El Amine Bayan, Fournier Joey, Minoves Mélanie, Baillieul Sébastien, Roche Frédéric, Perek Nathalie, Pépin Jean-Louis, Tamisier Renaud, Khouri Charles, Rome Claire, Briançon-Marjollet Anne
Univ. Grenoble Alpes, Inserm U1300, CHU Grenoble Alpes, HP2 Laboratory, Grenoble, France.
Univ. Grenoble Alpes, Inserm U1216, Grenoble Institut Neurosciences, Grenoble, France.
Eur Respir Rev. 2024 Dec 18;33(174). doi: 10.1183/16000617.0162-2024. Print 2024 Oct.
Obstructive sleep apnoea (OSA) contributes to cerebrovascular diseases and cognitive decline. Preclinical studies support the deleterious impact on the brain of intermittent hypoxia (IH), one of the main components of OSA, but heterogeneity in rodent species and brain regions studied, or induced by IH paradigms, can challenge interpretation of the studies. Hence, we conducted a systematic review and meta-analysis to evaluate the impact of IH on rodent brain oxidative stress, inflammation, apoptosis and the expression of brain-derived neurotrophic factor (BDNF) and hypoxia-inducible factor 1 (HIF-1). PubMed and Web of Science searches identified 663 articles related to IH exposure, of which 60 were included. The examined outcomes were oxidative stress, inflammation, apoptosis, HIF-1 or BDNF in brains. Standardised mean difference was used to compare studies. Metaregressions were performed to clarify the impact of IH exposure parameters, rodent characteristics or cerebral localisation on these outcomes. IH-induced oxidative stress (increased malondialdehyde (MDA) and NADPH oxidase (NOX) and decreased superoxide dismutase), increased inflammation (tumour necrosis factor-α, NF-κB and inducible nitric oxide synthase), HIF-1 and apoptosis evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labelling and cleaved caspase-3. In contrast, B-cell lymphoma 2 (BCL2) and BDNF expression were not significantly modified. Metaregressions showed that MDA, NOX and BDNF were associated with determinants of IH cycles (inspired oxygen fraction and duration of hypoxia) and some parameters depended on localisation. Rodent characteristics had little impact on the outcomes. Our meta-analysis robustly establishes that IH, independently of other confounders, has a strong effect on the brain by inducing oxidative stress, inflammation and apoptosis in rodent models. Our findings support the interest of considering and treating cerebral consequences of OSA in clinical practice.
阻塞性睡眠呼吸暂停（OSA）会导致脑血管疾病和认知功能下降。临床前研究支持间歇性缺氧（IH）对大脑的有害影响，IH是OSA的主要组成部分之一，但所研究的啮齿动物物种和脑区的异质性，或由IH范式引起的异质性，可能会对研究结果的解释提出挑战。因此，我们进行了一项系统综述和荟萃分析，以评估IH对啮齿动物脑氧化应激、炎症、细胞凋亡以及脑源性神经营养因子（BDNF）和缺氧诱导因子1（HIF-1）表达的影响。通过检索PubMed和Web of Science，共识别出663篇与IH暴露相关的文章，其中60篇被纳入研究。所检测的结果为大脑中的氧化应激、炎症、细胞凋亡、HIF-1或BDNF。采用标准化均数差来比较各研究。进行元回归分析以阐明IH暴露参数、啮齿动物特征或脑定位对这些结果的影响。IH诱导氧化应激（丙二醛（MDA）和烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）增加，超氧化物歧化酶减少）、炎症增加（肿瘤坏死因子-α、核因子-κB和诱导型一氧化氮合酶）、HIF-1以及通过末端脱氧核苷酸转移酶dUTP缺口末端标记和裂解的半胱天冬酶-3评估的细胞凋亡。相比之下，B细胞淋巴瘤2（BCL2）和BDNF的表达没有显著改变。元回归分析表明，MDA、NOX和BDNF与IH周期的决定因素（吸入氧分数和缺氧持续时间）相关，且一些参数取决于定位。啮齿动物特征对结果影响较小。我们的荟萃分析有力地证实，独立于其他混杂因素，IH通过在啮齿动物模型中诱导氧化应激、炎症和细胞凋亡，对大脑有强烈影响。我们的研究结果支持在临床实践中考虑和治疗OSA对大脑的影响的重要性。
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