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Hypoxia is the natural trigger for endogenous EPO production but recently the use of intermittent hyperoxia to stimulate EPO has been postulated and this phenomenon has been called the "normobaric oxygen paradox" (NOP). The "NOP" is a mechanism by which oxygen regulates the expression of the Hypoxia Inducible Factor 1 alpha (HIF-1α). The HIF-1α-depending gene regulation is responsible for many different genetic expressions including EPO and VEGF. It has been proposed that relative changes of oxygen availability rather than steady state hypoxic or hyperoxic conditions, play an important role in HIF transcriptional effects. According to this hypothesis, the cell interprets the return to normoxia after a hyperoxic event as an oxygen shortage, and induces HIF-1-regulated gene synthesis, including EPO. Being both a hormone and a cytokine, the actual actions of EPO are complex; its clinical utility has been postulated for neuroprotection and cardioprotection. The precise level of inspired oxygen and the exact timeframe for its iterative administration are not totally known. N-Acetyl-L-Cysteine (NAC) supplementation has been shown to help. All the reported data demonstrate how hyperoxic and hypoxic states can potentially be manipulated if oxygen is been considered as a multifaceted molecule more than just a gas.

Erythropoiesis is affected during deep saturation dives. The mechanism should be related to a downregulation of serum Erythropoietin (s-EPO) concentration or to a toxic effect of the hyperbaric hyperoxia. We evaluated s-EPO and other haematological parameters in 6 scuba divers before, during and after a 14-days guinness saturation dive (8-10 m). Athletes were breathing air at 1.8-2 ATA, under the control of a team of physicians. Serum parameters were measured before diving (T0) and: 7 days (T1), 14 days (T2) after the beginning of the dive and 2 h (T3) and 24 h (T4) after resurfacing. Hgb, and many other haematological parameters did not change whereas Ht, s-EPO, the ratio between s-EPO predicted and that observed and reticulocytes (absolute, percent) declined progressively from T0 to T3. At T4 a significant rise in s-EPO was observed. Hgb did not vary but erythropoiesis seemed to be affected as s-EPO and reticulocyte counts showed. All these changes were statistically significant. The experiment, conducted in realistic conditions of dive length, oxygen concentration and pressure, allows us to formulate some hypotheses about the role of prolonged hyperbarism on erythropoiesis. The s-EPO rise, 24 h after resurfacing, is clearly documented and related to the "Normobaric Oxygen Paradox". This evidence suggests interesting hypotheses for new clinical applications such as modulation of s-EPO production and Hgb content triggered by appropriate O₂ administration in pre-surgical patients or in some anemic disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

Renal (peritubular) tissue hypoxia is a well-known physiological trigger for erythropoietin (EPO) production. We investigated the effect of rebound relative hypoxia after hyperoxia obtained under normo- and hyperbaric oxygen breathing conditions. A group of 16 healthy volunteers were investigated before and after a period of breathing 100% normobaric oxygen for 2 h and a period of breathing 100% oxygen at 2.5 ATA for 90 min (hyperbaric oxygen). Serum EPO concentration was measured using a radioimmunoassay at various time points during 24-36 h. A 60% increase (P < 0.001) in serum EPO was observed 36 h after normobaric oxygen. In contrast, a 53% decrease in serum EPO was observed at 24 h after hyperbaric oxygen. Those changes were not related to the circadian rhythm of serum EPO of the subjects. These results indicate that a sudden and sustained decrease in tissue oxygen tension, even above hypoxia thresholds (e.g., after a period of normobaric oxygen breathing), may act as a trigger for EPO serum level. This EPO trigger, the "normobaric oxygen paradox," does not appear to be present after hyperbaric oxygen breathing.