Endocrine, inflammatory and immune responses and individual differences in acute hypobaric hypoxia in lowlanders

doi:10.21203/rs.3.rs-2730026/v1

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Endocrine, inflammatory and immune responses and individual differences in acute hypobaric hypoxia in lowlanders

https://doi.org/10.21203/rs.3.rs-2730026/v1

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published 04 Aug, 2023

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When lowlanders are exposed to hypobaric hypoxia (HH) environments such as high mountains, hemodynamic changes occur to maintain oxygen levels in the body. However, changes to other physiological functions under such conditions have yet to be clarified. This study aimed to investigate changes to endocrine, inflammatory and immune responses and individual differences during acute HH exposure using a climatic chamber (75 min of exposure to conditions mimicking 3500 m) in healthy lowlanders. Aldosterone and cortisol were significantly decreased and interleukin (IL)-6, IL-8 and white blood cell (WBC) count were significantly increased after HH. Lower peripheral oxygen saturation (SpO₂) was associated with higher IL-6 and WBC count, and higher IL-8 was associated with higher cortisol. These results suggest that endocrine, inflammatory and immune responses are evoked even with a short 75-min exposure to HH and individuals with lower SpO₂ show more pronounced responses. Our results provide basic data for understanding physiological responses and interactions of homeostatic systems with acute HH.

Biological sciences/Biochemistry

Health sciences/Biomarkers

Health sciences/Endocrinology

Biological sciences/Immunology

Biological sciences/Immunology/Cytokines

Biological sciences/Immunology/Inflammation

Biological sciences/Physiology/Circulation

Biological sciences/Physiology/Kidney

Biological sciences/Physiology/Metabolism

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Biological sciences/Evolution/Anthropology

In high-altitude environments, the decrease in barometric pressure and the consequent fall in partial pressure of oxygen in the alveoli evoke a condition defined as hypobaric hypoxia (HH). Tibetan and Andean populations are well known to show adaptation to the high-altitude environment and ethnic differences in these adaptations have been identified ^1–5. Typically, Tibetan populations show lower hemoglobin concentrations and high blood flow ^2,4,6, whereas Andean populations show higher hemoglobin concentrations and higher ventilatory features such as barrel chest ^2,7. Each phenotype contributes to maintaining oxygen levels under HH. Conversely, lowlanders exposed to acute or sub-acute HH display several hemodynamic changes (increase in heart rate, ventilation, respiratory rate, cardiac output and hemoglobin concentration) to maintain oxygen levels ^8–10. However, other physiological responses to HH remain poorly understood.

Among lowlanders, acute mountain sickness (AMS) often occurs at altitudes over 3000 m ^11,12, and peripheral oxygen saturation (SpO₂) has been identified as a strong predictor of AMS ^13–15. However, other physiological changes occur in the human body. Notably, HH leads to strong natriuresis and diuresis via the reduction of aldosterone ^16,17, and AMS is often associated with fluid retention ^17,18. Cortisol also changes in response to HH; most studies have reported increases in cortisol ^19–21, while some studies have found no changes ^21–23. Adrenaline and noradrenaline responses in HH are more controversial. Noradrenaline appears to increase with chronic HH exposure ^23,24, but with exposure less than around 1 week, no changes are seen in either ²⁴. In addition, hypoxia and inflammatory responses are known to be related at the molecular, cellular, and clinical levels ^25–28, and inflammatory cytokines such as interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α increase during HH ^8,29,30. In parallel, some studies have reported increases in white blood cell (WBC) count during HH ^31,32. Such findings suggest that not only hemodynamics, but also endocrine, inflammatory and immune responses interact during HH to maintain human homeostasis.

Many studies have reported important data from field research, but factors such as cold, physical burdens, exercise loads and other environmental factors during mountain climbing may well affect physiological responses. In addition, individual differences are seen in physiological responses to HH, including AMS risk ^9,11,28, but such differences have not been fully considered in previous studies. This study therefore aimed to investigate endocrine, inflammatory and immune responses and individual differences during acute HH in healthy lowlanders, to better understand the basic effects of HH on the human body and interactions with human homeostatic systems.

One-way ANOVA showed that SpO₂ and changed significantly after HH (p < 0.001) (Table 1). SpO₂ was significantly decreased 75–135 min during HH compared to at 15 min (baseline), while HR was significantly increased at 60–135 min during HH compared to baseline (Table 1). SBP and DBP showed no significant differences between HH and baseline (Table 1).

Table 1

Time series changes in physiological data during baseline and HH exposure.
Altitude (m)	0		0 to 3500		3500					3500 to 0
Time (min)	15	30	45	60	75	90	105	120	135	150	165
	Mean (SD)											p for ANOVA
SpO₂ (%)	99.1 (0.8)	98.9 (0.8)	98.3 (1.0)	94.4 (1.9)	87.9 (4.1)	86.9 (3.6)	86.5 (3.5)	85.5 (3.9)	86.2 (3.5)	90.3 (3.6)	97.6 (1.4)	< 0.001
HR (beats/min)	67.2 (6.1)	66.6 (6.2)	65.3 (6.5)	70.3 (6.6)	74.4 (7.8)	74.1 (7.5)	75.6 (7.6)	75.7 (9.0)	77.6 (8.8)	73.0 (8.2)	69.1 (7.0)	< 0.001
SBP (mmHg)	-	111.4 (5.6)	110.2 (6.5)	111.3 (5.9)	110.4 (5.0)	110.9 (7.7)	110.1 (6.6)	109.3 (8.1)	109.8 (7.1)	110.9 (8.2)	112 (8.9)	0.553
DBP (mmHg)	-	64 (5.2)	64.8 (6.4)	66.7 (5.2)	66.3 (4.8)	67.3 (6.7)	66.2 (7.2)	66.4 (5.9)	67.1 (6.3)	67.3 (7.0)	65.9 (7.2)	0.115
Bold indicates significant difference (p < 0.05) from 30-min data in post hoc test.

In terms of blood components, after HH exposure, WBC count was significantly increased (p = 0.033) and aldosterone and cortisol were significantly decreased (p < 0.001 and p = 0.003, respectively) (Table 2, Fig. 2). Noradrenaline was marginally increased after HH exposure (p = 0.070) (Table 2). Cytokines IL-6 and IL-8 were significantly increased after HH exposure (p = 0.007 and p = 0.043, respectively) (Table 3, Fig. 2).

Table 2

Changes in blood components and hormone levels.
		Pre		Post
		Mean	SD	Mean	SD	p-value
WBC	(⋅10⁴/µL)	5087.5	930.0	6000.0	1448.3	0.033
RBC	(⋅10⁴/µL)	513.5	24.6	516.4	21.3	0.517
Hemoglobin	(g/dL)	15.6	0.8	15.8	0.7	0.358
Hematocrit	(%)	46.5	2.1	46.8	2.0	0.476
Adrenaline	(ng/mL)	0.04	0.02	0.04	0.03	0.777
Noradrenaline	(ng/mL)	0.27	0.12	0.35	0.14	0.070
Aldosterone	(pg/mL)	220.9	76.2	112.6	23.4	< 0.001
Cortisol	(g/dL)	11.0	4.8	7.5	2.7	0.003
Bold indicates significant difference (p < 0.05).

Table 3

Changes in cytokine levels.
		Pre		Post
		Mean	SD	Mean	SD	p-value
IFN-γ	(pg/mL)	3.94	4.48	4.12	4.70	0.547
IL-10	(pg/mL)	0.21	0.16	0.22	0.18	0.956
IL-12p70	(pg/mL)	0.12	0.12	0.15	0.14	0.117
IL-13	(pg/mL)	0.77	0.85	0.72	0.93	0.201
IL-1β	(pg/mL)	0.07	0.06	0.08	0.10	0.500
IL-2	(pg/mL)	0.10	0.10	0.11	0.11	0.354
IL-4	(pg/mL)	0.02	0.02	0.02	0.02	0.571
IL-6	(pg/mL)	0.34	0.13	0.53	0.29	0.007
IL-8	(pg/mL)	2.10	0.95	2.56	1.57	0.043
TNF-α	(pg/mL)	1.25	0.28	1.25	0.31	0.962
Bold indicates significant difference (p < 0.05).

SpO₂ and HR showed significant negative correlations at 75, 105, 120, and 135 min during HH (r=-0.637, -0.619, -0.625 and − 0.618, respectively) (Fig. 3).

In correlation analyses of other parameters (Table 4), a significant negative correlation was seen between changes in IL-6 and SpO₂ at 135 min (r=-0.634, p = 0.020; Fig. 4) and a significant positive correlation was seen between changes in IL-6 and changes in WBC count (r = 0.545, p = 0.029; Fig. 5). A significant positive correlation was found between changes in IL-8 and changes in cortisol (r = 0.699, p = 0.003; Fig. 6). A marginal correlation was noted between changes in WBC count and SpO₂ at 135 min (r=-0.513, p = 0.073), and a significant negative correlation was identified between changes in noradrenaline and HR at 135 min (r=-0.700, p = 0.003).

Table 4

Correlation coefficients of blood components, cytokines, SpO₂ and HR.
	Aldosterone	Cortisol	Noradrenaline	IL-6	IL-8	SpO₂	HR
WBC	0.036	0.406	-0.149	0.545^*	0.100	-0.513^†	0.412
Aldosterone	-	0.391	0.077	0.050	0.346	-0.045	-0.212
Cortisol	-	-	-0.043	0.371	0.699^**	-0.247	0.179
Noradrenaline	-	-	-	-0.061	0.061	0.420	-0.700^**
IL-6	-	-	-	-	0.211	-0.634^*	0.360
IL-8	-	-	-	-	-	0.142	-0.148
SpO₂	-	-	-	-	-	-	-0.618^*
** p < 0.01; * p < 0.05; † p < 0.1
Blood data represent amount of change (post – pre) and SpO₂ and HR data represent values at end of HH (135 min).

SpO₂ was significantly decreased during HH from 60 to 135 min, while HR was increased from 75 to 150 min. These responses represent typical hemodynamic responses to HH in lowlanders. Moreover, SpO₂ and HR showed negative correlations during HH, indicating that individuals with lower SpO₂ experienced increased HR to enhance cardiac output and maintain blood oxygen levels. This suggested individual differences in adaptability to HH. These results were consistent with previous studies of lowlanders ^9,10,33 and even highlanders ^4,5. Although individual variations were seen in hemodynamic responses to HH, subjects were certainly exposed to HH and physiological changes were evoked.

On the other hand, no significant differences in SBP or DBP were seen. Under conditions of hypoxia, peripheral vascular resistance is decreased by nitric oxide released from vascular endothelial cells ³⁴, which seems to decrease blood pressure, but some studies have reported that blood pressure does not change or is even slightly increased during long and/or severe hypoxic exposure (equivalent to over 4000 m) due to chemoreflex activation of the sympathetic nervous system ^35–37. Responses of blood pressure to HH remain controversial. In this study, the level of HH was not severe and the exposure was relatively short, so blood pressures were unchanged.

All subjects showed decreases in aldosterone after HH, indicating natriuresis and diuresis completely consistent with previous studies ^16,17,38. In addition, cortisol was significantly decreased after HH. In a field study, Wood et al. ²¹ reported cortisol at rest was increased over 5150 m, but was unchanged at 3400 m and 4270 m. In addition, cortisol was subdued at 4270 m and increased at 5150 m after exercise. They suggested a threshold of HH effects for cortisol response. Cortisol secretion is stimulated by adrenocorticotropic hormone (ACTH). Mclean ³⁸ reported decreased levels of salivary cortisol and aldosterone at 4500 m, and assumed that high altitude impaired ACTH stimulation of cortisol and aldosterone secretion. Similarly, Bouissou et al. ³⁹ reported that the rise in ACTH in response to 60 min of exercise was unchanged in a climatic chamber at 3000 m compared to 0 m, but that cortisol response was subdued. They found that post-exercise ACTH and cortisol levels correlated strongly at 0 m, but not at all during HH, suggesting ACTH-driven steroidogenesis at 0 m, but some disconnect at HH with an apparent reduction in cortisol sensitivity to ACTH. Cortisol is thus increased by stress under severe HH conditions ^19,20,22, whereas mild HH conditions (up to 4000 m) might suppress cortisol secretion due to changes in steroidogenesis or sensitivity to ACTH.

Noradrenaline tended to increase during HH in this study. Many previous studies have found no changes in noradrenaline during acute HH ^23,24, but increases with chronic HH (> 1 week) ^24,40. Interestingly Rostrup et al. ²⁴ reported that noradrenaline was decreased with 2 days at 4200 m and showed a significant positive correlation between noradrenaline and SpO₂, suggesting individual variations in acclimatization to HH due to oxygen sensitivity of tyrosine hydroxylase. In the present study, a non-significant tendency toward a positive correlation was seen between noradrenaline and SpO₂. Furthermore, noradrenaline correlated strongly with HR and SpO₂ correlated negatively with HR (Table 4). These findings suggest that individuals who maintain a higher SpO₂ have higher noradrenaline levels with lower HR due to the effects of noradrenaline on α₁-adrenoreceptors ⁴¹. Although the causal direction of the relationship was unclear, our results suggest that individuals with good adaptability to HH (i.e., maintenance of higher SpO₂) maintain a lower HR via the effects of noradrenaline.

IL-6, IL-8 and WBC count were increased after HH in this study (Table 3). First, we provided evidence that inflammatory and immune responses were evoked by acute HH even with 75 min of exposure. These results are consistent with previous studies ^8,29,30. IL-6 has various functions ⁴², one of which is stimulation of WBC production and immune responses ⁴³. Similarly, IL-8 is known as a neutrophil chemoattractant ⁴⁴ and evokes angiogenesis ⁴⁵. IL-6 and IL-8 are thus treated as mediators of inflammation ^43,45,46; as a result, WBC count increased as an immune response in this study. On the other hand, previous studies have reported increases in other cytokines such as IL-1β and TNF-α with longer HH exposures ^29,30. No such changes were seen in this study. Our results thus might suggest that changes in IL-6 and IL-8 represent first responses to acute HH.

Interestingly, individual variations were seen in relationships between cytokines, cortisol and SpO₂. The relationship between IL-6 and WBC appears reasonable, with higher IL-6 inducing higher WBC count and immune responses to inflammation. The underlying mechanisms might be explained by variations in SpO₂. Lower SpO₂ was significantly associated with higher IL-6 and marginally associated with higher WBC count, suggesting that individuals with lower blood oxygen levels (low adaptability to HH) show increased inflammatory and immune responses to HH. In addition, higher IL-8 was significantly associated with higher cortisol. Cortisol levels mostly decreased after HH, and this relationship is difficult to explain. However, cortisol has anti-inflammatory effects and increases under IL-6 stimulation ⁴⁷, and cortisol exposure is known to increase IL-6 and IL-8 levels in lymphomonocytes ⁴⁸. Crosstalk interactions probably exist between cortisol and cytokines, and higher levels of IL-8 might induce secretion of cortisol to mitigate inflammation. IL-6 also showed a similar, non-significant relationship to cortisol.

With these physiological responses, the starting point seems to be lower blood oxygen levels. Individuals with lower SpO₂ evoke greater inflammatory and immune responses than those with higher SpO₂. Malacrida et al. ⁸ reported that HIF-1α, HIF-2α and NRF2 mRNA levels in WBC increased with HH (3830 m) and increased IL-6 levels and oxidative stress. They also reported negative associations between SpO₂ and IL-6, HIF-1α, HIF-2α and NRF2 mRNA levels, and suggested temporal regulation of transcription factors, inflammatory state, and oxidative stress homeostasis in humans during HH. Although we did not measure oxidative stress or levels of HIF-1α or HIF-2α, similar responses seem likely to have occurred in our study, especially among individuals with lower SpO₂. In addition, the factors underlying individual variations in SpO₂ remain unclear, although some genetic components are likely involved ^9,49. In particular, genetic variations in HIF-2α (EPAS1) are known to represent a key factor in the low hemoglobin adaptation among Tibetan highlanders ^6,50. HIF-1α and HIF-2α are also known as mediator of inflammatory and immune responses ^25,51. Some genetic variations in HIF-2α are seen in the Japanese population and might contribute to SpO₂ levels and responses to HH.

Taken together, lower SpO₂ appears to evoke various physiological responses, not only in hemodynamics, but also in hormonal, inflammatory and immune responses even with short HH exposures. While none of our subjects experienced AMS symptoms (LLS score > 3), these responses may precede AMS symptoms. A previous study also reported no associations between cytokine levels and AMS ⁵². More interestingly, complex physiological interactions and individual variations in hormonal, inflammatory and immune responses seem to be evoked by low oxygen levels in the body. Controversial results in previous studies might thus have been due to wide individual variations in such responses to HH. Cytokine storm in coronavirus disease 2019 has been speculated to involve the secretion of various cytokines, particularly IL-6 ⁵³, and our results suggest that individuals with lower SpO₂ under HH stress might be at higher risk of cytokine storm, since they may secrete more cytokines in response to hypoxia during lung inflammation. Although we examined some parameters related to lower SpO₂, further genetic and transcriptome analyses are needed to clarify the detailed physiological mechanisms and individual differences involved in responses to HH in humans.

This study showed a number of limitations. First, the small sample size limited the ability to analyze individual variations, and more data need to be accumulated. Second, blood was only sampled before and after HH for safety reasons in this study. Some hormone or cytokine levels may thus have rapidly normalized during changes in pressurization. More time points and longer HH exposures are needed for better temporal analyses of physiological responses.

In conclusion, cortisol and aldosterone were decreased and HR, IL-6, IL-8 and WBC count were increased by acute HH. Lower SpO₂ was associated with higher HR, IL-6 and WBC count, and higher IL-8 was associated with higher cortisol. These results suggest that inflammatory and immune responses are evoked even with short (75-min) HH and higher responses are evoked in individuals with lower SpO₂ (poor adaptability to HH).

Study subjects

Participants were 16 healthy male students. Mean age was 23.3 (standard deviation [SD] 2.7) years, mean height was 173.3 (6.5) cm, mean weight was 60.1 (5.7) kg and mean BMI was 20.1 (2.2) kg/m². Exclusion criteria were age < 20 years, current smoker status, current use of antioxidant or anti-inflammatory substances at baseline visit, acute illness (infectious, cardiovascular, cerebrovascular or respiratory), or any prior acute high-altitude illness. The Kyushu University Institutional Review Board for Human Genome/Gene Research approved this study protocol and all procedures were carried out in accordance with the approved guidelines. The study is also registered at UMIN (registration no. UMIN000037557). After describing the experimental procedure to potential subjects, written informed consent was obtained prior to enrolment.

Study protocol

Participants were asked to refrain from eating and drinking 2 h prior to the beginning of the study. Participants wore t-shirts and shorts, and the experiment was conducted while the individual rested in a seated position in a chair. The experimental process is shown in Fig. 1. After blood sampling, various measurement sensors were attached to the participant before the experiment and room temperature was maintained at 28°C. Participants subsequently entered the climatic chamber and physiological measurements were started. After resting for 30 min in an environment at the same air temperature, the programmed operation of the climatic chamber decreased the atmospheric pressure from about 760 mmHg (equivalent to an altitude of 0 m) to 493 mmHg (equivalent to 3500 m). This altitude-equivalent was maintained for 75 min. Atmospheric pressure in the climatic chamber was then increased to 760 mmHg in 30 min and a blood sample was drawn as soon as possible.

Measurement parameters

Height, weight, and percentage body fat were measured before the experiment. SpO₂ and heart rate (HR) measurements were sampled at 1-min intervals using a pulse oximeter (Radical-7TM; Masimo Corporation, Tokyo, Japan). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured from the left arm by a digital automatic blood pressure monitor (HEM-7210; OMRON, Kyoto, Japan). SpO₂ and HR were averaged every 15 min and blood pressure was recorded every 15 min. Lake Louise Score (LLS) was assessed as physiological values were updated to evaluate risk of AMS ⁵⁴. SpO₂ data were unavailable for 3 subjects because of equipment failure.

Fourteen-milliliter blood samples were drawn from an antecubital vein before and after HH exposure for biochemical analyses. Blood components were measured by standard assay including high-performance liquid chromatography for catecholamines and chemiluminescent immunoassay for steroid hormones (LSI Medience, Tokyo, Japan). Blood cell count (including WBC), hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, and levels of adrenaline, noradrenaline, dopamine, aldosterone and cortisol were evaluated. Serum cytokine levels were measured using a V-PLEX Proinflammatory Panel 1 human Kit (LSI Medience) to obtain data for interferon (IFN)-γ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, and TNF-α. Changes in blood components and cytokines were calculated as the value after HH minus the value before HH.

Statistical analyses

Physiological data (SpO₂, HR, SBP and DBP) were compared using one-way analysis of variance (ANOVA) with Tukey post hoc tests. Blood components and serum cytokine levels were compared between pre- and post-HH using Student’s t-test. Pearson product-moment correlation analysis was used to determine relationships between parameters. All data are expressed as mean ± SD, with values of p < 0.05 considered statistically significant. Because of missing SpO₂ data, the sample size for data related to SpO₂ was n = 13. Data were analyzed using Statistical Analysis System software (version 9.4; SAS Institute, Cary, NC, USA).

Acknowledgments

We wish to express our gratitude to Mr. Maeda Yasuhiko for operating the climatic chamber in the present study. We also wish to thank all participants and the members of our laboratory for their cooperation. This study was supported by Grants-in-Aid for Scientific Researches (17H01453, 18K14808, 21H02571 and 23H02568) from JSPS.

Author contributions

TN, TK, KN, HO, SW and TM conceived and designed the experiments. TN, MM, HT, FK, SS and SH conducted the physiological experiments and collected data. TN, MM, TK and TM wrote the paper. All authors read and approved the final manuscript.

Competing financial interests

The authors declare that they have no competing interests.

Data availability

The datasets used and analyzed during the current study available from the corresponding author on reasonable request

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No competing interests reported.

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Endocrine, inflammatory and immune responses and individual differences in acute hypobaric hypoxia in lowlanders

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