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

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 homeostat...

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Published in:	Respiratory research Vol. 26; no. 1; pp. 241 - 14
Main Authors:	Liu, Qing, Zhang, Yushi, Duan, Ruirui, Li, Wanheng, Hou, Xuan, Chen, Yiling, Li, Baicun, Yang, Ting
Format:	Journal Article
Language:	English
Published:	London BioMed Central 10.07.2025 BioMed Central Ltd Nature Publishing Group BMC
Subjects:	Acids Altitude Alveolar macrophage homeostasis Alveoli Angiogenesis Animals Bioinformatics Cell Hypoxia - physiology Cells Cells, Cultured Chronic obstructive pulmonary disease Cigarette smoke Cigarette smoke extract Cigarette Smoking - adverse effects Cigarette Smoking - metabolism Cigarettes Disruption Enzymes Exposure Extracellular matrix Gene sequencing Glycolysis HIF-1α High altitude High-altitude environments Homeostasis Hypoxia Hypoxia - genetics Hypoxia - metabolism Hypoxia-Inducible Factor 1, alpha Subunit - genetics Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Hypoxia-inducible factor 1a Inflammatory diseases Lung diseases Macrophages Macrophages, Alveolar - drug effects Macrophages, Alveolar - metabolism Macrophages, Alveolar - pathology Medical research Medicine Medicine & Public Health Medicine, Experimental Mice Mice, Inbred C57BL Pathogenesis Physiological aspects Pneumology/Respiratory System Polarization Polymerase chain reaction Proteins Pulmonary alveoli Pulmonary Disease, Chronic Obstructive - genetics Pulmonary Disease, Chronic Obstructive - metabolism Ribonucleic acid RNA Sequence analysis Signal transduction Smoke Smoke - adverse effects Transcriptome - drug effects Transcriptome - physiology Transcriptomes China United States > US Hypoxia Chronic obstructive pulmonary disease HIF-1α Cigarette smoke extract Alveolar macrophage homeostasis
ISSN:	1465-993X, 1465-9921, 1465-993X
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Summary:	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. Conclusion Downstream HIF-1α signalling pathways drive inflammation, M1 macrophage polarization, glycolysis, extracellular matrix remodelling, and angiogenesis, potentially disrupting alveolar macrophages homeostasis during high-altitude COPD pathogenesis. This disruption may be one reason underlying the high prevalence of COPD in high-altitude regions.
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ISSN:	1465-993X 1465-9921 1465-993X
DOI:	10.1186/s12931-025-03303-9