Transcriptome reveals the landscape of alveolar macrophages exposed to combined hypoxia with cigarette smoke extract

作者：Qing Liu, Yushi Zhang, Ruirui Duan, Wanheng Li, Xuan Hou, Yi-Ling Chen, Baicun Li, Ting Yang · 发表于：Respiratory Research · 年份：2025 · DOI：10.1186/s12931-025-03303-9 · 被引用次数：6 · 研究领域：High Altitude and Hypoxia、Cancer, Hypoxia, and Metabolism、Immune cells in cancer

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous chronic inflammatory disease that is one of the leading causes of age-standardised deaths globally. While studies have investigated altitude's effects on COPD, none have explored alveolar macrophage homeostatic alterations during its pathogenesis at high altitudes. METHODS: We constructed a high-altitude COPD model through exposure of mouse alveolar macrophages (MH-S) to hypoxia and cigarette smoke extract (CSE). Hypoxia-inducible factor (HIF) expression was quantified in MH-S cells exposed to hypoxia combined with CSE and in the control group. HIF-1α short hairpin RNA (shRNA) was added to the MH-S cells. Transcriptome was used to characterise downstream signalling pathways of HIF-1α in MH-S cells treated with hypoxia and CSE exposure. Standard molecular techniques were used to validate the RNA sequencing results. RESULTS: HIF-1α but not HIF-2α was significantly up-regulated in MH-S cells after exposure to hypoxia and CSE. RNA-sequencing analysis of MH-S cells showed the relevant pathways downstream of HIF-1α are mainly inflammation, glycolysis, M1 polarization, extracellular matrix remodelling and angiogenesis. Validation of RNA-sequencing analysis confirmed that the above signalling pathways were abnormally up-regulated after CSE exposure, and that combined hypoxic exposure further exacerbated the induced aberrant up-regulation, which was inhibited after treatment with HIF-1α shRNA. CONC...