15±34．90μg／kg，P〈0．01）；高氧组在高氧暴露7d时，SOD活力呈代偿性增加，之后逐渐下降至空气组水平；MDA水平在高氧暴露后显著增加，但随日龄增加呈下降趋势。洛沙坦治疗能增加高氧肺组织SOD的活力，21d时差异有显著性（82.94±4.62U／mg protein VS 67.78±8.02U／mg protein，P〈0．01），同时降低MDA的水平（30．54±5．89nmol／mg protein VS 48．75±8．09nmol／mg protein，P〈0．01）。结论洛沙坦治疗能减轻高氧诱导新生鼠CLD肺纤维化的程度，该过程可能与肺组织抗氧化酶活性增加以及膜脂质过氧化减轻密切相关。Objective In addition to regulating blood pressure, angiotensin Ⅱ is involved in lung fibrogenesis. This study aimed to explore the effect of losartan, an angiotensin Ⅱ type 1 receptor antagonist, on lung fibrosis in neonatal rats with hyperoxia-induced chronic lung disease （ CLD ） and its possible mechanisms. Methods Neonatal Wistar rats were randomly divided into four groups within 24 hrs after birth： room air exposure, hyperoxia exposure （85% -90% O2） , hyperoxia exposure ＋ losartan, and hyperoxia exposure ＋ placebo. Losartan （5 mg/kg ·d） or placebo was administered beginning on the 6th day after birth. After 7, 14 and 21 days of exposure, 8 rats in each group were sacrificed. Lung histological changes were evaluated by hematoxylin-eosin staining. Levels of hydroxyproline （HYP） , superoxide dismutase （SOD） and malondialdehyde （MDA） in lung tissues were determined by spectroscopy. Results Hyperoxia exposure resulted in decreased alveolar septation, enlarged terminal air space, increased collagen deposition, pulmonary hemorrhage, and pulmonary consolidation. In the hyperoxia exposure ＋ losartan group, the alveolar septum became thinner and lung fibrosis was alleviated, but the alveolar space was not obviously deflated and the number of secondary septum was not increased. Hyperoxia exposure increased significantly the HYP contents in lung tissues 14 and 21 days after exposure. Addition of losartan to the hyperoxia exposure resulted in decreased HYP contents （471.46±30.63μg/kg vs 545.15±34.90μg/kg for hypoxia alone; P 〈 0.01 ） after 21 days of exposure. SOD activity increased 7 days after hyperoxia exposure and then decreased to levels similar to the air exposure group. MDA levels increased to a peak at 7 days and remained at higher levels through 21 days of exposure when compared with the air exposure group （ P 〈 0.01 ）. Losartan treatment significantly increased SOD activities （82.94 ±4.62 U/mg protein vs 67.78±8.02 U/mg protein ; P 〈0.01 ） and decreas

关 键 词：慢性肺疾病 高氧 氧化应激 肺纤维化 洛沙坦 新生大鼠 

分 类 号：R722.1[医药卫生—儿科]