Physiological and Clinical Impact of Repeated Inhaled Oxygen Variation on Erythropoietin Levels in Patients After Surgery

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.

Increasing Oxygen Partial Pressures Induce a Distinct Transcriptional Response in Human PBMC: A Pilot Study on the “Normobaric Oxygen Paradox”

The term “normobaric oxygen paradox” (NOP), describes the response to the return to normoxia after a hyperoxic event, sensed by tissues as oxygen shortage, and resulting in up-regulation of the Hypoxia-inducible factor 1α (HIF-1α) transcription factor activity. The molecular characteristics of this response have not been yet fully characterized. Herein, we report the activation time trend of oxygen-sensitive transcription factors in human peripheral blood mononuclear cells (PBMCs) obtained from healthy subjects after one hour of exposure to mild (MH), high (HH) and very high (VHH) hyperoxia, corresponding to 30%, 100%, 140% O2, respectively. Our observations confirm that MH is perceived as a hypoxic stress, characterized by the activation of HIF-1α and Nuclear factor (erythroid-derived 2)-like 2 (NRF2), but not Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). Conversely, HH is associated to a progressive loss of NOP response and to an increase in oxidative stress leading to NRF2 and NF-kB activation, accompanied by the synthesis of glutathione (GSH). After VHH, HIF-1α activation is totally absent and oxidative stress response, accompanied by NF-κB activation, is prevalent. Intracellular GSH and Matrix metallopeptidase 9 (MMP-9) plasma levels parallel the transcription factors activation pattern and remain elevated throughout the observation time. In conclusion, our study confirms that, in vivo, the return to normoxia after MH is sensed as a hypoxic trigger characterized by HIF-1α activation. On the contrary, HH and VHH induce a shift toward an oxidative stress response, characterized by NRF2 and NF-κB activation in the first 24 h post exposure.

A diurnal carbon engine explains 13C-enriched carbonates without increasing the global production of oxygen

In the past 3 billion years, significant volumes of carbonate with high carbon-isotopic (δ13C) values accumulated on shallow continental shelves. These deposits frequently are interpreted as records of elevated global organic carbon burial. However, through the stoichiometry of primary production, organic carbon burial releases a proportional amount of O2, predicting unrealistic rises in atmospheric pO2 during the 1 to 100 million year-long positive δ13C excursions that punctuate the geological record. This carbon–oxygen paradox assumes that the δ13C of shallow water carbonates reflects the δ13C of global seawater-dissolved inorganic carbon (DIC). However, the δ13C of modern shallow-water carbonate sediment is higher than expected for calcite or aragonite precipitating from seawater. We explain elevated δ13C in shallow carbonates with a diurnal carbon cycle engine, where daily transfer of carbon between organic and inorganic reservoirs forces coupled changes in carbonate saturation (ΩA) and δ13C of DIC. This engine maintains a carbon-cycle hysteresis that is most amplified in shallow, sluggishly mixed waters with high rates of photosynthesis, and provides a simple mechanism for the observed δ13C-decoupling between global seawater DIC and shallow carbonate, without burying organic matter or generating O2.

Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling

The molecular oxygen (O2) paradox was coined to describe its essential nature and toxicity. The latter characteristic of O2is associated with the formation of reactive oxygen species (ROS), which can damage structures vital for cellular function. Mammals are equipped with antioxidant systems to fend off the potentially damaging effects of ROS. However, under certain circumstances antioxidant systems can become overwhelmed leading to oxidative stress and damage. Over the past few decades, it has become evident that ROS, specifically H2O2, are integral signaling molecules complicating the previous logos that oxyradicals were unfortunate by-products of oxygen metabolism that indiscriminately damage cell structures. To avoid its potential toxicity whilst taking advantage of its signaling properties, it is vital for mitochondria to control ROS production and degradation. H2O2elimination pathways are well characterized in mitochondria. However, less is known about how H2O2production is controlled. The present review examines the importance of mitochondrial H2O2in controlling various cellular programs and emerging evidence for how production is regulated. Recently published studies showing how mitochondrial H2O2can be used as a secondary messenger will be discussed in detail. This will be followed with a description of how mitochondria use S-glutathionylation to control H2O2production.

Oxidised protein metabolism: recent insights

The ‘oxygen paradox’ arises from the fact that oxygen, the molecule that aerobic life depends on, threatens its very existence. An oxygen-rich environment provided life on Earth with more efficient bioenergetics and, with it, the challenge of having to deal with a host of oxygen-derived reactive species capable of damaging proteins and other crucial cellular components. In this minireview, we explore recent insights into the metabolism of proteins that have been reversibly or irreversibly damaged by oxygen-derived species. We discuss recent data on the important roles played by the proteasomal and lysosomal systems in the proteolytic degradation of oxidatively damaged proteins and the effects of oxidative damage on the function of the proteolytic pathways themselves. Mitochondria are central to oxygen utilisation in the cell, and their ability to handle oxygen-derived radicals is an important and still emerging area of research. Current knowledge of the proteolytic machinery in the mitochondria, including the ATP-dependent AAA+ proteases and mitochondrial-derived vesicles, is also highlighted in the review. Significant progress is still being made in regard to understanding the mechanisms underlying the detection and degradation of oxidised proteins and how proteolytic pathways interact with each other. Finally, we highlight a few unanswered questions such as the possibility of oxidised amino acids released from oxidised proteins by proteolysis being re-utilised in protein synthesis thus establishing a vicious cycle of oxidation in cells.