Sexual Dimorphism of Dexamethasone as a Prophylactic Treatment in Pathologies Associated With Acute Hypobaric Hypoxia Exposure

Abstract

Dexamethasone can be taken prophylactically to prevent hypobaric hypoxia-associated disorders of high-altitude. While dexamethasone-mediated protection against high-altitude disorders has been clinically evaluated, detailed sex-based mechanistic insights have not been explored. As part of our India-Leh-Dexamethasone-expedition-2020 (INDEX 2020) programme, we examined the phenotype of control (n = 14) and dexamethasone (n = 13) groups, which were airlifted from Delhi (∼225 m elevation) to Leh, Ladakh (∼3,500 m), India, for 3 days. Dexamethasone 4 mg twice daily significantly attenuated the rise in blood pressure, heart rate, pulmonary pressure, and drop in SaO2 resulting from high-altitude exposure compared to control-treated subjects. Of note, the effect of dexamethasone was substantially greater in women than in men, in whom the drug had relatively little effect. Thus, for the first time, this study shows a sex-biased regulation by dexamethasone of physiologic parameters resulting from the hypoxic environment of high-altitude, which impacts the development of high-altitude pulmonary hypertension and acute mountain sickness. Future studies of cellular contributions toward sex-specific regulation may provide further insights and preventive measures in managing sex-specific, high-altitude–related disorders.

Dexamethasone prophylaxis protects from acute high-altitude illness by modifying the peripheral blood mononuclear cell inflammatory transcriptome

“…Banked PBMC samples, collected and banked during the collaborative INDEX2020 study, were analyzed. Results of the parent study have been published [ 14 ]. As Per the clinical protocol ( Figure 1 A), the subjects received DEX as prophylaxis (hereafter referred to as DEX-p) or no treatment (hereafter referred to as control), and traveled from LA to HA.…”

“…The clinical data from the present study were previously published [ 14 ]. Briefly, twenty-seven age and sex-matched healthy subjects living at lowland and of Indo-Aryan ethnicity were recruited in collaboration with the CSIR-IGIB, Delhi, India, and the SNM Hospital, Leh, Ladakh, India.…”

“…14 subjects in the first group received no treatment (referred to as control). Thirteen subjects in the second group were prophylactically given DEX (referred to as DEX-p) 4 mg orally twice a day (Wockhardt Ltd, India) [ 14 ]. Both groups were clinically assessed at LA (Delhi, India, 225 m from sea level) at Govind Ballabh Pant Institute of Postgraduate Medical Education and Research and Hospital, New Delhi, and then were flown to HA (Leh, 3500 m from sea level; equivalent to 13.5% F i O 2 ).…”

“…The potential concept of targeting inflammatory immune cells in HA diseases is supported by the therapeutic use of dexamethasone (DEX), a potent glucocorticoid [ 13 ]. DEX promotes acclimatization to HA, prevents acute HA illnesses [ 14 ], and treats HACE and HAPE, the latter representing a severe complication of HA-induced PH [ 15 ]. However, the underlying molecular mechanisms by which DEX functions in ameliorating HA pathology remain inadequately understood.…”

Pretreatment with Notoginsenoside R1 attenuates high‐altitude hypoxia‐induced cardiac injury via activation of the ERK1/2‐P90RSK‐Bad signaling pathway in rats

“…(6) Dexamethasone and hypobaric hypoxia (Dex + HH) group (set as a positive control group), rats received 4 mg/kg dexamethasone dissolved in 2% DMSO saline. Dexamethasone is a commonly used drug for the treatment of acute altitude sickness (Chanana et al, 2022; Simancas‐Racines et al, 2018). In accordance with published studies, the dose and method of pre‐treatment of dexamethasone were determined (Shi et al, 2021; Zhou, Huang, et al, 2017).…”