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).