目的：通过建立新生大鼠缺氧性肺动脉高压（hypoxia-induced pulmonary hypertension，HPH）模型，探讨HPH新生大鼠发病过程中肺血管重塑的变化。方法：将96只新生Wistar大鼠随机分为2组：缺氧组和常氧对照组，缺氧组建立新生大鼠HPH模型。分别于缺氧3、5、7、10、14、21 d 取缺氧组及对照组同日龄新生大鼠各8只测定其平均肺动脉压（mean pulmonary arteria pressure，mPAP）、右心室肥大指数（right ventricle hypertrophy index，RVHI），血管重塑指标MT%、MA%，观察肺血管超微结构。结果：缺氧组大鼠在缺氧3、5、7、10、14、21 d mPAP持续上升，明显高于对照组（P<0.05）；随着缺氧时间的延长，差异更为显著。缺氧7 d后MT%、MA%、RVHI明显高于对照组（P<0.05）；随着缺氧时间的延长，差异同样更为显著。透射电镜显示，缺氧7 d后大鼠肺小动脉内膜增厚，内皮细胞增生、变性，细胞器增多；细胞外基质见胶原纤维沉积；出现肺血管重塑改变。结论：新生大鼠缺氧3～5 d肺动脉压力增高，处于肺血管痉挛阶段；缺氧7 d后肺血管出现重塑，右心室肥厚，出现不可逆变化；随着缺氧时间延长，上述变化加剧。
Abstract
OBJECTIVE: To study the changes of pulmonary vascular remodeling in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH) in neonatal rats. METHODS: Ninety-six newborn Wistar rats were randomly divided into an HPH group (hypoxia exposure) and a control group (room air exposure). The mean pulmonary arteria pressure (mPAP), right ventricle hypertrophy index (RVHI), and vascular remodeling indexes MT% and MA% were measured 3, 5, 7, 10, 14 and 21 days after exposure (n=8 each time point). The ultrastructure of pulmonary vascular was observed under a transmission electron microscope. RESULTS: mPAP in the HPH group 3, 5, 7, 10, 14 and 21 days after hypoxia exposure increased compared with the control group (P<0.05). With the prolonged hypoxia time, mPAP in the HPH group increased more significantly. MT%, MA% and RVHI increased significantly in the HPH group after 7 days of hypoxia exposure in a time-dependent manner compared with the control group (P<0.05). The transmission electron microscopy demonstrated that small pulmonary arterials became thickened, endothelial cell hyperplasia and degeneration, and organelles increased in the HPH group after 7 days of hypoxia exposure. Besides, collagen deposition in the extracellular matrix and the changes of pulmonary vascular remodeling were observed. CONCLUSIONS: mPAP increases between 3 and 5 days of hypoxia exposure, resulting from pulmonary vascular spasm caused by hypoxia. After hypoxia of 7 days, the mPAP increases more significantly, pulmonary vascular remodeling occurs, and right ventricle becomes irreversibly hypertrophic. These changes may be intensified as the prolonged hypoxia time.
关键词
肺动脉高压 /
血管重塑 /
新生大鼠
Key words
Pulmonary hypertension /
Vascular remodeling /
Neonatal rats
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参考文献
［1］Greenough A, Khetriwal B. Pulmonary hypertension in the newborn［J］. Peadiatr Respir Rev, 2005, 6(2): 111-116.
［2］杜军保，齐建光. 肺动脉高压发病机制的新进展［J］. 武警医学，2006,17(11)：803-806.
［3］王红，张永红，李明霞. 缺氧性肺动脉高压发病机制研究进展［J］.中国实用儿科杂志，2009,24（3）:227-230.
［4］李启芳，戴爱国. 缺氧诱导因子-1α调控血管内皮生长因子对大鼠缺氧性肺动脉高压的作用［J］. 中华结核和呼吸杂志, 2004, 27(3):174-178.
［5］汤秀英，杜军保. 实验性缺氧性肺动脉高压肺腺泡内动脉的超微结构观察［J］. 电子显微学报, 2004, 23（5）:523-526.
［6］蒋永亮，戴爱国，李启芳，胡瑞成. 转化生长因子β1与诱导型一氧化氮合酶相互调控对大鼠低氧性肺动脉高压的作用［J］. 中华结核和呼吸杂志, 2005, 28(7):453-457.
［7］杜军保，唐朝枢. 肺动脉高压［M］// 北京:北京大学医学出版社, 2010:24-90.
［8］Kubo K, Ge RL, Koizumi T, Fujimoto K, Yamanda T, Haniuda M, et al. Pulmonary artery remodeling modifies pulmonary hypertension during exercise in severe emphysema［J］. Respir Physiol, 2000, 120(1): 71-79.
［9］王莉, 朱艳萍, 李明霞. HIF-1α、ET-1和iNOS在新生儿缺氧性肺动脉高压发病中的作用［J］.中国当代儿科杂志, 2011, 13(1):8-11.
［10］钟小宁,梁国容,何志义,陈一强,李山,李超乾. 血管内皮生长因子和内皮素在低氧性肺血管重建中的作用［J］. 中华内科杂志, 2001，40(8): 525-528.
［11］Chassagne C, Eddahibi S, Adamy C, Rideau D, Marotte F, Dubois-Randé JL, et al. Modulation of angiotensin II receptor expression during development and regression of hypoxic pulmonary hypertension［J］.Am J Respir Cell Mol Biol, 2000, 22（3）: 323-332.
［12］钟小宁, 姚龙.肺血管重建在低氧性肺动脉高压中的作用及其机制［J］.中国呼吸与危重监护杂志, 2003, 2（4）：58-60.
［13］刘斌, 彭军. 氧化应激和肺动脉高压血管重构［J］. 中国动脉硬化杂志, 2011, 19（6）, 539-542.
［14］Xu MH, Gong YS, Su MS, Dai ZY, Dai SS, Bao SZ, et al. Absence of the adenosine A2A receptor confers pulmonary arterial hypertension and increased pulmonary vascular remodeling in mice［J］. J Vasc Res, 2011, 48(2):171-183.
［15］Estrada KD, Chesler NC. Collagen related gene and protein expression changes in the lung in response to chronic hypoxia［J］. Biomech Model Mechanobiol, 2009, 8(4):263-272.
［16］Lu XH, Murphy TC, Nanes MS, Hart CM. PPAR-regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-κB［J］. Am J Physiol Lung Cell MolPhysiol, 2010, 299(4): L559-L566.
［17］Santos S, Peinado VI, Ramirez J, Morales-Blanhir J, Bastos R, Roca J, et al. Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease［J］. Am J Respir Crit Care Med, 2003, 167(9):1250-1256.
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