Hypoxia, a systemic condition defined by inadequate oxygen delivery to tissues, may arise from reduced environmental oxygen availability, as it occurs at high altitudes and in critically buried avalanche victims, or from any restriction to the oxygen flux along the oxygen cascade from atmosphere to mitochondria (Samaja the frequent coexistence of anaemia in pulmonary disease and polycythaemia in high-altitude adaptation; the contribution of systemic inflammation; and the differential handling of nitric oxide, which may profoundly shape vascular and muscular responses to hypoxemia versus hypercapnia. Addressing these issues will require experimental models that better reflect the complexity of human disease, but the most provocative implication of this article is perhaps the need to reassess CO2 from a passive by-product of metabolism to a pervasive chemical regulator of several body functions. In fact CO2 is the primary driver of ventilation via central and peripheral chemoreceptors, a key determinant of acid–base homeostasis, a critical modulator of oxygen release from haemoglobin and a tonic vasodilator, particularly in the cerebral and peripheral circulation. Importantly being CO2 produced by every nucleated cell as a product of the tricarboxylic acid cycle, it is also a ‘universal’ regulator rather than a specialized hormonal signal. Emerging evidence indicates that CO2 can modulate gene expression, inflammation and immune responses, further expanding its physiological relevance. Although its role in coronary circulation is secondary to local metabolic control, CO2 participates in coupling tissue metabolism to blood flow in multiple vascular beds and can have a detrimental role to determine cerebral hypoxia due to its effect on systemic blood, as well as cerebral perfusion pressure. CO2 also seems to elicit detrimental acute effect reducing muscle contractility in acute hypercapnia. By reframing hypoxemia and hypercapnia as biologically distinct yet intersecting stressors, the article by Balnis and Jaitovich advances our understanding of skeletal muscle dysfunction in respiratory disease and other conditions related to environmental exposure. More specifically this article emphasizes the raising need to integrate CO2 biology into models of hypoxic disease. In doing so, it provides a valuable conceptual roadmap for both basic scientists and clinicians − and invites a broader reconsideration of CO2 not merely as metabolic waste, but as a fundamental regulator of physiology both when decreased or increased. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.
Samaja et al. (Wed,) studied this question.