Inflammatory gene expression during acute high‐altitude exposure

The molecular signaling pathways that regulate inflammation and the
response to hypoxia share significant crosstalk and appear to play major
roles in high-altitude acclimatization and adaptation. Several studies
demonstrate increases in circulating candidate inflammatory markers during
acute high-altitude exposure, however significant gaps remain in our
understanding of how inflammation and immune function change at high
altitude and if these responses contribute to high-altitude pathologies,
such as Acute Mountain Sickness. To address this, we used an unbiased
transcriptomic approach, including RNA sequencing and direct digital mRNA
detection with NanoString, to identify changes in the inflammatory profile
of peripheral blood throughout three days of high-altitude acclimatization
in healthy sea-level residents (N = 15; 5 women). Several
inflammation-related genes were upregulated on the first day of
high-altitude exposure, including a large increase
in HMGB1 (High Mobility Group Box 1), a danger
associated molecular pattern (DAMP) molecule which amplifies immune
responses during tissue injury. Differentially expressed genes on the
first and third days of acclimatization was enriched for several
inflammatory pathways including NF-kB and toll-like receptor (TLR)
signaling. Indeed, both TLR4 and LY96, which
encodes the lipopolysaccharide binding protein (MD-2), were upregulated at
high altitude.
Finally, FASLG and SMAD7 were
associated with AMS scores and pulse oxygen saturation levels on the first
day at high altitude, suggesting a potential role of immune regulation in
response to high-altitude hypoxia. These results indicate that acute
high-altitude exposure upregulates inflammatory signaling pathways and may
sensitize the TLR4 signaling pathway to subsequent inflammatory stimuli.