Adaptation to Hypoxia: A Chimera?

Dear Colleagues,

The Chimera was, according to Greek mythology, a monstrous fire-breathing hybrid creature of Lycia in Asia Minor, composed of the parts of more than one animal. Hence, the term "chimera" has come to describe anything composed of very disparate parts, or perceived as wildly imaginative, implausible, or dazzling (adapted from Wikipedia).

A world-relevant clinical and environment issue that affects millions of people, hypoxia, i.e., the insufficient supply of oxygen with respect to demand, constitutes an important source of social and economic distress. Despite hypoxia representing a potentially lethal condition, the human body possesses reserves that enable the recruitment of defense mechanisms to grant survival during relatively acute episodes. Clearly, however, when sustained or chronic, hypoxia is predicted to request a greater effort to balance its harmful effects, despite a longer time allowed to recruit gene-based and proteomic compensatory mechanisms. Chronic exposure to stressors, however, implies the concept of adaptation, or the “modification of an organism or its parts that makes it more fit for existence under the conditions of its environment: a heritable physical or behavioral trait that serves a specific function and improves an organism's fitness or survival” (Merriam-Webster Dictionary). Because at least some of the biological systems that constitute complex living matter have limited regenerative capacity, such as the cerebral and cardiopulmonary systems, the concept of adaptation is, therefore, particularly relevant, but several unanswered undeveloped questions, arise:

1. How can we assess the onset of adaptation? In other words, which physiological (e.g., blunted erythropoiesis, control of alkalemia due to excess ventilation, recovery of body’s homeostasis), molecular (e.g., normalization of NO stores, recruitment of hypoxia-sensitive genes and proteins), pathological (e.g., weight at birth, resistance against cardiopulmonary diseases, integrity of the cerebral function) best represent a target of adaptation?
2. Does adaptation invest the whole body or can some organs/functions become better or faster adapted than others? This question may be linked to other important sub-questions: (1) Why are some populations better adapted than others, for example, Tibetan vs. South American dwellers? (2) How do Ethiopians, Kirgiz, long-term inhabitants of the Antarctica rank with respect to the mentioned Tibetan and South Americans dwellers? (3) Why do comparable degrees of hypoxia in some categories of patients lead to deleterious consequences, for example, blue babies and patients with COPD or pulmonary hypertension?
3. Sometimes, high-altitude people opt to reside at lower altitudes. Can adaptation work in a reverse mode by enabling altitude-adapted people to survive relatively oxygen-rich atmospheres?
4. Is adaptation always a positive factor, or are there instances where adaptation, or better maladaptation, might lead to deleterious patterns?
5. Are factors such as the degree of activity, intermittent exposure to different oxygen levels, and life habits critical to enabling better and faster adaptation? Is there a role for the hypoxia-induced oxidative stress in these patterns?
6. Is the classical HIF-1a pathway sufficient to explain the complexity of the responses to chronic hypoxia and to enable adaptive patterns?
7. Are appropriate biomarkers available to assess the degree of adaptation, or the lack of adaptation to hypoxia?

We believe that answering these questions may enable us to understand whether humans, who underwent a genetical selection as a low-altitude population, may ever be able to adapt to either environmental or pathological hypoxia, or if hypoxia adaptation is and will remain a chimera.

Prof. Dr. Michele Samaja
Dr. Giuseppina Milano
Guest Editors

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