Discussion
HA illness, impairment of peripheral immune, hypoxia, inflammation, PH
INFLAMMATION, HYPOXIA, DISEASES
This study aims to uncover mechanisms linking peripheral blood characteristics with lung vascular pathobiology, paving the way for more effective therapeutic strategies for HA diseases and potentially PH, even when its origins are not associated with HA etiologies. Our work builds upon prior research in this field by employing an impartial transcriptomic approach to study PBMCs including phenotypes of these cells, potential signaling pathways, and distribution of cells in the population.Significant changes in the PBMC transcriptome with HA challenge were observed, particularly related to either inflammation, or the regulation of cell division, translation, or transcription. Similar studies have been performed previously, including a cohort of 98 subjects who acutely travelled from sea level to 2835 m, which also observed increased expression in genes associated with translation and protein folding, and cell growth and apoptosis, as well as energy metabolism [In contrast, the impact of DEX prophylaxis was relatively modest on the PBMC transcriptome, despite the DEX dose being relatively large. For this clinical indication, the range of DEX dose varies from 2 to 8 mg twice daily [By PBMC transcriptome analysis alone, we observed little interaction between DEX and HA exposures, with no clear revealing of mechanisms by which DEX protects against HA exposure by this approach. There is a possibility that DEX may help maintain cellular integrity as a functional impairment of peripheral immune cells in chronic HA-induced PH patients has been reported [The effect of DEX may also be mediated by different impacts on cells in the bloodstream versus bodily tissues, stemming from divergent cellular behavior and distribution in these compartments. Concentrations of DEX in plasma and tissues will differ due to tissue-specific uptake, metabolism, and clearance mechanisms. These differences can lead to unique physiological outcomes in each compartment and require future studies to investigate DEX’s pharmacokinetics and pharmacodynamics in plasma and tissues to understand its effects.Other medications, most notably acetazolamide, are also clinically used in prophylaxis against HA illness. Acetazolamide inhibits carbonic anhydrase, leading to an increase in pCOWe suspect that DEX may modulate HA diseases by suppressing inflammation, as we found inflammation was increased by HA exposure, and suppressed by DEX prophylaxis. A key limitation of our analysis is that PBMC analysis does not reflect the phenotype of the lung tissue directly, and hypoxia is known to increase inflammation in the lungs [Other limitations of this work are the relatively small sample size, although the analysis of paired samples collected from the same subject at both LA and HA, does increase the statistical power. Our clinical cohort is relatively young, and the HA and DEX phenotype may be different in an older population. Similarly, our cohort was exclusively of Indo-Aryan ancestry, and the response to HA and DEX also can be different in other populations. This may explain differences between precise gene datasets in different studies, such as comparing our data to Pham et al., which enrolled subjects in California [In summary, we observed many significant changes in the PBMC transcriptome with HA exposure, and more modest changes in the transcriptome with DEX prophylaxis. There was little interaction in the PBMC transcriptome between concurrent HA and DEX exposures. There were changes in the potential cell populations within the deconvoluted bulk RNAseq data. These observations suggest that the mechanism by which DEX prophylaxis may mitigate the effects of HA exposure may be through blocking inflammation and modifying cell population numbers and locations.