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normobaric oxygen paradox

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Costantino Balestra
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The “Normobaric Oxygen Paradox” (NOP) is a physiologic mechanism that induces an increase of endogenous erythropoietin (EPO) production by creating a state of relative hypoxia in subjects previously exposed to hyperoxia, followed by a rapid return to normoxia. Oxygen exposure duration and inspired oxygen fraction required to observe a significant increase in EPO or hemoglobin are not clearly defined. Consequently, we here study the effect of one model of relative hypoxia on EPO, reticulocytes and hemoglobin stimulation in patients after surgery. Patients were prospectively randomized in two groups. The O2 group (n = 10) received 100% oxygen for 1 h per day for eight consecutive days, via a non-rebreathing mask. The control group (n = 12) received no oxygen variation. Serum EPO, hemoglobin and reticulocyte count were measured on admission and postoperatively on days seven and nine. Percentage EPO at day nine with respect to the baseline value was significantly elevated within the groups [O2 group: 323.7 (SD ± 139.0); control group: 365.6 (SD± 162.0)] but not between them. No significant difference was found between the groups in terms of reticulocytes count and hemoglobin. Our NOP model showed no difference on EPO increase between the two groups. However, both groups expressed separately significant EPO elevation.
Costantino Balestra
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Depending on the oxygen partial pressure in a tissue, the therapeutic effect of oxygenation can vary from simple substance substitution up to hyperbaric oxygenation when breathing hyperbaric oxygen at 2.5–3.0 ATA. Surprisingly, new data showed that it is not only the oxygen supply that matters as even a minimal increase in the partial pressure of oxygen is efficient in triggering cellular reactions by eliciting the production of hypoxia-inducible factors and heat-shock proteins. Moreover, it was shown that extreme environments could also interact with the genome; in fact, epigenetics appears to play a major role in extreme environments and exercise, especially when changes in oxygen partial pressure are involved. Hyperbaric oxygen therapy is, essentially, “intermittent oxygen” exposure. We must investigate hyperbaric oxygen with a new paradigm of treating oxygen as a potent stimulus of the molecular network of reactions.
Costantino Balestra
added 2 research items
Inflammation is an adaptive response to both external and internal stimuli including infection, trauma, surgery, ischemia-reperfusion, or malignancy. A number of studies indicate that physical activity is an effective means of reducing acute systemic and low-level inflammation occurring in different pathological conditions and in the recovery phase after disease. As a proof-of-principle, we hypothesized that low-intensity workout performed under modified oxygen supply would elicit a “metabolic exercise” inducing a hormetic response, increasing the metabolic load and oxidative stress with the same overall effect expected after a higher intensity or charge exercise. Herein, we report the effect of a 5-week low-intensity, non-training, exercise program in a group of young healthy subjects in combination with the exposure to hyperoxia (30% and 100% pO2, respectively) or light hypoxia (15% pO2) during workout sessions on several inflammation and oxidative stress parameters, namely hemoglobin (Hb), redox state, nitric oxide metabolite (NOx), inducible nitric oxide synthase (iNOS), inflammatory cytokine expression (TNF-α, interleukin (IL)-6, IL-10), and renal functional biomarkers (creatinine, neopterin, and urates). We confirmed our previous reports demonstrating that intermittent hyperoxia induces the normobaric oxygen paradox (NOP), a response overlapping the exposure to hypoxia. Our data also suggest that the administration of modified air composition is an expedient complement to a light physical exercise program to achieve a significant modulation of inflammatory and immune parameters, including cytokines expression, iNOS activity, and oxidative stress parameters. This strategy can be of pivotal interest in all those conditions characterized by the inability to achieve a sufficient workload intensity, such as severe cardiovascular alterations and articular injuries failing to effectively gain a significant improvement of physical capacity.
Exercise generates reactive oxygen species (ROS), creating a redox imbalance towards oxidation when inadequately intense. Normobaric and hyperbaric oxygen (HBO) breathed while not exercising induces antioxidant enzymes expression, but literature is still poor. Twenty-two athletes were assigned to five groups: controls; 30%, or 50% O2; 100% O2 (HBO) at 1.5 or 2.5 atmosphere absolute (ATA). Twenty treatments were administered on non-training days. Biological samples were collected at T0 (baseline), T1 (end of treatments), and T2 (1 month after) to assess ROS, antioxidant capacity (TAC), lipid peroxidation, redox (amino-thiols) and inflammatory (IL-6, 10, TNF-α) status, renal function (i.e., neopterin), miRNA, and hemoglobin. At T1, O2 mixtures and HBO induced an increase of ROS, lipid peroxidation and decreased TAC, counterbalanced at T2. Furthermore, 50% O2 and HBO treatments determined a reduced state in T2. Neopterin concentration increased at T1 breathing 50% O2 and HBO at 2.5 ATA. The results suggest that 50% O2 treatment determined a reduced state in T2; HBO at 1.5 and 2.5 ATA similarly induced protective mechanisms against ROS, despite the latter could expose the body to higher ROS levels and neopterin concentrations. HBO resulted in increased Hb levels and contributed to immunomodulation by regulating interleukin and miRNA expression.
David De Bels
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Oxygenation conditions are crucial for growth and tumor progression. Recent data suggests a decrease in cancer cell proliferation occurring after exposure to normobaric hyperoxia. Those changes are associated with fractal dimension. The purpose of this research was to study the impact of hyperoxia on apoptosis and morphology of leukemia cell lines. Two hematopoietic lymphoid cancer cell lines (a T-lymphoblastoid line, JURKAT and a B lymphoid line, CCRF-SB) were tested under conditions of normobaric hyperoxia (FiO2 > 60%, ± 18h) and compared to a standard group (FiO2 = 21%). We tested for apoptosis using a caspase-3 assay. Cell morphology was evaluated by cytospin, microphotography after coloration, and analysis by a fractal dimension calculation software. Our results showed that exposure of cell cultures to transient normobaric hyperoxia induced apoptosis (elevated caspase-3) as well as significant and precocious modifications in cell complexity, as highlighted by increased fractal dimensions in both cell lines. These features are associated with changes in structure (pycnotic nucleus and apoptosis) recorded by microscopic analysis. Such morphological alterations could be due to several molecular mechanisms and rearrangements in the cancer cell, leading to cell cycle inhibition and apoptosis as shown by caspase-3 activity. T cells seem less resistant to hyperoxia than B cells.
David De Bels
added a research item
A novel approach to increasing erythropoietin (EPO) using oxygen (O2) (the 'normobaric oxygen paradox') has been reported in healthy volunteers. We investigated whether the EPO increase is sufficient to induce erythropoiesis by comparing two protocols of O2 administration. We compared the effect of daily versus alternate days 100% O2, breathed for 30 minutes, on haemoglobin concentrations during a 12-day period. Nine subjects underwent the two protocols six weeks apart. We observed a significant increase in haemoglobin (as a percentage of baseline) in the alternate-days group compared to the daily group and to baseline after four days (105.5 ∓ 5.7 % vs. 99.6 ∓ 3.3 % difference from baseline; P < 0.01). At the end of the experimental period, haemoglobin values increased significantly compared to baseline in both groups. There was a significant percentage rise in reticulocyte count in the alternate-days group compared to the daily group (182 ∓ 94 % vs. 93 ∓ 34 %; P < 0.001). The normobaric oxygen paradox seems effective in increasing haemoglobin in non-anaemic, healthy volunteers, providing sufficient time is allowed between O2 applications. The exact time interval is not clearly defined by this study but should probably be at least or greater than two days. Further studies are needed to define more precisely clinical applications in the use of O2 as a pharmaceutical agent.