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Extramedullary Stress Erythropoiesis as an Adaptive Response to High-Altitude Hypoxemia

  • Author(s): Ghukasyan, David
  • Advisor(s): Heinrich, Erica C
  • et al.
Abstract

Systemic inflammation has been observed in sojourners traveling acutely to high-altitude. While chronic systemic inflammation is often associated with anemia, an alternative mechanism of extramedullary erythropoiesis, aptly named Stress Erythropoiesis (SE), has been shown in murine models to become activated in response to acute inflammatory and hypoxic stress. SE seems to play a protective role against inflammation-induced decreases in red blood cell production. While the mechanisms of SE are unclear in humans, it is likely that a similar protective response is activated in response to acute inflammation and hypoxic stress, such as in sepsis, acute lung injury, or travel to high-altitude. Therefore, the goal of my research was to identify and measure biomarkers of SE in high-altitude sojourners. I investigated Fetal Hemoglobin (HbF), Heme-Oxygenase 1 (HO-1), and Carbon Monoxide (CO) as potential candidate biomarkers of SE. Biomarkers were measured in peripheral blood of 15 participants at sea-level and high-altitude. Expression of HBG1, one of the genes that codes for the characteristic gamma (ɣ ) subunit of HbF, was significantly upregulated on day 3 at high-altitude (p < 0.01). Moreover, physiological assessments of participants on day 1 at high-altitude showed a significant increase in exhaled CO concentration when compared to measurements taken at sea-level (t(28) = -2.57, p = 0.01). Conversely, analysis of RNA sequencing of the gene coding for HO-1, HMOX1, resulted in a significant downregulation of HO-1 at high-altitude (p <0.01). Additionally, differential expression of proteomic output reveals other potential biomarkers of SE, such as AXIN1 which serves an important role in the regulation of Wnt signaling and SE. These findings provide support for potential activation of SE during acute high-altitude exposure and provide suggest an important role of hypoxia-induced inflammation in regulating erythropoiesis during acclimatization.

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