Inflammatory Profiles and Immune Responses to High-Altitude Acclimatization

High altitude is a physiologically stressful environment due to oxygen limitation and low atmospheric pressure. Despite these conditions, over 160 million people live, work, or travel to high altitude annually. Several systemic physiological changes in response to hypoxia promote acclimatization to high altitude. However, even in acclimatized individuals, there is still a significant risk of developing high-altitude illnesses (HAIs), such as acute mountain sickness, high-altitude pulmonary edema, or high-altitude cerebral edema. While it is clear that HAIs result from high altitude/hypoxia, gaps in our knowledge remain regarding the underlying mechanisms that drive the development of these pathologies. The molecular pathways that control hypoxia responses are evolutionary conserved and have significant crosstalk to essential mechanisms that drive inflammation. While these responses may be key for acute adaptation to hypoxia, they may become maladaptive if not properly mediated. For example, native highlanders show evidence of natural selection for traits that promote adaptation to chronic hypoxia, but different native high-altitude populations display distinct adaptations. However, not all these adaptations are beneficial. Most notably, Andean highlanders have a high prevalence of Chronic Mountain Sickness (CMS), an incapacitating syndrome induced by lifelong exposure to hypoxia. The underlying mechanisms behind CMS are also unknown, however it has been suspected that inflammation may play a role in CMS pathogenesis. The goal of my dissertation research was to determine how high-altitude hypoxia induces changes in inflammatory profiles and immune cell populations. Furthermore, I aimed to investigate if immune cells at high altitude are sensitized to inflammatory stimuli, and if these responses are dependent on hypoxia inducible factor (HIF) activity. To accomplish these goals, I employed several techniques such as multi-parameter flow cytometry, multiplex immunoassa