OSAHS慢性间歇性低氧大鼠模型的建立及意义

doi:10.6040/j.issn.1671-7554.0.2020.1469

摘要/Abstract

摘要： 目的建立阻塞性睡眠呼吸暂停低通气综合征(OSAHS)慢性间歇性低氧大鼠模型。方法采用彩色触摸屏、可编程逻辑控制器(PLC)自动控制和自动数据采集监测系统,制造建立实验模型所需要的装备。低氧舱控制装置的主体设备主要由以下三个部分组成:主机部分、低氧舱体和气路控制部分。采用随机数字表法将30只大鼠分成常氧对照组(CON组)和慢性间歇性低氧模型组(CIH组),每组15只。普通喂养,9周后解剖取肝脏标本,进行油红“O”染色、苏木精-伊红染色、透射电镜观察。结果形态学改变:CIH组的苏木精-伊红HE染色可见脂质积聚、脂肪空泡形成,导致肝细胞脂肪变性;电镜下超微结构见大量簇状脂滴、自噬小体和溶酶体大量出现,粗面内质网糖原的灶性聚积,毛细胆管微绒毛变得稀疏。CON组此征象较少。此模型下CIH组大鼠肝细胞形态学明显改变。脂质油红“O”染色结果:CON组与CIH组IOD/Area(有效统计区域面积内的累计光密度平均值)差异有统计学意义(P<0.001),检验统计量=-56.308,P<0.001,CIH组肝细胞脂质明显染红。结论 OSAHS慢性间歇性低氧大鼠模型建立成功,可靠有效,符合OSAHS的病理生理特点,为进一步研究大鼠各组织器官功能异常的发生机制及可能有关药物的治疗作用奠定了坚实的基础。

关键词: 睡眠呼吸暂停综合征, 低氧, 动物, 模型, 大鼠

Abstract: Objective To construct a rat model of obstructive sleep apnea hypopnea syndrome(OSAHS)with chronic intermittent hypoxia. Methods A color touch screen, a programmable logic controller(PLC)automatic control, and an automated data acquisition and monitoring system were used to assemble the equipment needed to construct the experimental model. The hypoxic chamber was composed of the main engine, the hypoxic chamber and the gas path control. A total of 30 rats were randomly divided into two groups, normoxic control(CON)group and CIH model(CIH). After 9 weeks of normal feeding, the rats were sacrificed, and liver samples were collected for hematoxylin and eosin(HE)staining, transmission electron microscopy, and Oil Red “O” staining. Results Morphological changes: HE staining of the CIH group showed lipid accumulation and lipid vacuole formation leading to hepatocyte steatosis. Microscopy of the ultrastructure showed large clusters of fat droplets and appearance of large numbers of autophagosomes and lysosomes, focal accumulation of glycogen in the rough endoplasmic reticulum, and sparse microvilli in the bile canaliculi. these were rarely seen in the CON group. The CIH group showed obvious morphological changes. Oil Red O staining results: the difference in IOD/Area was statistically significant between the CIH group and CON group(The test statistic=-56.308, P=0.001). Hepatocytes in the CIH group were obviously stained red. Conclusion The rat model of OSAHS with chronic intermittent hypoxia is successful, reliable and effective, which is consistent with the pathophysiological characteristics of OSAHS, and lays a solid foundation for further research on the pathogenesis of abnormal function of various tissues and organs in rats and the possible therapeutic effects of related drugs.

Key words: Sleep apnea syndrome, Hypoxia, Animal, Model, Rats

中图分类号:

R766.3

王海鹏,邹娟娟,高春苗,王孝,王岩,李延忠. OSAHS慢性间歇性低氧大鼠模型的建立及意义[J]. 山东大学学报 (医学版), 2021, 59(2): 7-13.

WANG Haipeng, ZOU Juanjuan, GAO Chunmiao, WANG Xiao, WANG Yan, LI Yanzhong. Construction and significance of a rat model of OSAHS with chronic intermittent hypoxia[J]. Journal of Shandong University (Health Sciences), 2021, 59(2): 7-13.

参考文献

[1] 徐劲松, 袁春华, 宋宁燕, 等. 间歇性缺氧及睡眠剥夺建立大鼠睡眠呼吸暂停模型[J]. 实验动物与比较医学, 2010, 30(2): 95-99. XU Jinsong, YUAN Chunhua, SONG Ningyan, et al. Establishment of sleep apnea syndrome model in rats with intermittent hypoxia and sleep deprivation [J]. Lab Animal Comp Med, 2010, 30(2): 95-99.
[2] 王璋, 司良毅, 廖友斌. 大鼠睡眠呼吸暂停综合征动物模型的建立[J]. 中国实验动物学报, 2006, 14(1): 40-43. WANG Zhang, SI Liangyi, LIAO Youbin. Establishment of sleep apnea syndrome model in rats [J]. Acta Lab Animalis Sci Sin, 2006, 14(1): 40-43.
[3] 谭胜玉, 杨宇, 罗荧荃, 等. 慢性间歇性缺氧大鼠模型的初步研究[J]. 中国医学工程, 2006, 14(6): 595-598. TAN Shengyu, YANG Yu, LUO Yingquan, et al. Primary study on an established chronic-intermittent hypoxia model in rat [J]. China Med Eng, 2006, 14(6): 595-598.
[4] Wang Y, Guo SZ, Bonen A, et al. Monocarboxylate transporter 2 and stroke severity in a rodent model of sleep apnea [J]. J Neurosci, 2011, 31(28): 10241-10248.
[5] Iturriaga R, Moya EA, Rio RD. Cardiorespiratory alterations induced by intermittent hypoxia in a rat model of sleep apnea[C] //New Front Respir Control, 2010. doi:10.1007/978-1-4419-5692-7_55.
[6] Li XC, Cai XH, Wen ZW, et al. Development and validation of intermittent hypoxia models [J]. J Med Res, 2012, 41(7): 57-61.
[7] Briançon-Marjollet A, Monneret D, Henri M, et al. Endothelin regulates intermittent hypoxia-induced lipolytic remodelling of adipose tissue and phosphorylation of hormone-sensitive lipase [J]. J Physiol, 2016, 594(6): 1727-1740.
[8] Menal MJ, Jorba I, Torres M, et al. Alzheimers disease mutant mice exhibit reduced brain tissue stiffness compared to wild-type mice in both normoxia and following intermittent hypoxia mimicking sleep apnea [J]. Front Neurol, 2018, 9: 1. doi:10.3389/fneur.
[9] Feng YQ, Ju AC, Liu CH, et al. Protective effect of the extract of Yi-Qi-Fu-Mai preparation on hypoxia-induced heart injury in mice [J]. Chin J Nat Med, 2016, 14(6): 401-406.
[10] Xue J, Zhou D, Poulsen O, et al. Intermittent hypoxia and hypercapnia accelerate atherosclerosis, partially via trimethylamine-oxide [J]. Am J Respir Cell Mol Biol, 2017, 57(5): 581-588.
[11] Shin MK, Han W, Joo H, et al. Effect of adrenal medullectomy on metabolic responses to chronic intermittent hypoxia in the frequently sampled intravenous glucose tolerance test [J]. J Appl Physiol(1985), 2017, 122(4): 767-774.
[12] Mankouski A, Kantores C, Wong MJ, et al. Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: a new rat model of BPD [J]. Am J Physiol Lung Cell Mol Physiol, 2017, 312(2): 208-216.
[13] Liu KX, Chen GP, Lin PL, et al. Detection and analysis of apoptosis-and autophagy-related miRNAs of mouse vascular endothelial cells in chronic intermittent hypoxia model [J]. Life Sci, 2018, 193: 194-199. doi:10.1016/j.lfs.2017.11.001.
[14] Souza GM, Bonagamba LG, Amorim MR, et al. Inspiratory modulation of sympathetic activity is increased in female rats exposed to chronic intermittent hypoxia [J]. Exp Physiol, 2016, 101(11): 1345-1358.
[15] Moraes DJA, Bonagamba LGH, da Silva MP, et al. Respiratory network enhances the sympathoinhibitory component of baroreflex of rats submitted to chronic intermittent hypoxia [J]. Hypertens Dallas Tex, 2016, 68(4): 1021-1030.
[16] Khalyfa A, Qiao Z, Gileles-Hillel A, et al. Activation of the integrated stress response and metabolic dysfunction in a murine model of sleep apnea [J]. Am J Respir Cell Mol Biol, 2017, 57(4): 477-486.
[17] Chopra S, Polotsky VY, Jun JC. Sleep apnea research in animals. past, present, and future [J]. Am J Respir Cell Mol Biol, 2016, 54(3): 299-305.
[18] Hoyos CM, Drager LF, Patel SR. OSA and cardiometabolic risk: Whats the bottom line? [J]. Respirology, 2017, 22(3): 420-429.
[19] Xu LF, Zhou XF, Hu K, et al. Establishment of a rabbit model of chronic obstructive sleep apnea and application in cardiovascular consequences [J]. Chin Med J(Engl), 2017, 130(4): 452-459.
[20] Jameson H, Bateman R, Byrne P, et al. Oxytocin neuron activation prevents hypertension that occurs with chronic intermittent hypoxia/hypercapnia in rats [J]. Am J Physiol Heart Circ Physiol, 2016, 310(11): 1549-1557.
[21] Pedroso D, Nunes AR, Diogo LN, et al. Hippocampal neurogenesis response: What can we expect from two different models of hypertension? [J]. Brain Res, 2016, 1646: 199-206. doi:10.1016/j.brainres.
[22] Weiszenstein M, Shimoda LA, Koc M, et al. Inhibition of lipolysis ameliorates diabetic phenotype in a mouse model of obstructive sleep apnea [J]. Am J Respir Cell Mol Biol, 2016, 55(2): 299-307.
[23] Jorba I, Menal MJ, Torres M, et al. Ageing and chronic intermittent hypoxia mimicking sleep apnea do not modify local brain tissue stiffness in healthy mice [J]. J Mech Behav Biomed Mater, 2017, 71: 106-113. doi: 10.1016/j.jmbbm.
[24] Perini S, Martinez D, Montanari CC, et al. Enhanced expression of melanoma progression markers in mouse model of sleep apnea[J]. Rev Port Pneumol(2006), 2016, 22(4): 209-213.
[25] Chen TI, Tu WC. Exercise attenuates intermittent hypoxia-induced cardiac fibrosis associated with sodium-hydrogen exchanger-1 in rats [J]. Front Physiol, 2016, 7: 462. doi:10.3389/fphys.
[26] Wu J, Sun X, Wu Q, et al. Disrupted intestinal structure in a rat model of intermittent hypoxia[J]. Mol Med Rep, 2016, 13(5): 4407-4413.
[27] Moreno-Indias I, Torres M, Sanchez-Alcoholado L, et al. Normoxic recovery mimicking treatment of sleep apnea does not reverse intermittent hypoxia-induced bacterial dysbiosis and low-grade endotoxemia in mice [J]. Sleep, 2016, 39(10): 1891-1897.
[28] Chen L, Zadi ZH, Zhang J, et al. Intermittent hypoxia in utero damages postnatal growth and cardiovascular function in rats [J]. J Appl Physiol Bethesda Md, 2018, 124(4): 821-830.
[29] Castro-Grattoni AL, Alvarez-Buvé R, Torres M, et al. Intermittent hypoxia-induced cardiovascular remodeling is reversed by normoxia in a mouse model of sleep apnea [J]. Chest, 2016, 149(6): 1400-1408.
[30] Yu HZ, Shao HX, Wu Q, et al. Altered gene expression of hepatic cytochrome P450 in a rat model of intermittent hypoxia with emphysema [J]. Mol Med Rep, 2017, 16(1): 881-886.
[31] Kukwa W, Migacz E, Druc K, et al. Obstructive sleep apnea and cancer: effects of intermittent hypoxia? [J]. Future Oncol, 2015, 11(24): 3285-3298.

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