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\begin{document}

\title{Human Hypoxia Models: From Space Medicine to Human Pharmacological
Studies}



\author[1]{Titiaan Post}%
\author[2]{Cayla Denney}%
\author[3]{Adam Cohen}%
\author[4]{Jens Jordan}%
\author[1]{Ulrich Limper}%
\affil[1]{Institute of Aerospace Medicine, German Aerospace Center}%
\affil[2]{ Institute of Aerospace Medicine, German Aerospace Center}%
\affil[3]{DDCD Consulting and Leiden University Medical Centre}%
\affil[4]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Space medicine has developed controlled terrestrial models to
investigate the impacts on human health and performance, and their
application should be expanded to encompass disease conditions involving
hypoxia and other factors, in order to make valuable contributions to
clinical drug development. Hypoxia, a condition in which the body is
deprived of adequate oxygen supply, profoundly affects human physiology
at multiple levels and contributes to the pathogenesis of various
diseases. Experimental exposure to hypoxic conditions has gained
recognition as a valuable model for studying diseases like pulmonary
hypertension, chronic obstructive pulmonary disease (COPD), obstructive
sleep apnea (OSA), migraine, and kidney disease. The approach may be
particularly useful in mechanism-oriented early-stage clinical studies.
This review will discuss the ability to mimic or induce these conditions
in a controlled laboratory setting using hypoxia, making it a valuable
tool for testing the efficacy and safety of new pharmaceutical
interventions.%
\end{abstract}%



\sloppy


\textbf{Human Hypoxia Models: From Space Medicine to Human
Pharmacological Studies}

Titiaan E. Post\textsuperscript{1,2}, Cayla Denney\textsuperscript{1},
Adam Cohen\textsuperscript{3}, Jens Jordan\textsuperscript{1,4}, Ulrich
Limper\textsuperscript{1,5}

\emph{\textsuperscript{1}Institute of Aerospace Medicine, German
Aerospace Center (DLR), Cologne, Germany}

\emph{\textsuperscript{2}Center for Human Drug Research (CHDR), Leiden,
the Netherlands}

\emph{\textsuperscript{3}DDCD Consulting and Leiden University Medical
Centre, Leiden, The Netherlands}

\emph{\textsuperscript{4}Medical Faculty, University of Cologne,
Cologne, Germany}

\textsuperscript{5}\emph{Department of Anesthesiology and Intensive Care
Medicine, Merheim Medical Center, Hospitals of Cologne, University of
Witten/Herdecke, Cologne, Germany}

\textbf{Corresponding author:}

Jens Jordan, M.D.

Institute for Aerospace Medicine

Linder Hoehe

51147 Cologne, Germany

Phone: +49 2203 601 3115

Fax: +49 2203 69 5211

Email: jens.jordan@dlr.de



\textbf{ABSTRACT}

Space medicine has developed controlled terrestrial models to
investigate the impacts on human health and performance, and their
application should be expanded to encompass disease conditions involving
hypoxia and other factors, in order to make valuable contributions to
clinical drug development. Hypoxia, a condition in which the body is
deprived of adequate oxygen supply, profoundly affects human physiology
at multiple levels and contributes to the pathogenesis of various
diseases. Experimental exposure to hypoxic conditions has gained
recognition as a valuable model for studying diseases like pulmonary
hypertension, chronic obstructive pulmonary disease (COPD), obstructive
sleep apnea (OSA), migraine, and kidney disease. The approach may be
particularly useful in mechanism-oriented early-stage clinical studies.
This review will discuss the ability to mimic or induce these conditions
in a controlled laboratory setting using hypoxia, making it a valuable
tool for testing the efficacy and safety of new pharmaceutical
interventions.



\textbf{INTRODUCTION}

In space and in aeronautics, human beings are exposed to harsh
environmental conditions which pose risks for health and performance. An
important example is altered atmospheric pressure and composition.
Aircraft cabins and spacesuits used during extravehicular activities in
space face reduced atmospheric pressure {[}1{]}, while carbon dioxide
concentrations in spacecraft cabins can increase significantly due to
the closed environment {[}2, 3{]}. However, testing influences of these
conditions in space is difficult given the relatively low number of
astronauts and limited availability of medical and psychological testing
capabilities. Therefore, space medicine developed highly controlled
terrestrial models exposing human beings to environmental conditions
that are relevant to space or aeronautics. Influences of these
conditions on human health and performance are then investigated using
high-fidelity phenotyping. A study testing the interaction between
simulated weightlessness through head-down tilt bedrest and elevated
ambient carbon dioxide is prime example for this approach {[}4{]}. In
this review, we will discuss how this approach could be utilized in
modeling disease conditions in clinical drug development with a
particular focus on hypoxia. We will focus on commonly used human
preclinical hypoxia models and their relevance to human pathophysiology,
with the aim of providing a comprehensive analysis of the translational
gap filled by these models.

Hypoxia is a state in which the body or parts of the body are
inadequately supplied with oxygen. The condition can occur for various
reasons, including high altitude exposure, heart failure, intoxications,
anemia, chronic vascular diseases, obstructive sleep apnea (OSA), as
well as lung diseases such as cystic fibrosis, asthma and chronic
obstructive pulmonary disease (COPD) {[}5-8{]}. Oxygen plays an
essential role in human physiology as it is central to the tissues
ability to generate energy and to maintain their cellular functions
{[}9, 10{]}. Inhaled oxygen is exchanged in the lungs across the
alveolar capillary membrane and transported into the blood via passive
diffusion, which is driven by the difference in the partial pressures of
oxygen across the membrane. Oxygen is then circulated throughout the
body in the blood, primarily bound to hemoglobin, and propelled by the
heart {[}11-13{]}. Once the blood reaches the capillary beds of organs,
oxygen is again passively transferred by a partial pressure gradient
into cells. Hence, hypoxia arises when the partial pressure gradient
between alveoli and pulmonary capillaries and subsequently between
capillary beds of organs is low or when blood oxygen transport capacity
is reduced. Furthermore, hypoxia on a tissue level develops when
capillaries are rarefied, poorly perfused, or when the distance between
capillaries and cells is increased, e.g. by edema formation. As the
final electron acceptor in the electron transport chain, oxygen is
necessary for aerobic respiration which typically generates the majority
of the cell's chemical energy {[}14{]}. Thus, hypoxia arises when oxygen
levels drop and fall below energetic demands, where causing inadequate
oxygenation of tissues and a poorly regulated response can contribute to
chronic diseases {[}15{]}.

Translational science is the process of translating findings from basic
scientific research into clinical applications, and often the limiting
factor in drug development. Compounds that address specific cellular
processes involved in disease often show promise in animal and cellular
models but fail to succeed in clinical trials {[}16, 17{]}. One of the
reasons for this phenomenon is that preclinical models may not
accurately reflect the complex biology of human disease. For example,
animal models do not fully capture the genetic, physiological, and
environmental factors, particularly with regards to aging, that
contribute to a particular disease, and cellular models cannot perfectly
represent the in vivo environment {[}18{]}. Moreover, the results can be
muddled by the complex nature of chronic diseases, creating a challenge
in isolating the exact mechanisms that can be specifically targeted by
drugs. Also, adequate phase II dosing and timing studies are often
curtailed for the aim of fast clinical outcome trials {[}19{]}. This
generates the need for human models that allow the study of diseases
mechanisms in a controlled manner (Figure 1).

Experimentally induced hypoxia has the potential to serve as a valuable
research tool. Hypoxia could be used as a human disease model mimicking
or inducing the pathological responses observed in certain diseases. A
potential advantage of the approach is that hypoxia exposure can elicit
physiological responses in isolation from common confounding variables,
in controlled and measurable amounts, with graded doses, and safely in
otherwise healthy individuals. Improving the accuracy of preclinical
testing is essential for improving the success rate of new drugs in
clinical trials. Sophisticated models such as laboratory induced hypoxia
may help bridging the gap between basic research and drug testing in
patients (Figure 1).

\textbf{PHYSIOLOGICAL RESPONSE TO HYPOXIA}

The response to both acute, intermittent (repeat cycling in and out of
hypoxia), and chronic hypoxia, is sensed by chemoreceptors. Peripheral
chemoreceptors are chemical sensory cells in the aortic and carotid
bodies that are activated by changes in oxygen, carbon dioxide, and pH
levels in the blood which they communicate to the central nervous
system. The response restores homeostasis by increasing ventilation,
optimizing pulmonary ventilation-perfusion ratio, increasing cardiac
function, and raising the oxygen carrying capacity of the blood {[}20,
21{]}. In addition to optimizing gas exchange, inadequate supply
triggers hyperacute responses (seconds to minutes) of vascular beds
which are initiated by mitochondria, acting as oxygen sensor {[}22{]}. A
hypoxic vasomotor response leads to vasodilation and increased tissue
blood flow in most organs, with the exception of the lungs, where
hypoxia induces vasoconstriction. This hyperacute response is followed
by a subacute response (minutes to hours), during which the master
switch of cellular hypoxia defense, known as hypoxia-inducible factor
(HIFs), is activated. These are proteins which mediate alterations in
the expression of various hypoxia-sensitive genes such as erythropoietin
(EPO), endothelin-1 and vascular endothelial growth factor (VEGF) {[}5,
20, 23{]}. HIF's are rapidly broken down by pyrolyl-hydroxylase enzymes
under normoxic conditions, but are allowed to accumulate and alter gene
transcription under hypoxia due to the oxygen dependent activity of
their degrading enzymes. Increased EPO and VEGF expression promote
erythropoiesis and angiogenesis respectively, which augments the oxygen
delivery to cells and tissues {[}24{]}. HIF-1\selectlanguage{greek}α \selectlanguage{english}can also induce glucose
transporter genes to improve glucose transport and metabolism {[}25{]}.
Furthermore, inflammatory stimuli trigger a metabolic shift in immune
cells from oxidative phosphorylation towards glycolysis {[}26{]}.
Interestingly, HIF may also be activated under normoxic conditions, thus
hypoxia-independent, for instance in the situation of severe systemic
bacterial infection {[}27, 28{]}. Similarly, HIF activation can occur in
situations mimicking hypoxia, such as severe iron deficiency {[}29{]}.
Whereas HIF-1\selectlanguage{greek}α \selectlanguage{english}is the dominating HIF molecule during the first 24 hours
of hypoxia exposure, HIF-2\selectlanguage{greek}α \selectlanguage{english}gains dominance thereafter {[}30{]}. HIF-2\selectlanguage{greek}α
\selectlanguage{english}upregulation contributes to serious systemic diseases like pulmonary
hypertension, pulmonary and cardiac fibrosis and polycythemia {[}31{]}.
Furthermore, HIF activates the transcription of genes which are pivotal
for cancer genesis, progression and metastasis {[}32{]}.

\textbf{LEVEL-RESPONSE RELATIONSHIP AND LIMITS OF HYPOXIA TOLERANCE}

The physiological response to hypoxia involves a complex cascade of
adaptive mechanisms aimed at restoring oxygen delivery to vital organs
and maintaining cellular homeostasis. The time-dependent patterns of
physiological responses to hypoxia observed during the acclimatization
process at high altitude, are shown in Figure 2. The severity of hypoxia
determines the intensity and extent of these physiological responses
{[}33, 34{]}.

In mild hypoxia, characterized by a modest decrease in oxygen
availability, the body initiates several compensatory mechanisms to
mitigate the impact of oxygen deficiency. These responses include
activation of the sympathetic nervous system, increased ventilation to
enhance oxygen uptake in the lungs, peripheral vasodilation to
facilitate increased blood flow and oxygen delivery to organs, increased
cardiac output to ensure adequate oxygen supply, and enhanced oxygen
extraction by tissues.

As hypoxia worsens to a moderate level, additional physiological
responses come into play. The body increases red blood cell production
to enhance oxygen-carrying capacity, and cells increasingly rely on
anaerobic (glycolytic) metabolism to generate energy. This shift leads
to the production of lactate and subsequent metabolic acidosis.
Furthermore, the activation of HIFs occurs, regulating the expression of
genes involved in oxygen transport, angiogenesis, and metabolism.

In cases of severe hypoxia, where oxygen availability reaches critical
levels, the physiological responses become more pronounced. Breathing
becomes more labored with increased respiratory effort. Lactate
production further increases as reliance on anaerobic metabolism
intensifies, resulting in severe metabolic acidosis. Cognitive function
becomes impaired, resulting in confusion, impaired judgment, and
potential loss of consciousness. Cardiovascular disturbances may arise,
including arrhythmias, decreased cardiac output, and increased pulmonary
artery pressure, which can lead to organ failure.

The limits of hypoxia tolerance refer to the thresholds beyond which the
body's compensatory mechanisms are overwhelmed, resulting in critical
physiological dysfunction and potentially irreversible damage. These
limits can be conceptualized as a ''defense zone'' or a range within
which compensatory mechanisms can maintain cellular homeostasis despite
reduced oxygen availability. It has been postulated that this defence
zone lies around 35 mmHg of arterial oxygen partial pressure {[}35{]}.

It is important to recognize that individuals have different thresholds
of hypoxia tolerance, influenced by factors such as genetical
background, age, health status, physical fitness, and acclimatization
{[}36{]}. Prolonged exposure to severe hypoxia can exceed an
individual's tolerance, leading to severe complications, including organ
failure and death. Furthermore, each organ exhibits a distinctive
normoxic tissue oxygen partial pressure threshold, below which its
physiological functions become compromised: 72 mmHg for kidneys, 58 mmHg
for intestinal tissue, 41 mmHg for liver, 34 mmHg for brain, and 29 mmHg
for skeletal muscle {[}10, 37{]}.

Understanding the limits of hypoxia tolerance is crucial for assessing
risks associated with high-altitude activities, occupational settings,
and medical conditions involving hypoxia. Careful monitoring and
assessment are necessary to ensure safety and mitigate potential health
risks. However, the Operation Everest studies I - III, all performed in
hypobaric laboratory chambers, have demonstrated safety and feasibility
of exposing highly selected, healthy, young individuals, under well
controlled conditions to prolonged exposure of extreme hypoxia spanning
several weeks {[}38, 39{]}. In a series of current pilot trials,
evidence has demonstrated the safety and feasibility of subjecting not
only healthy, middle-aged individuals but also those with prior
myocardial infarction to normobaric hypoxia approaching the human
hypoxic limit {[}40-43{]}. Both kind of study series pave the way for
pharmacological studies using human hypoxia models.

\textbf{HYPOBARIC AND NORMOBARIC HYPOXIA}

There are two distinct approaches to elicit ambient hypoxia: hypobaric
hypoxia and normobaric hypoxia. In hypobaric hypoxia, as described by
the Dalton's law of partial pressures, oxygen concentration of air
remains constant at approximately 21\% but hypoxia results from reduced
ambient air pressure. In a large meta-analysis of high-altitude studies,
a linear relationship between altitude and resulting arterial oxygen
pressure could be identified for altitudes below 6000 meters. Notably,
the analysis revealed a consistent decrease in arterial oxygen partial
pressure by 1.6 kPa for every 1000 meters of altitude ascended {[}44{]}.

In normobaric hypoxia, oxygen concentration is lowered through the
addition of an inert gas, typically nitrogen, while ambient air pressure
remains unchanged. Differences in the physiological response to
hypobaric and normobaric hypoxia exist but have not yet been fully
characterised {[}45, 46{]}. Effects of reduced pressure on the middle
ear and other closed air-containing organs are evident. Important
disadvantages of hypobaric hypoxia compared with normobaric hypoxia are
that sophisticated and costly hypobaric chambers are required and that
study participants and staff cannot easily move in and out of the
hypoxia environment. Decompression to severe hypoxia may already go
along with the risk of decompression illness. Despite these challenges,
hypobaric chambers offer distinct advantages over alternative methods
for simulating hypoxia. These chambers can be used to precisely control
the level of hypoxia, which is important for studies that require
consistent and repeatable conditions. By means of air pumps, pressure
regulators, and control systems, the pressure inside the chamber can be
adjusted relatively rapidly as needed. Furthermore, hypobaric chambers
are often used for research or training programs that require large
groups to be exposed to hypoxic conditions simultaneously. On the other
hand, normobaric hypoxia is easier to implement, but requires more time
to adjust the oxygen concentrations. The nitrogen required for
normobaric hypoxia can be supplied onsite through concentrators, which
operate with molecular sieves, or from a nitrogen tank. Room-in-room
solutions for normobaric hypoxia are commercially available. For short
term applications, hypoxic gas mixtures can also be supplied through a
face mask, which offers the notable advantage of excluding the
experimenters from the condition while allowing them in close proximity
to the participants.

\textbf{INSIGHT FROM POPULATIONS DWELLING AT HIGH ALTITUDE}

Hypoxia can also serve as a model for certain adaptations that create
resilience to disease but this can only be studied by an experiment of
nature. For example, studying high-lander populations has revealed a
number of genes that allow for adaptation to chronic hypoxia {[}47{]}.
These groups, such an Andean's, Ethiopians, and Tibetans have evolved
variations in their erythrocyte homeostasis, angiogenesis,
vaso-regulation, cell death, immune response, cognition, and various
other processes that are often implicated in disease. The aforementioned
populations had adapted a lower expression of the gene EDNRB, which has
a large regulatory region of single-nucleotide polymorphisms and
transcription binding sites {[}48{]}. Mice with this gene knocked out
showed extreme hypoxia tolerance {[}49{]}. Congruently, patients with
ischemic heart disease show significantly higher levels of EDNRB and
antagonists of this gene are used to reduce induced high-altitude
pulmonary artery pressure {[}50, 51{]}. All of this evidence supports
this highlander adaptation as a valuable model for cardiac disease. Such
studies have also identified key epigenetic shifts that require further
mechanism investigation. Despite the promising translational model of
highlanders, studying these groups has its limitations; they are
difficult to access and have been isolated for long enough to have
accrued hypoxia-unrelated and thus confounding genetic differences. This
emphasizes the need to categorize variations in hypoxia related
adaptations amongst the general population as well as investigate how
easily inducible these epigenetic changes are for possible therapeutic
intervention.

\textbf{GAUGING AND MITIGATING RISKS ASSOCIATED WITH HYPOXIA EXPOSURE}

Hypoxia exposure can have negative effects on human health, with the
severity and duration of exposure combined with individual factors such
as age, health status, and activity level influencing the risks.
Cognitive impairment, cardiovascular and respiratory effects, metabolic
changes, and an increased risk of accidents and injuries are among the
potential consequences. Even mild hypoxia can cause temporary cognitive
impairment, typically starting with impaired twilight vision at
approximately 2000 meters {[}42, 52, 53{]}, while severe or prolonged
hypoxia can result in permanent brain damage and cognitive deficits
{[}54{]}. Mitigative strategies such as gradual exposure, supplemental
oxygen, hydration, and medications are recommended to reduce the risks
associated with hypoxia {[}55{]}. Different levels of hypoxia exposure
are considered safe for different populations, and individuals with
underlying medical conditions or who are pregnant may require special
precautions.

\textbf{RESPONSE TO ACUTE HYPOXIA: A Challenge to Mimic Disease}

Because hypoxia affects human physiology at multiple levels ranging from
reflex mechanisms, such as the peripheral chemoreflex, to specific
cellular pathways regulated through oxygen, experimental hypoxia could
have utility in clinical research in various settings. Tonic
chemoreceptor hyperactivity with subsequent sympathetic nervous system
activation has been implicated in the pathogenesis of arterial
hypertension {[}56{]}. Thus, peripheral chemoreceptor modulation could
have therapeutic utility in this condition, particularly in patients not
responding sufficiently to established therapies {[}57{]}. Recent
studies demonstrated that acute hypoxia during high-resolution
functional magnetic resonance imaging (fMRI) can be used to trace
peripheral chemoreceptor responses in human beings {[}58{]}. Because
changes in CO\textsubscript{2} confound the response to hypoxic
peripheral chemoreceptor stimulation, isocapnic hypoxia protocols have
been proven useful in clinical research {[}59{]}.

Acute hypoxia can also be used to test the tolerance in patients or
those in occupational settings such as in fighter pilots. Moreover,
hypoxia may produce a phenotype resembling a clinical condition, which
could then be utilized to probe new therapies. However, hypoxia may also
regulate a disease-relevant signaling pathway. Indeed, hypoxia plays a
major role in a multitude of human diseases, either as a result of the
disease, like in the case of pulmonary dysfunction, or by modifying the
disease process as seen in some forms of cancer, where local hypoxia may
affect differentiation of the tumor to more aggressive phenotypes
{[}60{]}.

\textbf{PULMONARY ARTERIAL HYPERTENSION}

\emph{Pathophysiological background of the disease}

Pulmonary arterial hypertension is a serious, progressive vasculopathy
of the lungs of different aetiologies. Patients experience dyspnea,
fatigue, exercise intolerance, syncope and edema. An increased arterial
pulmonary pressure is the result of an increased vascular resistance of
the pulmonary vessels.

There are five main classifications of both acute and chronic mechanisms
that can provoke pulmonary arterial hypertension. One group contains
idiopathic and hereditary forms of primary vascular pathologies with
normal lung function and basically no cardiopulmonary comorbidities.
These patients show only mild to no hypoxia {[}61{]}. Other forms of
pulmonary arterial hypertension are the result of failure of the left
heart, chronic thromboembolic disease or of mixed or unknown origin.
Because these disease forms do not originate from the pulmonary system,
they are less suitable to be modelled by a human hypoxia platform. This
model is better suited for the types of pulmonary arterial hypertension
caused primarily by impaired lung functions or hypoxia, like COPD,
interstitial lung disease, sleep-disordered breathing, and chronic
exposure to high altitude.

\emph{Disease mechanisms which can be modelled with experimental
hypoxia}

Systemic hypoxic stress, as seen at high altitude or in a hypoxia
chamber, leads to hypoxic pulmonary vasoconstriction and a large
increase in pulmonary arterial pressure. Pulmonary arterial hypertension
up to 66 mmHg systolic arterial pressure has been safely induced over
weeks in healthy individuals by normobaric hypoxia {[}40{]}. Pulmonary
arterial hypertension at altitude is not a disease per se, but it can
cause a life-threatening condition if it progresses into high-altitude
pulmonary edema. Studies in mountaineers have revealed that the
vasoactive factors that are involved in the development of the hypoxic
pulmonary vasoconstriction at altitude are also responsible for the
pulmonary arterial hypertension in patients. Chronic sojourn at high
altitude may eventually result in pulmonary arterial hypertension and,
remodeling of the pulmonary vasculature and right heart failure.

Pulmonary arterial hypertension is caused by a disbalance between
vasodilatory and vasoconstrictive factors. Relative to healthy
individuals, patients with pulmonary hypertension have reduced levels of
the key vasodilators nitric oxide (NO), its second messenger cGMP, and
prostacyclin while vasoconstrictors endothelin-1 and thromboxane A2 are
increased. Additionally, the production of reactive oxygen species is
increased, which is caused by the induction of oxidase systems {[}62{]}.

\emph{Open questions which can be addressed with human hypoxia models}

Human hypoxia models would be particularly suitable for the testing of
pharmacological interventions for pulmonary arterial hypertension that
share arterial hypoxia caused by high altitude or by underlying
pulmonary disease, as it captures the fundamental pathophysiological
mechanism underlying the increased pulmonary vascular resistance.
Considering that home oxygen therapy is often effective in reducing
dyspnea and improving physical capacity in these conditions, it can be
extrapolated that clinical trials under controlled ambient hypoxia can
serve as a meaningful research tool. Episodes of desaturation during
sleep is another trait of pulmonary arterial hypertension, which could
be easily modelled by periodic reduction of ambient oxygen.

The 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension call on to perform more studies on the responses of
patients with pulmonary arterial hypertension at altitude {[}63{]}. 120
million people worldwide live above 2500 meters. Because research at
geographic altitude can be a logistical challenge, these conditions
could be perfectly simulated under the optimal conditions of a
laboratory human hypoxia model.

\emph{Limitations of the pulmonary arterial hypertension hypoxia model}

There are some limitations to the human hypoxia model for investigating
pulmonary arterial hypertension that must be carefully addressed. Whilst
arterial hypoxia and increased pulmonary vascular resistance can be
effectively modelled, other disease characteristics are less
reproducible. The duration of the experimental hypoxic exposition will
not be long enough to induce relevant pulmonary remodelling in healthy
participants. Trials should therefore aim to investigate acute responses
in the vasculature liker oxygen metabolism, and the hypoxia-induced
inflammation and fibrosis. Furthermore, pulmonary arterial hypertension
related comorbidities should be carefully considered. Patients with
chronic pulmonary arterial hypertension may develop right heart
insufficiency, which proceeds to alter the physiology of the whole
cardio-circulatory system. Healthy participants will maintain right
heart function with higher cardiac outputs than pulmonary arterial
hypertension patients.

\textbf{CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)}

\emph{Pathophysiological background of the disease}

COPD encompasses inflammatory diseases that cause structural
abnormalities to the airways and or pulmonary parenchyma {[}64{]},
usually caused by smoking or inhaled particulates {[}65{]}. Pronounced
ventilation-perfusion inequalities within poorly ventilated, yet
well-perfused alveoli, result in hypoxemia and, in certain patients,
hypercapnia {[}66{]}. As the disease progresses, inflammation-induced
hyperplasia of respiratory glands significantly increases the production
of viscoid mucus, leading to the obstruction of both smaller and larger
airways. Consequently, this obstruction culminates in hypoxia and
respiratory endothelial cell failure. Cough and dyspnea represent the
primary symptoms of this condition. Hypoxic respiratory endothelial
cells in COPD lungs exhibit an increased sodium absorption, attributed
to the upregulated expression of epithelial Na+ channels (ENaC),
consequently leading to mucus thickening {[}67{]}. Paradoxically, the
opposite effect has been observed in healthy individuals who developed
high altitude pulmonary edema. In these individuals, hypoxia reduced
transepithelial sodium transport mediated by ENaC, resulting in the
accumulation of fluid in the alveoli {[}68{]}.

COPD is associated with systemic inflammation and numerous
comorbidities, most notably cardiovascular disease {[}69, 70{]}. Hypoxia
plays a vital role in this process because the increase in the HIF
cascade stimulates angiogenesis within atherosclerotic plaques {[}69{]}.
There is a vicious cycle between the COPD-induced inflammation and
hypoxia where inflammation increases metabolic demand and hypoxia
increases the levels of reactive oxidative species, an inflammatory
agent. In mice, the combination of a high/fat diet and chronic
intermittent hypoxia has been shown to have a significant negative
impact on atherosclerosis {[}6{]}. However, the direct effect of hypoxia
in connecting COPD and atherosclerosis in the absence of associated
inflammation requires further investigation, which could be addressed
through laboratory-induced hypoxia studies.

\emph{Disease mechanisms which can be modelled with experimental
hypoxia}

By isolating the effects of hypoxia in the absence of inflammation,
laboratory-induced hypoxia studies can provide insights into the direct
relationship between hypoxia and atherosclerosis. Additionally, human
hypoxia models can be utilized to study respiratory failure in COPD
{[}71{]}. Type I respiratory failure, characterized by a
ventilation/perfusion mismatch with normal or low arterial partial
pressure of oxygen (PaCO\textsubscript{2}) levels and a reduced arterial
partial pressure of oxygen (PaO\textsubscript{2}), can be modeled using
hypoxia in combination with hypocapnia or isocapnia. Type II respiratory
failure, characterized by elevated PaCO\textsubscript{2} levels and
reduced PaO\textsubscript{2} levels, can be modeled using hypoxia and
hypercapnia conditions. Human hypoxia models offer the opportunity to
optimize treatment strategies during these phases of the disease.

\emph{Open questions which can be addressed with human hypoxia models}

Human hypoxia models can help address several open questions in COPD
research. The direct impact of hypoxia on the development of
atherosclerosis in COPD, independent of associated inflammation, can be
investigated. The effects of different levels and durations of hypoxic
exposure on COPD progression, exacerbations, and the underlying
mechanisms can also be explored {[}72{]}. Furthermore, the optimization
of treatments for respiratory failure in COPD during both type I and
type II phases can be studied using human hypoxia models.

\emph{Limitations of the COPD hypoxia model}

It should be noted that the model may not fully replicate the complex
pathophysiology of COPD: as the disease involves multiple factors beyond
hypoxia, such as chronic inflammation, respiratory endothelial failure
and airway remodeling. Additionally, individual variations and
comorbidities associated with COPD, including cardiovascular diseases,
may influence the response to hypoxia and limit generalizability.
Cautious interpretation and consideration of these limitations are
necessary when using the COPD hypoxia model.

\textbf{CENTRAL \& OBSTRUCTIVE SLEEP APNEA (CSA \& OSA)}

\emph{Pathophysiological background of the diseases}

In central sleep apnea (CSA) a dysfunctional respiratory drive results
in apnea events during sleep. These events appear periodically together
with phases of hyperventilation. CSA is common in patients with heart
failure. OSA is a sleep disorder characterized by recurrent episodes of
cessation of airflow, with or without partial or complete upper airway
obstruction during sleep, leading to disruptions in normal breathing
patterns. The obstruction results in intermittent hypoxia and
hypercapnia, as well as sleep fragmentation. OSA is primarily caused by
anatomical and physiological factors that contribute to airway collapse,
such as obesity, anatomical abnormalities, and decreased upper airway
muscle tone. Newer data also suggest a pathomechanism in OSA that is
dependent on respiratory drive {[}73{]}. The repetitive episodes of
hypoxia and hypercapnia trigger physiological responses, including
sympathetic activation, systemic inflammation, oxidative stress, and
endothelial dysfunction {[}74{]}. These responses contribute to the
development of neurocognitive, cardiovascular and metabolic
comorbidities commonly associated with OSA, such as daytime sleepiness,
hypertension, coronary artery disease, and insulin resistance {[}75{]}.

\emph{Disease mechanisms which can be modelled with experimental
hypoxia}

Above 2000 meters, sleep in hypobaric and normobaric hypoxia produces a
characteristic periodic breathing pattern, similar to central sleep
apnea, which is called Cheyne-Stokes breathing (Figure 3). The apnea
hypopnoea index is directly proportionally associated with increasing
sleeping altitude whereas mean oxygen saturation during sleep is
inversely associated {[}76{]}.

Intermittent hypoxia, which mirrors the repetitive cycles of hypoxia and
reoxygenation experienced by individuals with OSA during sleep can be
used to model OSA. This modeling approach allows researchers to study
the effects of intermittent hypoxia on various physiological processes.
Oxidative stress, another important mechanism in OSA, can be replicated
through hypoxia-induced imbalance between reactive oxygen species
production and neutralization. Furthermore, hypoxia-induced inflammation
and endothelial dysfunction, key contributors to OSA-related
complications, can be investigated by simulating the inflammatory
responses and impaired vascular function associated with hypoxia
exposure. It is important for hypoxia models to accurately replicate the
intermittent nature of hypoxia during sleep and consider the specific
characteristics of OSA, including upper airway obstruction and sleep
architecture. Controlling the duration and severity of hypoxia exposure
is crucial to mimic the varying degrees of intermittent hypoxia observed
in OSA patients. By employing hypoxia as a modeling tool, researchers
can gain valuable insights into the underlying disease mechanisms of OSA
and its associated complications, paving the way for the development of
targeted therapeutic strategies.

\emph{Open questions which can be addressed with human hypoxia models}

The animal and human models used to study OSA through intermittent
hypoxia induction are inadequate as they do not fully represent all
aspects of the disease {[}77{]}. Researchers are therefore seeking
better models to gain a deeper understanding of the underlying
mechanisms. The healthy human model of OSA is continually evolving, with
some limitations that can be resolved through technological adjustments.
To maximize construct validity, experiments should be conducted
overnight on sleeping participants rather than during the waking hours
{[}78{]}. Secondly, the intermittent hypoxia model must include
hypercapnia, which is present during obstruction in OSA. Thirdly, the
dose and duration of intermittent hypoxia used in healthy human models
should be equivalent to moderate to severe OSA, with mild to moderate
OSA and equivalent intermittent hypoxia providing beneficial
physiological stimuli {[}79{]}. Fourthly, the experimental model's
intermittent hypoxia should mimic the disease's characteristic slow
desaturation and rapid re-saturation of oxygen during obstructive
events, as opposed to the current model with a square-wave design of
rapid desaturation and re-saturation. Lastly, full polysomnography is
necessary to characterize sleep architecture, including frequent brain
arousals. The use of dial-down CPAP during sleep can induce upper airway
obstruction and negative intrathoracic pressure swings, thus creating an
experimental model that closely simulates OSA {[}80{]}. However, this
technique is labor-intensive, invasive, and risky. The experimental
model for OSA should be tailored to the research question at hand and
may or may not require the complete simulation of OSA.

\emph{Limitations of the OSA hypoxia model}

There are notable construct barriers such as how the model primarily
focuses on the hypoxic aspect of OSA and may not fully capture the
complexities of other contributing factors, such as airway collapse and
sleep fragmentation. Additionally, the duration and frequency of hypoxic
exposure in experimental settings may not perfectly replicate the
intermittent hypoxia experienced during sleep apnea episodes. Individual
variations and comorbidities in OSA patients, as well as the influence
of sleep architecture, may affect the response to hypoxia and limit
generalizability. Therefore, careful interpretation and consideration of
these limitations are necessary when using the OSA hypoxia model.

\textbf{MIGRAINE}

\emph{Pathophysiological background of the disease}

Recurrent migraine is a common, debilitating, and highly elusive
disorder that is notoriously difficult to treat. The condition is
characterized by recurrent, enduring, unilateral, and pulsating
headaches often accompanied by nausea, light and sound sensitivity, and
sometimes preceded by a period of altered sensory experience (often
visual hallucination) called auras. The origin of migraine is argued to
be vascular and/or neurogenic but this is still under investigation
{[}81{]}, but the aura symptoms are known to result from a wave of
neuron depolarization and subsequent depression propagating across the
cortex, whereas the pain results from the activation of the
trigeminovascular system and meningeal blood vessels, both through
unconfirmed mechanisms {[}82{]}.

\emph{Disease mechanisms which can be modelled with experimental
hypoxia}

Symptoms of acute mountain sickness, a disease of the brain which is
developed by individuals who ascent to high altitudes to fast, are often
migraine-like and include headache, nausea and vomiting {[}83{]}. An
association between migraine and hypoxia has been suggested for patients
with patent foramen ovale (a hole between the left and right atria of
the heart). In these patients, who also suffer from migraine,
PaO\textsubscript{2} was lower than in healthy controls and normobaric
oxygen treatment attenuated the frequency and severity of their
migraines {[}84{]}. Furthermore, hypoxia has been shown to act as a
reliable trigger for a complete physiological migraine {[}85-87{]}.
Frank et al. used normobaric hypoxia at 12.6\% oxygen for 6 hours which
triggered migraines in 80\% of participants with over 16\% presenting
with aura {[}85{]}. Schoonman et al. showed that hypoxia was a more
reliable migraine trigger than nitroglycerine, which is the current
experimental standard {[}87{]}. Hypoxia also offers a major safety
advantage over the pharmacological models as it can be easily reversed
at any point in the trial, whereas a dose of nitroglycerine cannot be
withdrawn and requires the addition of a second medication like triptans
to terminate its effects {[}88{]}. However, this phenomenon is under
investigated as the few existing studies have relatively small
population sizes. Migraine research can greatly benefit from a greater
emphasis on hypoxia, both as a dependable and physiologically accurate
trigger for interventional studies and as a window into the causational
mechanism.

Experimental hypoxia models have been utilized to study various disease
mechanisms associated with migraine. One such mechanism is cortical
spreading depression (CSD), a wave of neuronal depolarization and
subsequent depression that spreads across the cerebral cortex {[}89{]}.
CSD has been implicated in the generation of migraine aura and is
hypothesized to contribute to the initiation and propagation of migraine
attacks. Hypoxia-induced CSD models have provided insights into the
underlying mechanisms and potential therapeutic targets for migraine
{[}90{]}. Furthermore, experimental hypoxia can be used to investigate
the role of oxygen levels in modulating neurovascular function and the
release of neurotransmitters, such as serotonin and CGRP, which are
involved in migraine pathophysiology {[}91{]}. Hypoxia models allow
researchers to examine the effects of reduced oxygen levels on cerebral
blood flow, vascular reactivity, and neuroinflammatory processes,
providing valuable information about the interplay between hypoxia and
migraine mechanisms.

\emph{Open questions which can be addressed with human hypoxia models}

Human hypoxia models offer a unique opportunity to address several open
questions in migraine research. For instance, the impact of hypoxia on
the trigeminovascular system and its contribution to migraine attacks
can be studied in controlled settings. Understanding how hypoxia affects
the release of vasoactive substances, neuronal excitability, and the
propagation of CSD can provide insights into the triggers and mechanisms
of migraine. Additionally, human hypoxia models can shed light on the
interplay between hypoxia and other migraine triggers, such as stress,
exercise, or sleep disturbances {[}92{]}. Investigating how hypoxia
interacts with these triggers and influences migraine susceptibility can
help uncover the complex interactions between multiple factors involved
in migraine pathogenesis. Furthermore, studying the effects of hypoxia
on sensory processing and perception may provide insights into the
mechanisms underlying migraine-associated sensory hypersensitivity
{[}93{]}.

\emph{Limitations of the migraine hypoxia model}

Despite having strong advantages over the leading pharmacologically
induced model, the hypoxia-induced models may not fully replicate the
complex and multifactorial nature of migraine attacks. Migraine is a
heterogeneous disorder with various triggers and individual variations,
which may not be fully captured in experimental settings. Furthermore,
it is challenging to directly translate findings from hypoxia models to
clinical practice. The severity, duration, and frequency of
hypoxia-induced migraine-like symptoms may differ from those experienced
during spontaneous migraine attacks. Moreover, hypoxia models may not
fully capture the contributions of other key mechanisms involved in
migraine, such as genetic factors, cortical excitability, or
neuroinflammatory processes. These aspects require further investigation
using complementary approaches, including genetic studies, advanced
neuroimaging techniques, and animal models. Overall, experimental
hypoxia models provide valuable insights into specific aspects of
migraine pathophysiology, they should be interpreted in the context of
the broader understanding of the disease and its multifaceted nature.

\textbf{KIDNEY FUNCTION}

\emph{Pathophysiological background of the disease}

The oxygen sensors in the kidney control the hematocrit, produce
erythropoietin in the cortex, and are able to translate tissue oxygen
pressure into a measure of plasma volume {[}94{]}. However, in severe
hypoxia below pO\textsubscript{2} 40 mmHg, glomerular filtration rate
declines, leading to sodium retention and water retention {[}95, 96{]}.
Hence, renal function in chronic respiratory failure, like OSA or COPD,
is often impaired and these patients show fluid and sodium retention
{[}97{]}. This excess retention has also been described at high
altitude, especially in altitude maladapted individuals {[}98{]}. The
effect of hypoxia on patients with impaired renal function can be
studied in hypoxia models and this would have implications for
determining their risks of long air travel or dwelling at high altitude.

\emph{Disease mechanisms which can be modelled with experimental
hypoxia}

Experimental hypoxia models have been used to study the mechanisms
underlying kidney dysfunction. Hypoxia, or reduced oxygen availability,
can occur in various renal diseases due to impaired blood flow,
ischemia, or inadequate oxygenation {[}99{]}. Hypoxia can trigger
cellular responses, including the activation of hypoxia-inducible
factors (HIFs), which play a crucial role in adaptive mechanisms to
maintain cellular homeostasis under low-oxygen conditions {[}100{]}.
Experimental hypoxia models can simulate and study the impact of reduced
oxygen levels on kidney cells and tissues, providing insights into the
molecular and cellular responses involved in renal hypoxia-related
diseases.

Furthermore, experimental hypoxia models allow researchers to
investigate the effects of hypoxia on renal blood flow, glomerular
filtration rate, tubular function, and electrolyte handling. These
models can simulate renal ischemia-reperfusion injury, a common cause of
acute kidney injury, and elucidate the mechanisms underlying renal
tissue damage, inflammation, and impaired renal function in hypoxic
conditions.

\emph{Open questions which can be addressed with human hypoxia models}

Human hypoxia models offer valuable opportunities to address several
open questions regarding kidney function and hypoxia-related diseases.
These models can help elucidate the cellular and molecular responses of
the kidneys to hypoxic stress in real-time, providing insights into the
adaptive mechanisms and potential therapeutic targets. Furthermore,
human hypoxia models can aid in studying the interplay between hypoxia
and other factors contributing to kidney disease progression, such as
oxidative stress, inflammation, and metabolic disturbances.

By utilizing human hypoxia models, researchers can investigate the
effects of controlled oxygen levels on specific renal cell types,
including proximal tubular cells, podocytes, and endothelial cells
{[}101{]}. This can enhance our understanding of the impact of hypoxia
on cellular metabolism, cell death pathways, and cellular communication
within the renal microenvironment. Additionally, human hypoxia models
can help explore the potential benefits of oxygen-based therapies and
interventions in kidney diseases {[}102{]}.

\emph{Limitations of the kidney function hypoxia model}

Despite its utility, the kidney function hypoxia model has several
limitations that should be acknowledged. First, the model oversimplifies
the complex pathophysiological processes involved in renal hypoxia. The
kidney is a highly intricate organ with multiple cell types, intricate
blood supply, and complex regulatory mechanisms. The model's simplified
representation may not fully capture the intricacies of these processes
and their interactions.

Second, the model relies on experimental hypoxia models, which may not
perfectly replicate the conditions seen in human kidney diseases.
Experimental models often involve controlled and acute hypoxia, whereas
human kidney diseases often involve chronic and multifactorial hypoxia.
Therefore, extrapolating findings from experimental models to human
conditions should be done cautiously.

Third, the model primarily focuses on the role of hypoxia in kidney
dysfunction, overlooking other contributing factors. Kidney diseases are
multifactorial, and hypoxia is just one piece of the puzzle. Other
factors such as inflammation, oxidative stress, immune responses, and
genetic factors also play significant roles in kidney disease
development and progression. Neglecting these factors in the model may
limit its ability to provide a comprehensive understanding of kidney
dysfunction.

Lastly, the model's generalizability may be limited. Human kidney
diseases exhibit considerable heterogeneity, and the response to hypoxia
can vary among individuals and disease subtypes. The model may not fully
capture this heterogeneity and may not be applicable to all kidney
disease scenarios.

\textbf{APPLICATIONS OF SPACE MEDICINE MODELS IN CLINICAL RESEARCH}

Human hypoxia models, which are the focus of this review, offer a tool
for studying various physiological processes and diseases. These models
have gained popularity, particularly for replicating hypoxic conditions
in healthy humans and studying the effects of hypoxia on the body in a
controlled manner. One promising application of hypoxia models is in
cancer research, as tumor cells are known to thrive in low-oxygen
environments. Similarly, hypoxia models could aid in the study of
cardiovascular and neurological diseases, which are also characterized
by a decrease in oxygen supply to tissues. Furthermore, by understanding
how the body responds to hypoxia in extreme environments such as high
altitudes and space travel, researchers could develop new ways to
improve human health in the future. There is a need for more
standardisation and validation of the different published models
{[}103{]}. Overall, healthy human hypoxia models offer significant
potential for advancing our understanding of various diseases and
physiological processes. However, other human models developed for space
medicine may also have applications for human drug development. A good
example are head-down tilt bedrest studies, which produces
musculoskeletal and cardiovascular deconditioning as well as cephalad
fluid shifts resembling those produced by real weightlessness {[}104{]}.

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