Proteomics and network biology insights into inflammation suppression during prolonged high-altitude hypoxia acclimatization

Abstract

For decades, the study of high-altitude acclimatization has been a vital area of scientific inquiry aimed at enhancing human resilience, particularly in the context of military deployments. While most existing research has focused on acute inflammatory responses to hypoxia, limited information is available on the molecular mechanisms underlying long-term high-altitude acclimatization. To address this gap, the present study investigated the plasma proteomic alterations associated with 120 days of high-altitude exposure at 14,500 ft by employing quantitative proteomics combined with computational network biology. Our proteomic analysis revealed molecular signatures associated with sustained high-altitude acclimatization. Notably, the inhibition of the IL-12 signaling pathway together with the activation of the DHCR24 pathway may correlate with the inferred downregulation of NF-κB signaling, which may reflect a shift toward reduced inflammation during sustained hypoxia. Additionally, LXR/RXR and NO signaling pathways may contribute to prolonged high-altitude acclimatization through their roles in lipid metabolism regulation and anti-inflammatory responses. To corroborate the proteomic and pathway-based predictions, ELISA-based quantification of selected inflammatory mediators was performed following prolonged hypoxia exposure. Following 120 days of high-altitude exposure, elevated levels of SIRT1 and thioredoxin-1 (TRX1) were observed, along with reduced circulating levels of inflammatory cytokines, including IL-1α, IL-1β, IL-6, IL-8, GM-CSF, IFN-γ, MCP-1 and TNF-α. These findings suggest that prolonged exposure to hypoxia may modulate inflammatory responses during acclimatization. Collectively, this study provides new insights into the molecular processes that may facilitate the regulation of inflammation during long-term high-altitude hypoxic acclimatization.