Inflammation at High Altitude and Potential Links to Physiological Responses to Hypoxia

Abstract

Inflammation plays a critical role in the physiological response to hypoxic stress. Evolutionary conserved inflammatory responses to oxygen limitation promote adaptation to the hypoxic environment. However, these responses may also become maladaptive during chronic exposure if not properly resolved, possibly contributing to pathologies such as Acute or Chronic Mountain Sickness. We hypothesize that pro‐inflammatory gene expression increases upon acute high‐altitude exposure, followed by a subsequent blunting of the inflammatory profile with acclimatization. We compared the inflammatory profiles in whole blood samples collected in the morning during fasting at sea level and after one and three nights at high altitude (3800 m elevation) in 15 healthy sojourners (5 women, 10 men). RNA sequencing was coupled with a nanoString Human Inflammatory Panel. Previously, we found key components of the TLR4 signaling pathway upregulated under acute high‐altitude exposure. To complement this, we found that IL8, a chemotactic cytokine that induces neutrophil recruitment, was significantly upregulated upon the first and third day at high altitude, and larger increases in IL8 may be associated with lower oxygen saturation (SpO2) at high altitude (R= ‐0.51; p=0.05). Additionally, FASLG, which is essential for immune system regulation, was associated with both SpO2 (R=0.68; p<0.01) and AMS score (R= ‐0.71; p<0.01) at high altitude. The upregulation of TLR4 signaling pathway genes observed during high‐altitude exposure in vivo suggested that hypoxia may exacerbate responses to inflammatory stimuli. To test this, we cultured whole blood in the presence of normoxia or hypoxia with or without a lipopolysaccharide (LPS) stimulus for 24 hours. Cultures were further treated with DMOG (HIF prolyl hydroxylase inhibitor), PX‐478 (HIF inhibitor), or media (control) to determine if any of these outcomes were HIF‐dependent. Preliminary data suggests that, in the presence of both inflammatory stimuli (LPS and hypoxia), TNF production was exacerbated (p=0.03). However, when HIF was inhibited with PX‐478, this exacerbated response was mitigated. Additionally, we found that DMOG abrogated TNF, IL6, and IL8 production in all treatments, suggesting a key role of prolyl hydroxylase activity in inflammation. In conclusion, our results indicate that acute high‐altitude exposure may cause an initial priming of the innate immune system with a synergistic TLR4‐induced sensitization to subsequent inflammatory stimuli and neutrophil activation and recruitment. In the case that the inflammatory response is not properly blunted during acclimatization, this may lead to the development of hypoxia‐induced pathologies. This may be particularly important in the context of pulmonary diseases if hypoxemia initiates an exacerbated inflammatory response to infection.