Zhou Ling, Zhang Huojun, Liu Lu, Zhang Fengqin, Wang Lingling, Zheng Pengdou, Mao Zhenyu, Zhu Xiaoyan, Zi Guisha, Chen Lixiang, Cai Xiaojing, Liu Huiguo, Liu Wei
Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei 430030, China.
Chin Med J (Engl). 2025 Jul 20;138(14):1714-1729. doi: 10.1097/CM9.0000000000003608. Epub 2025 Jun 25.
Asthma is a common chronic inflammatory airway disease and intermittent hypoxia is increasingly recognized as a factor that may impact disease progression. The present study investigated whether intermittent hypoxia (IH) could aggravate asthma by promoting hypoxia-inducible factor-1α (HIF-1α)/nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3)/interleukin (IL)-1β-dependent pyroptosis and the inflammatory response and further elucidated the underlying molecular mechanisms involved.
A total of 49 patients diagnosed with severe bronchial asthma and diagnosed by polysomnography were enrolled at Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, between January 2022 and December 2022, and their general data and induced sputum were collected. BEAS-2B cells were treated with IL-13 and subjected to IH. An ovalbumin (OVA)-treated mouse model was also used to assess the effects of chronic intermittent hypoxia (CIH) on asthma. Pyroptosis, the inflammatory response, and related signalling pathways were assessed in vivo and in vitro .
In this study, as the apnoea and hypopnea index (AHI) increased, the proportion of patients with uncontrolled asthma increased. The proportions of neutrophils and the levels of IL-6, IL-8, HIF-1α and NLRP3 in induced sputum were related to the AHI. NLRP3-mediated pyroptosis, which could be mediated by the HIF-1α signalling pathway, was activated in IL-13 plus IH-treated BEAS-2B cells and in the lungs of OVA/CIH mice. HIF-1α downregulation significantly reduced lung pyroptosis and ameliorated neutrophil inflammation by modulating the NLRP3/IL-1β pathway both in vitro and in vivo . Similarly, pretreatment with LW6, an inhibitor of HIF-1α, effectively blocked the generation of inflammatory cytokines in neutrophils. In addition, administration of the NLRP3 activator nigericin obviously increased lung neutrophil inflammation.
Obstructive sleep apnoea-hypopnea syndrome (OSAHS) is a risk factor for asthma exacerbation. IH aggravates neutrophil inflammation in asthma via NLRP3/IL-1β-dependent pyroptosis mediated by the HIF-1α signalling pathway, which should be considered a potential therapeutic target for the treatment of asthma with OSAHS.
哮喘是一种常见的慢性炎症性气道疾病，间歇性缺氧越来越被认为是可能影响疾病进展的一个因素。本研究调查间歇性缺氧（IH）是否通过促进缺氧诱导因子-1α（HIF-1α）/核苷酸结合寡聚化结构域（NOD）样受体含吡咯结构域蛋白3（NLRP3）/白细胞介素（IL）-1β依赖性细胞焦亡和炎症反应来加重哮喘，并进一步阐明其中涉及的潜在分子机制。
2022年1月至2022年12月期间，在华中科技大学同济医学院附属同济医院招募了49例经多导睡眠图诊断为重度支气管哮喘的患者，收集他们的一般资料和诱导痰。用IL-13处理BEAS-2B细胞并使其经历间歇性缺氧。还使用卵清蛋白（OVA）处理的小鼠模型来评估慢性间歇性缺氧（CIH）对哮喘的影响。在体内和体外评估细胞焦亡、炎症反应及相关信号通路。
在本研究中，随着呼吸暂停低通气指数（AHI）增加，未控制哮喘患者的比例增加。诱导痰中中性粒细胞比例以及IL-6、IL-8、HIF-1α和NLRP3水平与AHI相关。在IL-13加IH处理的BEAS-2B细胞和OVA/CIH小鼠肺中，由HIF-1α信号通路介导的NLRP3介导的细胞焦亡被激活。HIF-1α下调通过在体外和体内调节NLRP3/IL-1β途径显著减少肺细胞焦亡并改善中性粒细胞炎症。同样，用HIF-1α抑制剂LW6预处理可有效阻断中性粒细胞中炎性细胞因子的产生。此外，给予NLRP3激活剂尼日利亚菌素明显增加肺中性粒细胞炎症。
阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是哮喘加重的一个危险因素。IH通过HIF-1α信号通路介导的NLRP3/IL-1β依赖性细胞焦亡加重哮喘中的中性粒细胞炎症，这应被视为治疗合并OSAHS哮喘的一个潜在治疗靶点。
