Influence of High Hemoglobin-Oxygen Affinity on Humans During Hypoxia

Humans elicit a robust series of physiological responses to maintain adequate oxygen delivery during hypoxia, including a transient reduction in hemoglobin-oxygen (Hb-O2) affinity. However, high Hb-O2 affinity has been identified as a beneficial adaptation in several species that have been exposed to high altitude for generations. The observed differences in Hb-O2 affinity between humans and species adapted to high altitude pose a central question: is higher or lower Hb-O2 affinity in humans more advantageous when O2 availability is limited? Humans with genetic mutations in hemoglobin structure resulting in high Hb-O2 affinity have shown attenuated cardiorespiratory adjustments during hypoxia both at rest and during exercise, providing unique insight into this central question. Therefore, the purpose of this review is to examine the influence of high Hb-O2 affinity during hypoxia through comparison of cardiovascular and respiratory adjustments elicited by humans with high Hb-O2 affinity compared to those with normal Hb-O2 affinity.

Dose- and Sex-Dependent Changes in Hemoglobin Oxygen Affinity by the Micronutrient 5-Hydroxymethylfurfural and α-Ketoglutaric Acid

5-Hydroxymethylfurfural (5-HMF) is known to increase hemoglobin oxygen affinity (Hb–O2 affinity) and to induce a left shift of the oxygen dissociation curve (ODC). It is under investigation as a therapeutic agent in sickle cell anemia and in conditions where pulmonary oxygen uptake is deteriorated or limited (e.g., various clinical conditions or altitude exposure). The combination of 5-HMF and α-ketoglutaric acid (αKG) is commercially available as a nutritional supplement. To further elucidate dose effects, ODCs were measured in vitro in venous whole blood samples of 20 healthy volunteers (10 female and 10 male) after the addition of three different doses of 5-HMF, αKG and the combination of both. Linear regression analysis revealed a strong dose-dependent increase in Hb–O2 affinity for 5-HMF (R2 = 0.887; p < 0.001) and the commercially available combination with αKG (R2 = 0.882; p < 0.001). αKG alone increased Hb–O2 affinity as well but to a lower extent. Both the combination (5-HMF + αKG) and 5-HMF alone exerted different P50 and Hill coefficient responses overall and between sexes, with more pronounced effects in females. With increasing Hb–O2 affinity, the sigmoidal shape of the ODC was better preserved by the combination of 5-HMF and αKG than by 5-HMF alone. Concerning the therapeutic effects of 5-HMF, this study emphasizes the importance of adequate dosing in various physiological and clinical conditions, where a left-shifted ODC might be beneficial. By preserving the sigmoidal shape of the ODC, the combination of 5-HMF and αKG at low (both sexes) and medium (males only) doses might be able to better maintain efficient oxygen transport, particularly by mitigating potentially deteriorated oxygen unloading in the tissue. However, expanding knowledge on the interaction between 5-HMF and Hb–O2 affinity in vitro necessitates further investigations in vivo to additionally assess pharmacokinetic mechanisms.

Features of ozone effect on oxygen-dependent processes in the blood under hypoxic conditions

Introduction. Ozone is a physiological factor that can change hemoglobin oxygen affinity and the formation of gaseous transmitters (NO, H2S). The aim is to study the effect of ozone with gaseous transmitters donors on oxygen-dependent processes in the blood under hypoxic conditions in vitro. Materials and methods. Blood samples were divided into 6 groups of 3 ml each. Groups 2, 4, 5, 6 were pretreated with a deoxygenating gas mixture (5.5 % CO2; 94.5 % N2). In groups 3, 4, 5, 6, ozonized isotonic sodium chloride solution (with an ozone concentration of 6 mg/l) was added, and in groups 5 and 6, the donors of gas transmitters nitroglycerin and sodium hydrosulfide, respectively, were additionally introduced. Results. Pre-deoxygenation reduces the effect of ozone on oxygen transport in the blood. Nitroglycerin prevents this effect. The action of ozone under hypoxic conditions leads to an increase of content of NO3-/NO2- and H2S, and combination with nitroglycerin and sodium hydrosulfide increase these parameters. Deoxygenation due to ozone reduces parameters of lipid peroxidation (malonic dialdehyde, diene conjugates), retinol and α-tocopherol, and the same result in the nitroglycerin group. Conclusion. Under hypoxic conditions, a decrease in the effect of ozone on oxygen-dependent processes is reported. Nitroglycerin reduces its manifestation, while sodium hydrosulfide does not have a similar effect.

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

Evolved increases in hemoglobin-oxygen affinity and the Bohr effect coincided with the aquatic specialization of penguins

Dive capacities of air-breathing vertebrates are dictated by onboard O2 stores, suggesting that physiologic specialization of diving birds such as penguins may have involved adaptive changes in convective O2 transport. It has been hypothesized that increased hemoglobin (Hb)-O2 affinity improves pulmonary O2 extraction and enhances the capacity for breath-hold diving. To investigate evolved changes in Hb function associated with the aquatic specialization of penguins, we integrated comparative measurements of whole-blood and purified native Hb with protein engineering experiments based on site-directed mutagenesis. We reconstructed and resurrected ancestral Hb representing the common ancestor of penguins and the more ancient ancestor shared by penguins and their closest nondiving relatives (order Procellariiformes, which includes albatrosses, shearwaters, petrels, and storm petrels). These two ancestors bracket the phylogenetic interval in which penguin-specific changes in Hb function would have evolved. The experiments revealed that penguins evolved a derived increase in Hb-O2 affinity and a greatly augmented Bohr effect (i.e., reduced Hb-O2 affinity at low pH). Although an increased Hb-O2 affinity reduces the gradient for O2 diffusion from systemic capillaries to metabolizing cells, this can be compensated by a concomitant enhancement of the Bohr effect, thereby promoting O2 unloading in acidified tissues. We suggest that the evolved increase in Hb-O2 affinity in combination with the augmented Bohr effect maximizes both O2 extraction from the lungs and O2 unloading from the blood, allowing penguins to fully utilize their onboard O2 stores and maximize underwater foraging time.

The Fundamentals of Respiratory Physiology to Manage the COVID-19 Pandemic: An Overview

The growing coronavirus disease (COVID-19) crisis has stressed worldwide healthcare systems probably as never before, requiring a tremendous increase of the capacity of intensive care units to handle the sharp rise of patients in critical situation. Since the dominant respiratory feature of COVID-19 is worsening arterial hypoxemia, eventually leading to acute respiratory distress syndrome (ARDS) promptly needing mechanical ventilation, a systematic recourse to intubation of every hypoxemic patient may be difficult to sustain in such peculiar context and may not be deemed appropriate for all patients. Then, it is essential that caregivers have a solid knowledge of physiological principles to properly interpret arterial oxygenation, to intubate at the satisfactory moment, to adequately manage mechanical ventilation, and, finally, to initiate ventilator weaning, as safely and as expeditiously as possible, in order to make it available for the next patient. Through the expected mechanisms of COVID-19-induced hypoxemia, as well as the notion of silent hypoxemia often evoked in COVID-19 lung injury and its potential parallelism with high altitude pulmonary edema, from the description of hemoglobin oxygen affinity in patients with severe COVID-19 to the interest of the prone positioning in order to treat severe ARDS patients, this review aims to help caregivers from any specialty to handle respiratory support following recent knowledge in the pathophysiology of respiratory SARS-CoV-2 infection.