阻塞性睡眠呼吸暂停的动物模型研究进展

doi:10.3969/j.issn.1674-8115.2024.04.011

摘要/Abstract

摘要：

阻塞性睡眠呼吸暂停（obstructive sleep apnea，OSA）是一种常见的睡眠障碍，其病理生理机制复杂且尚未完全明了。该文介绍了自然OSA动物模型、直接OSA动物模型以及间接OSA动物模型，分别分析了它们在模拟OSA病理生理过程中的优缺点。自然OSA动物模型主要关注自发性上气道阻塞，直接OSA动物模型通过直接阻塞引起OSA，而间接OSA动物模型主要通过模拟慢性间歇性低氧以及睡眠剥夺来研究其对机体的影响。这3类模型在研究OSA的病理生理学机制和开发治疗新方法方面发挥了重要作用，但它们也存在一些局限性和挑战。未来的研究方向包括非侵入性监测技术的发展、建立OSA联合模型以及基因编辑技术的应用，以期更全面、精确地模拟人类OSA的复杂性和多样性，为理解其机制和开发新的治疗方法提供更多信息。

关键词: 阻塞性睡眠呼吸暂停, 间歇性低氧, 睡眠剥夺, 动物模型

Abstract:

Obstructive sleep apnea (OSA) is a common sleep disorder, and its pathophysiological mechanism complex and not fully understood. This article elaborately explores three categories of OSA animal models: natural, direct and indirect, emphasizing their advantages and disadvantages in simulating OSA pathophysiological processes. Natural OSA models primarily focus on spontaneous upper airway obstructions. Direct OSA models induce OSA through direct obstruction of the airway, while indirect OSA models mainly investigate the impacts of chronic intermittent hypoxia (IH) and sleep deprivation (SD) on the organism. Although these models have played a pivotal role in studying the pathophysiological mechanisms of OSA and developing new therapeutic methods, they also present certain limitations and challenges. Future research directions include the development of non-invasive monitoring technologies, establishing OSA-combined models, and the application of gene-editing technologies, aiming to more comprehensively and accurately simulate the complexity and diversity of human OSA, providing more insights into its mechanisms and developing new therapeutic methods.

Key words: obstructive sleep apnea, intermittent hypoxia, sleep deprivation, animal model

中图分类号:

R562.1

沈煜斌, 欧茜文, 刘松. 阻塞性睡眠呼吸暂停的动物模型研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(4): 501-508.

SHEN Yubin, OU Xiwen, LIU Song. Progress in animal model research on obstructive sleep apnea[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(4): 501-508.

图/表 1

参考文献 30

1	SALZANO G, MAGLITTO F, BISOGNO A, et al. Obstructive sleep apnoea/hypopnoea syndrome: relationship with obesity and management in obese patients[J]. Acta Otorhinolaryngol Ital, 2021, 41(2): 120-130.
2	BENJAFIELD A V, AYAS N T, EASTWOOD P R, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis[J]. Lancet Respir Med, 2019, 7(8): 687-698.
3	CHEN X L, WANG R, ZEE P, et al. Racial/ethnic differences in sleep disturbances: the multi-ethnic study of atherosclerosis (MESA)[J]. Sleep, 2015, 38(6): 877-888.
4	YOUNG T, SKATRUD J, PEPPARD P E. Risk factors for obstructive sleep apnea in adults[J]. JAMA, 2004, 291(16): 2013-2016.
5	LÉVY P, KOHLER M, MCNICHOLAS W T, et al. Obstructive sleep apnoea syndrome[J]. Nat Rev Dis Primers, 2015, 1: 15015.
6	KAPUR V K, AUCKLEY D H, CHOWDHURI S, et al. Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American academy of sleep medicine clinical practice guideline[J]. J Clin Sleep Med, 2017, 13(3): 479-504.
7	LV R J, LIU X Y, ZHANG Y, et al. Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome[J]. Signal Transduct Target Ther, 2023, 8(1): 218.
8	HENDRICKS J C, KLINE L R, KOVALSKI R J, et al. The English bulldog: a natural model of sleep-disordered breathing[J]. J Appl Physiol, 1987, 63(4): 1344-1350.
9	CHOPRA S, POLOTSKY V Y, JUN J C. Sleep apnea research in animals. Past, present, and future[J]. Am J Respir Cell Mol Biol, 2016, 54(3): 299-305.
10	LONERGAN R P 3rd, WARE J C, ATKINSON R L, et al. Sleep apnea in obese miniature pigs[J]. J Appl Physiol, 1998, 84(2): 531-536.
11	BRENNICK M J, PICKUP S, CATER J R, et al. Phasic respiratory pharyngeal mechanics by magnetic resonance imaging in lean and obese zucker rats[J]. Am J Respir Crit Care Med, 2006, 173(9): 1031-1037.
12	HERNANDEZ A B, KIRKNESS J P, SMITH P L, et al. Novel whole body plethysmography system for the continuous characterization of sleep and breathing in a mouse[J]. J Appl Physiol, 2012, 112(4): 671-680.
13	CROSSLAND R F, DURGAN D J, LLOYD E E, et al. A new rodent model for obstructive sleep apnea: effects on ATP-mediated dilations in cerebral arteries[J]. Am J Physiol Regul Integr Comp Physiol, 2013, 305(4): R334-R342.
14	KING E D, O'DONNELL C P, SMITH P L, et al. A model of obstructive sleep apnea in normal humans. Role of the upper airway[J]. Am J Respir Crit Care Med, 2000, 161(6): 1979-1984.
15	LIU Y Y, GAO L, LV W N, et al. Pathologic and hemodynamic changes of common carotid artery in obstructive sleep apnea hypopnea syndrome in a porcine model[J]. Turk J Med Sci, 2019, 49(3): 939-944.
16	LEBEK S, HEGNER P, SCHACH C, et al. A novel mouse model of obstructive sleep apnea by bulking agent-induced tongue enlargement results in left ventricular contractile dysfunction[J]. PLoS One, 2020, 15(12): e0243844.
17	PHILIP P, GROSS C E, TAILLARD J, et al. An animal model of a spontaneously reversible obstructive sleep apnea syndrome in the monkey[J]. Neurobiol Dis, 2005, 20(2): 428-431.
18	QIAN L, RAWASHDEH O, KASAS L, et al. Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer's disease[J]. Nat Commun, 2022, 13(1): 6543.
19	张秀娟, 李庆云, 许华俊. 睡眠呼吸暂停模式间歇低氧动物模型的建立及应用[J]. 中华结核和呼吸杂志, 2011, 34(10): 777-779.
	ZHANG X J, LI Q Y, XU H J. Establishment and application of chronic intermittent hypoxia animal model mimicking sleep apnea[J]. Zhonghua Jie He He Hu Xi Za Zhi, 2011, 34(10): 777-779.
20	MESARWI O A, SHARMA E V, JUN J C, et al. Metabolic dysfunction in obstructive sleep apnea: a critical examination of underlying mechanisms[J]. Sleep Biol Rhythms, 2015, 13(1): 2-17.
21	JUN J C, SHIN M K, YAO Q L, et al. Thermoneutrality modifies the impact of hypoxia on lipid metabolism[J]. Am J Physiol Endocrinol Metab, 2013, 304(4): E424-E435.
22	ZAMORE Z, VEASEY S C. Neural consequences of chronic sleep disruption[J]. Trends Neurosci, 2022, 45(9): 678-691.
23	VILLAFUERTE G, MIGUEL-PUGA A, RODRÍGUEZ E M, et al. Sleep deprivation and oxidative stress in animal models: a systematic review[J]. Oxid Med Cell Longev, 2015, 2015: 234952.
24	SENEL M, DERVISEVIC E, ALHASSEN S, et al. Microfluidic electrochemical sensor for cerebrospinal fluid and blood dopamine detection in a mouse model of Parkinson's disease[J]. Anal Chem, 2020, 92(18): 12347-12355.
25	PLA L, BERDÚN S, MIR M, et al. Non-invasive monitoring of pH and oxygen using miniaturized electrochemical sensors in an animal model of acute hypoxia[J]. J Transl Med, 2021, 19(1): 53.
26	QIU X H, LI L L, WEI J Y, et al. The protective role of Nrf2 on cognitive impairment in chronic intermittent hypoxia and sleep fragmentation mice[J]. Int Immunopharmacol, 2023, 116: 109813.
27	LIU W, ZHAO D, WU X F, et al. Rapamycin ameliorates chronic intermittent hypoxia and sleep deprivation-induced renal damage via the mammalian target of rapamycin (mTOR)/NOD-like receptor protein 3 (NLRP3) signaling pathway[J]. Bioengineered, 2022, 13(3): 5537-5550.
28	CAMPOS A I, INGOLD N, HUANG Y R, et al. Discovery of genomic loci associated with sleep apnea risk through multi-trait GWAS analysis with snoring[J]. Sleep, 2023, 46(3): zsac308.
29	XU H J, LIU F, LI Z Q, et al. Genome-wide association study of obstructive sleep apnea and objective sleep-related traits identifies novel risk loci in Han Chinese individuals[J]. Am J Respir Crit Care Med, 2022, 206(12): 1534-1545.
30	CHEN H, CADE B E, GLEASON K J, et al. Multiethnic meta-analysis identifies RAI1 as a possible obstructive sleep apnea-related quantitative trait locus in men[J]. Am J Respir Cell Mol Biol, 2018, 58(3): 391-401.

Classification	Name	Advantage	Limitation	Applicable scenario
Natural OSA animal model	Obese pigs, English bulldogs, Obese Zucker rats, New Zealand Obese mice	No intervention required; closer to actual conditions	Difficult to fully control variables, adjust research conditions, and cover features closely related to unique human lifestyles and environmental factors	Studying the physiological, genetic, metabolic impacts and the long-term effects of chronic OSA
Direct OSA animal model	OSA animal model with tracheal intubation	Consistently inducing the same degree of upper airway narrowing; easy to control the frequency and duration of apnea events	Technical difficulty and high cost; invasive models are prone to stress responses, and the airway obstruction plane differs from humans	Studying the acute physiological effects of short-term OSA; not suitable for large-scale studies
	OSA animal model of airway collapse induced by negative pressure	Simple, stable, and repeatable operation; no need for complex surgeries or equipment	Unable to stably induce the same degree of upper airway collapse	Researching the chronic impacts of long-term OSA, such as the development of cardiovascular diseases
	OSA animal model with filling material injection	Relatively simple operation; spontaneous chronic IH pathophysiological changes occur; imaging can be used as support	Animals show individual differences, poor repeatability; potential for injection site infections	Studying the effects of anatomical and functional changes in the upper airway on OSA
	Chemically induced OSA animal model	Minimally invasive, few surgery-related complications; high repeatability	High technical requirements and complexity in operation; requiring precise and skilled experimental techniques and high-end experimental equipment	Researching the pathophysiological characteristics of OSA during specific sleep stages
	Special mask ventilation blockage method, Head-enclosed ventilation blockage method, oral-nasal airbag ventilation blockage method	Controllable ventilation and occlusion times	High equipment requirements; difficult operation; insufficient precision in control; restricting animal free movement	Not suitable for more complex or larger-scale studies
Indirect OSA animal model	Chronic IH model	No anesthesia required; non-invasive; precise control of gas concentrations within the chamber; safe and repeatable modeling process	Unable to simulate upper airway narrowing or collapse; CO₂ partial pressure changes do not match actual conditions	Suitable for mechanistic research, long-term studies, and large-scale physiological and pharmacological research
Indirect OSA animal model	Sleep deprivation model	Ability to adjust the intensity and duration of sleep deprivation as needed; facilitating a repeatable process	Introduction of additional stress factors; possibility of leading to a certain degree of exercise deprivation effect, confinement, and fixation stress	Researching the impact of decreased sleep quality and disordered sleep structure on cognitive function, learning and memory, emotional regulation, and metabolic diseases in OSA, and the treatment effects of improving sleep quality on these diseases

Classification	Name	Advantage	Limitation	Applicable scenario
Natural OSA animal model	Obese pigs, English bulldogs, Obese Zucker rats, New Zealand Obese mice	No intervention required; closer to actual conditions	Difficult to fully control variables, adjust research conditions, and cover features closely related to unique human lifestyles and environmental factors	Studying the physiological, genetic, metabolic impacts and the long-term effects of chronic OSA
Direct OSA animal model	OSA animal model with tracheal intubation	Consistently inducing the same degree of upper airway narrowing; easy to control the frequency and duration of apnea events	Technical difficulty and high cost; invasive models are prone to stress responses, and the airway obstruction plane differs from humans	Studying the acute physiological effects of short-term OSA; not suitable for large-scale studies
	OSA animal model of airway collapse induced by negative pressure	Simple, stable, and repeatable operation; no need for complex surgeries or equipment	Unable to stably induce the same degree of upper airway collapse	Researching the chronic impacts of long-term OSA, such as the development of cardiovascular diseases
	OSA animal model with filling material injection	Relatively simple operation; spontaneous chronic IH pathophysiological changes occur; imaging can be used as support	Animals show individual differences, poor repeatability; potential for injection site infections	Studying the effects of anatomical and functional changes in the upper airway on OSA
	Chemically induced OSA animal model	Minimally invasive, few surgery-related complications; high repeatability	High technical requirements and complexity in operation; requiring precise and skilled experimental techniques and high-end experimental equipment	Researching the pathophysiological characteristics of OSA during specific sleep stages
	Special mask ventilation blockage method, Head-enclosed ventilation blockage method, oral-nasal airbag ventilation blockage method	Controllable ventilation and occlusion times	High equipment requirements; difficult operation; insufficient precision in control; restricting animal free movement	Not suitable for more complex or larger-scale studies
Indirect OSA animal model	Chronic IH model	No anesthesia required; non-invasive; precise control of gas concentrations within the chamber; safe and repeatable modeling process	Unable to simulate upper airway narrowing or collapse; CO₂ partial pressure changes do not match actual conditions	Suitable for mechanistic research, long-term studies, and large-scale physiological and pharmacological research
Indirect OSA animal model	Sleep deprivation model	Ability to adjust the intensity and duration of sleep deprivation as needed; facilitating a repeatable process	Introduction of additional stress factors; possibility of leading to a certain degree of exercise deprivation effect, confinement, and fixation stress	Researching the impact of decreased sleep quality and disordered sleep structure on cognitive function, learning and memory, emotional regulation, and metabolic diseases in OSA, and the treatment effects of improving sleep quality on these diseases

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