Abstract
Acute mountain sickness (AMS), which may progress to life-threatening high-altitude cerebral edema, is a major threat to millions of people who live in or travel to high altitude. Although studies have revealed the risk factors and pathophysiology theories of AMS, the molecular mechanisms of it do not comprehensively illustrate. Here, we used a system-level methodology, RNA sequencing, to explore the molecular mechanisms of AMS at genome-wide level in 10 individuals. After exposure to high altitude, a total of 1,164 and 1,322 differentially expressed transcripts were identified in AMS and non-AMS groups, respectively. Among them, only 328 common transcripts presented between the two groups. Immune and inflammatory responses were overrepresented in participants with AMS, but not in non-AMS individuals. Anti-inflammatory cytokine IL10 and inflammation cytokines IF17F and CCL8 exhibited significantly different genetic connectivity in AMS compared to that of non-AMS individuals based on network analysis. IL10 was downregulated and both IF17F and CCL8 were upregulated in AMS individuals. Moreover, the serum concentration of IL10 significantly decreased in AMS patients after exposure to high altitude (p = 0.001) in another population (n = 22). There was a large negative correlation between the changes in IL10 concentration, r(22) = −0.52, p = 0.013, and Lake Louise Score. Taken together, our analysis provides unprecedented characterization of AMS transcriptome and identifies that genes involved in immune and inflammatory responses were disturbed in AMS individuals by high-altitude exposure. The reduction of IL10 after exposure to high altitude was associated with AMS.
Highlights
Acute mountain sickness (AMS) is the most common disease caused by the lower pressure and reduced oxygen amounts at high altitudes and can progress to high-altitude cerebral edema in severe cases, which has a high mortality [1, 2]
We found that rapid ascent to a high-altitude environment initiated a cascade of physiological responses: oxygen saturation decreased substantially once individuals were at high altitude; heart rate and blood pressure increased; the mean hemoglobin concentration was higher in individuals postexposure to high altitude in contrast to preexposure to high altitude
Targeted therapy with IL-10 might be more beneficial in AMS prevention
Summary
Acute mountain sickness (AMS) is the most common disease caused by the lower pressure and reduced oxygen amounts at high altitudes (above 2,500 m) and can progress to high-altitude cerebral edema in severe cases, which has a high mortality [1, 2]. The awareness of altitude-related health hazards increased, the prevalence of AMS was ~16–100% in different study. Insufficient cerebrospinal compliance [8], alterations in fluid balance [9], activation of nociceptors induced by free radicals [10], and vasogenic edema caused by increased capillary permeability [11, 12] have all been associated with AMS development, but the biological pathways and exact molecular mechanisms underlying AMS remain unknown [13]. Comparison of transcriptome differences in samples from individuals with and without AMS can reveal distinct differences in gene regulation changes related to AMS at genome-wide level.
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