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).