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Aim: Numerous studies have shown that H 2 S serves as an acute oxygen sensor in a variety of cells. We hypothesize that H 2 S also serves in extended oxygen sensing., Methods: Here, we compare the effects of extended exposure (24-48 hours) to varying O 2 tensions on H 2 S and polysulphide metabolism in human embryonic kidney (HEK 293), human adenocarcinomic alveolar basal epithelial (A549), human colon cancer (HTC116), bovine pulmonary artery smooth muscle, human umbilical-derived mesenchymal stromal (stem) cells and porcine tracheal epithelium (PTE) using sulphur-specific fluorophores and fluorometry or confocal microscopy., Results: All cells continuously produced H 2 S in 21% O 2 and H 2 S production was increased at lower O 2 tensions. Decreasing O 2 from 21% to 10%, 5% and 1% O 2 progressively increased H 2 S production in HEK293 cells and this was partially inhibited by a combination of inhibitors of H 2 S biosynthesis, aminooxyacetate, propargyl glycine and compound 3. Mitochondria appeared to be the source of much of this increase in HEK 293 cells. H 2 S production in all other cells and PTE increased when O 2 was lowered from 21% to 5% except for HTC116 cells where 1% O 2 was necessary to increase H 2 S, presumably reflecting the hypoxic environment in vivo. Polysulphides (H 2 S n , where n = 2-7), the key signalling metabolite of H 2 S also appeared to increase in many cells although this was often masked by high endogenous polysulphide concentrations., Conclusion: These results show that cellular H 2 S is increased during extended hypoxia and they suggest this is a continuously active O 2 -sensing mechanism in a variety of cells., (© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

In lung epithelial cells, hypoxia decreases the expression and activity of sodium-transporting molecules, thereby reducing the rate of transepithelial sodium absorption. The mechanisms underlying the sensing of hypoxia and subsequent coupling to sodium-transporting molecules remain unclear. Hydrogen sulfide (H2S) has recently been recognized as a cellular signaling molecule whose intracellular concentrations critically depend on oxygen levels. Therefore, it was questioned whether endogenously produced H2S contributes to hypoxic inhibition of sodium transport. In electrophysiological Ussing chamber experiments, hypoxia was established by decreasing oxygen concentrations in the chambers. Hypoxia concentration dependently and reversibly decreased amiloride-sensitive sodium absorption by cultured H441 monolayers and freshly dissected porcine tracheal epithelia due to inhibition of basolateral Na(+)/K(+)-ATPase. Exogenous application of H2S by the sulfur salt Na2S mimicked the effect of hypoxia and inhibited amiloride-sensitive sodium absorption by both tissues in an oxygen-dependent manner. Hypoxia increased intracellular concentrations of H2S and decreased the concentration of polysulfides. Pretreatment with the cystathionine-γ-lyase inhibitor d/l-propargylglycine (PAG) decreased hypoxic inhibition of sodium transport by H441 monolayers, whereas inhibition of cystathionine-β-synthase (with aminooxy-acetic acid; AOAA) or 3-mercaptopyruvate sulfurtransferase (with aspartate) had no effect. Inhibition of all of these H2S-generating enzymes with a combination of AOAA, PAG, and aspartate decreased the hypoxic inhibition of sodium transport by H441 cells and pig tracheae and decreased H2S production by tracheae. These data suggest that airway epithelial cells endogenously produce H2S during hypoxia, and this contributes to hypoxic inhibition of transepithelial sodium absorption., (Copyright © 2016 the American Physiological Society.)

Stepwise one-electron reduction of oxygen to water produces reactive oxygen species (ROS) that are chemically and biochemically similar to reactive sulfide species (RSS) derived from one-electron oxidations of hydrogen sulfide to elemental sulfur. Both ROS and RSS are endogenously generated and signal via protein thiols. Given the similarities between ROS and RSS, we wondered whether extant methods for measuring the former would also detect the latter. Here, we compared ROS to RSS sensitivity of five common ROS methods: redox-sensitive green fluorescent protein (roGFP), 2', 7'-dihydrodichlorofluorescein, MitoSox Red, Amplex Red, and amperometric electrodes. All methods detected RSS and were as, or more, sensitive to RSS than to ROS. roGFP, arguably the "gold standard" for ROS measurement, was more than 200-fold more sensitive to the mixed polysulfide H2Sn(n = 1-8) than to H2O2 These findings suggest that RSS may be far more prevalent in intracellular signaling than previously appreciated and that the contribution of ROS may be overestimated. This conclusion is further supported by the observation that estimated daily sulfur metabolism and ROS production are approximately equal and the fact that both RSS and antioxidant mechanisms have been present since the origin of life, nearly 4 billion years ago, long before the rise in environmental oxygen 600 million years ago. Although ROS are assumed to be the most biologically relevant oxidants, our results question this paradigm. We also anticipate our findings will direct attention toward development of novel and clinically relevant anti-(RSS)-oxidants., (Copyright © 2016 the American Physiological Society.)

Significance: Although oxygen (O2)-sensing cells and tissues have been known for decades, the identity of the O2-sensing mechanism has remained elusive. Evidence is accumulating that O2-dependent metabolism of hydrogen sulfide (H2S) is this enigmatic O2 sensor., Recent Advances: The elucidation of biochemical pathways involved in H2S synthesis and metabolism have shown that reciprocal H2S/O2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O2 controls H2S inactivation, and the effects of H2S on downstream signaling events are consistent with those activated by hypoxia. H2S-mediated O2 sensing has been demonstrated in a variety of O2-sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors., Critical Issues: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H2S and its metabolites., Future Directions: Development of specific inhibitors of H2S metabolism and effector activation as well as cellular organelle-targeted compounds that release H2S in a time- or environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications.

H2S derived from organic thiol metabolism has been proposed serve as an oxygen sensor in a variety of systems because of its susceptibility to oxidation and its ability to mimic hypoxic responses in numerous oxygen-sensing tissues. Thiosulfate, an intermediate in oxidative H2S metabolism can alternatively be reduced and regenerate H2S. We propose that this contributes to the H2S-mediated oxygen-sensing mechanism. H2S formation from thiosulfate in buffers and in a variety of mammalian tissues and in lamprey dorsal aorta was examined in real time using a polarographic H2S sensor. Inferences of intracellular H2S production were made by examining hypoxic pulmonary vasoconstriction (HPV) in bovine pulmonary arteries under conditions in which increased H2S production would be expected and in mouse and rat aortas, where reducing conditions should mediate vasorelaxation. In Krebs-Henseleit (mammalian) and Cortland (lamprey) buffers, H2S was generated from thiosulfate in the presence of the exogenous reducing agent, DTT, or the endogenous reductant dihydrolipoic acid (DHLA). Both the magnitude and rate of H2S production were greatly increased by these reductants in the presence of tissue, with the most notable effects occurring in the liver. H2S production was only observed when tissues were hypoxic; exposure to room air, or injecting oxygen inhibited H2S production and resulted in net H2S consumption. Both DTT and DHLA augmented HPV, and DHLA dose-dependently relaxed precontracted mouse and rat aortas. These results indicate that thiosulfate can contribute to H2S signaling under hypoxic conditions and that this is not only a ready source of H2S production but also serves as a means of recycling sulfur and thereby conserving biologically relevant thiols.

The ability to monitor oxygen (O2) availability and delivery is crucial to an animal's survival. Vertebrates have a number of O2 'sensing' cells that monitor environmental oxygen and ensure adequate delivery to the tissues. While there is little doubt that these cells perform important homeostatic functions, there is little consensus on how a change in O2 concentration, or partial pressure (pO2), is transduced into a physiological response. We recently proposed that the metabolism of hydrogen sulfide (H2S) functions as the O2 sensor in a variety of tissues. In this mechanism, the concentration of biologically active H2S is regulated by the simple balance between constitutive H2S production and its oxidation by mitochondria. This hypothesis is supported by a number of experimental observations in a wide range of O2 sensing tissues: 1) exogenous H2S produces the same physiological response as hypoxia; 2) cellular H2S production is inversely related to pO2 at physiologically relevant pO2s; 3) agonists and antagonists of H2S biosynthesis augment and inhibit hypoxic responses, respectively; and 4) H2S and hypoxia appear to act via common effector pathways. The reciprocal relationship between H2S and O2 also has a long evolutionary history suggesting these gases have been inexorably intertwined throughout evolution. The intent of this review is to elaborate on the mechanism of H2S-mediated O2 sensing.

The role of the gaseous mediator hydrogen sulfide (H2S) in hemorrhagic shock is still a matter of debate. This debate is emphasized by the fact that available literature data on blood and tissue H2S concentrations vary by three orders of magnitude, both under physiological conditions as well as during stress states. Therefore, in a rat model of unresuscitated, lethal hemorrhagic shock, Van de Louw and Haouzi tested the two hypotheses of whether blood and tissue H2S levels would increase due to the shock-related tissue hypoxia, and whether vitamin B12 would attenuate organ injury and improve survival as a result of enhanced H2S oxidation. Hemorrhage did not affect the blood and tissue H2S content, and, despite the increased capacity to oxidize H2S, vitamin B12 did not affect any parameter of shock severity. The authors concluded that H2S concentrations cannot be used as a marker of shock, most probably as a result of tissue's capacity to oxidize H2S even under conditions of severe oxygen debt. This research paper elegantly re-adjusts the currently available data on blood and tissue H2S levels, and thereby adds an important piece to the puzzle of whether H2S release should be enhanced or lowered during stress conditions associated with tissue hypoxia.

Sulfur is a versatile molecule with oxidation states ranging from -2 to +6. From the beginning, sulfur has been inexorably entwined with the evolution of organisms. Reduced sulfur, prevalent in the prebiotic Earth and supplied from interstellar sources, was an integral component of early life as it could provide energy through oxidization, even in a weakly oxidizing environment, and it spontaneously reacted with iron to form iron-sulfur clusters that became the earliest biological catalysts and structural components of cells. The ability to cycle sulfur between reduced and oxidized states may have been key in the great endosymbiotic event that incorporated a sulfide-oxidizing α-protobacteria into a host sulfide-reducing Archea, resulting in the eukaryotic cell. As eukaryotes slowly adapted from a sulfidic and anoxic (euxinic) world to one that was highly oxidizing, numerous mechanisms developed to deal with increasing oxidants; namely, oxygen, and decreasing sulfide. Because there is rarely any reduced sulfur in the present-day environment, sulfur was historically ignored by biologists, except for an occasional report of sulfide toxicity. Twenty-five years ago, it became evident that the organisms in sulfide-rich environments could synthesize ATP from sulfide, 10 years later came the realization that animals might use sulfide as a signaling molecule, and only within the last 4 years did it become apparent that even mammals could derive energy from sulfide generated in the gastrointestinal tract. It has also become evident that, even in the present-day oxic environment, cells can exploit the redox chemistry of sulfide, most notably as a physiological transducer of oxygen availability. This review will examine how the legacy of sulfide metabolism has shaped natural selection and how some of these ancient biochemical pathways are still employed by modern-day eukaryotes.

There is considerable controversy surrounding the initial step that transduces a fall in [Formula: see text] into a physiological signal, i.e., the "oxygen sensor" in chemoreceptors. Initial studies on systemic and respiratory vessels suggested that the metabolism of hydrogen sulfide (H(2)S) could serve as the oxygen sensor. This model was subsequently extended to chemoreceptors in fish and tissues of other animals. In this model, constitutive production of biologically active H(2)S is offset by H(2)S oxidation; when oxygen availability falls, production of H(2)S exceeds metabolism, and the resultant increase in intracellular H(2)S initiates the appropriate physiological responses. This model is supported by observations that the effects of hypoxia and H(2)S are similar, if not identical in many tissues: hypoxic responses are inhibited by inhibitors of H(2)S biosynthesis and augmented by sulfur donating molecules, and the tipping point between H(2)S production and oxidation occurs at physiologically relevant [Formula: see text] . Recent studies from other laboratories support this mechanism of O(2) sensing in the carotid body. This review summarizes information that supports the H(2)S metabolic hypothesis in these tissues with emphasis on the carotid chemoreceptors. Evidence suggesting that H(2)S is not involved in oxygen sensing in the carotid body is also critically evaluated., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H(2)S) has been shown to affect gastrointestinal (GI) motility and signaling in mammals and O(2)-dependent H(2)S metabolism has been proposed to serve as an O(2) 'sensor' that couples hypoxic stimuli to effector responses in a variety of other O(2)-sensing tissues. The low P(O2) values and high H(2)S concentrations routinely encountered in the GI tract suggest that H(2)S might also be involved in hypoxic responses in these tissues. In the present study we examined the effect of H(2)S on stomach, esophagus, gallbladder and intestinal motility in the rainbow trout (Oncorhynchus mykiss) and coho salmon (Oncorhynchus kisutch) and we evaluated the potential for H(2)S in oxygen sensing by examining GI responses to hypoxia in the presence of known inhibitors of H(2)S biosynthesis and by adding the sulfide donor cysteine (Cys). We also measured H(2)S production by intestinal tissue in real time and in the presence and absence of oxygen. In tissues exhibiting spontaneous contractions, H(2)S inhibited contraction magnitude (area under the curve and amplitude) and frequency, and in all tissues it reduced baseline tension in a concentration-dependent relationship. Longitudinal intestinal smooth muscle was significantly more sensitive to H(2)S than other tissues, exhibiting significant inhibitory responses at 1-10 μmol l(-1) H(2)S. The effects of hypoxia were essentially identical to those of H(2)S in longitudinal and circular intestinal smooth muscle; of special note was a unique transient stimulatory effect upon application of both hypoxia and H(2)S. Inhibitors of enzymes implicated in H(2)S biosynthesis (cystathionine β-synthase and cystathionine γ-lyase) partially inhibited the effects of hypoxia whereas the hypoxic effects were augmented by the sulfide donor Cys. Furthermore, tissue production of H(2)S was inversely related to O(2); addition of Cys to intestinal tissue homogenate stimulated H(2)S production when the tissue was gassed with 100% nitrogen (~0% O(2)), whereas addition of oxygen (~10% O(2)) reversed this to net H(2)S consumption. This study shows that the inhibitory effects of H(2)S on the GI tract of a non-mammalian vertebrate are identical to those reported in mammals and they provide further evidence that H(2)S is a key mediator of the hypoxic response in a variety of O(2)-sensitive tissues.

Vertebrate cardiorespiratory homeostasis is inextricably dependent upon specialized cells that provide feedback on oxygen status in the tissues, blood, and on occasion, environment. These "oxygen sensing" cells include chemoreceptors and oxygen-sensitive chromaffin cells that initiate cardiorespiratory reflexes, vascular smooth muscle cells that adjust perfusion to metabolism or ventilation, and other cells that condition themselves in response to episodic hypoxia. Identification of how these cells sense oxygen and transduce this into the appropriate physiological response has enormous clinical applicability, but despite intense research there is no consensus regarding the initial hypoxia-effector coupling mechanism. This review examines an alternative mechanism of oxygen sensing using oxidation of endogenously produced hydrogen sulfide (H(2)S) as the O(2)-sensitive couple. Support for this hypothesis includes the similarity of effects of hypoxia and H(2)S on a variety of tissues, augmentation of hypoxic responses by precursors of H(2)S production and their inhibition by inhibitors of H(2)S synthesis, and the rapid consumption of H(2)S by O(2) in the range of intracellular/mitochondrial Po(2). These studies also indicate that, under normoxic conditions, it is doubtful that free H(2)S has longer than a transient existence in tissue or extracellular fluid.

Hypoxic pulmonary vasoconstriction (HVC), an intrinsic and assumed ubiquitous response of mammalian pulmonary blood vessels, matches regional ventilation to perfusion via an unknown O(2)-sensing mechanism. Global pulmonary hypoxia experienced by individuals suffering from chronic obstructive pulmonary disease or numerous hypoventilation syndromes, including sleep apnea, often produces maladaptive pulmonary hypertension, but pulmonary hypertension is not observed in diving mammals, where profound hypoxia is routine. Here we examined the response of cow and sea lion pulmonary arteries (PA) to hypoxia and observed the expected HVC in the former and a unique hypoxic vasodilation in resistance vessels in the latter. We then used this disparate response to examine the O(2)-sensing mechanism. In both animals, exogenous H(2)S mimicked the vasoactive effects of hypoxia in isolated PA. H(2)S-synthesizing enzymes, cystathionine beta-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate sulfur transferase, were identified in lung tissue from both animals by one-dimensional Western blot analysis and immunohistochemistry. The relationship between H(2)S production/consumption and O(2) was examined in real time by use of amperometric H(2)S and O(2) sensors. H(2)S was produced by sea lion and cow lung homogenate in the absence of O(2), but it was rapidly consumed when O(2) was present. Furthermore, consumption of exogenous H(2)S by cow lung homogenate, PA smooth muscle cells, and heart mitochondria was O(2) dependent and exhibited maximal sensitivity at physiologically relevant Po(2) levels. These studies show that HVC is not an intrinsic property of PA and provide further evidence for O(2)-dependent H(2)S metabolism in O(2) sensing.

Although all cells are variously affected by oxygen, a few have the responsibility of monitoring oxygen tensions and initiating key homeostatic responses when P(O2) falls to critical levels. These ;oxygen-sensing' cells include the chemoreceptors in the gills (neuroepithelial cells), airways (neuroepithelial bodies) and vasculature (carotid bodies) that initiate cardiorespiratory reflexes, oxygen sensitive chromaffin cells associated with systemic veins or adrenal glands that regulate the rate of catecholamine secretion, and vascular smooth muscle cells capable of increasing blood flow to systemic tissues, or decreasing it through the lungs. In spite of intense research, and enormous clinical applicability, there is little, if any, consensus regarding the mechanism of how these cells sense oxygen and transduce this into the appropriate physiological response. We have recently proposed that the metabolism of hydrogen sulfide (H2S) may serve as an 'oxygen sensor' in vertebrate vascular smooth muscle and preliminary evidence suggests it has similar activity in gill chemoreceptors. In this proposed mechanism, the cellular concentration of H2S is determined by the simple balance between constitutive H2S production in the cytoplasm and H2S oxidation in the mitochondria; when tissue oxygen levels fall the rate of H2S oxidation decreases and the concentration of biologically active H2S in the tissue increases. This commentary briefly describes the oxygen-sensitive tissues in fish and mammals, delineates the current hypotheses of oxygen sensing by these tissues, and then critically evaluates the evidence for H2S metabolism in oxygen sensing.

O2 chemoreceptors elicit cardiorespiratory reflexes in all vertebrates, but consensus on O2-sensing signal transduction mechanism(s) is lacking. We recently proposed that hydrogen sulfide (H2S) metabolism is involved in O2 sensing in vascular smooth muscle. Here, we examined the possibility that H2S is an O2 sensor in trout chemoreceptors where the first pair of gills is a primary site of aquatic O2 sensing and the homolog of the mammalian carotid body. Intrabuccal injection of H2S in unanesthetized trout produced a dose-dependent bradycardia and increased ventilatory frequency and amplitude similar to the hypoxic response. Removal of the first, but not second, pair of gills significantly inhibited H2S-mediated bradycardia, consistent with the loss of aquatic chemoreceptors. mRNA for H2S-synthesizing enzymes, cystathionine beta-synthase and cystathionine gamma-lyase, was present in branchial tissue. Homogenized gills produced H2S enzymatically, and H2S production was inhibited by O2, whereas mitochondrial H2S consumption was O2 dependent. Ambient hypoxia did not affect plasma H2S in unanesthetized trout, but produced a PO2-dependent increase in a sulfide moiety suggestive of increased H2S production. In isolated zebrafish neuroepithelial cells, the putative chemoreceptive cells of fish, both hypoxia and H2S, produced a similar approximately 10-mV depolarization. These studies are consistent with H2S involvement in O2 sensing/signal transduction pathway(s) in chemoreceptive cells, as previously demonstrated in vascular smooth muscle. This novel mechanism, whereby H2S concentration ([H2S]) is governed by the balance between constitutive production and oxidation, tightly couples tissue [H2S] to PO2 and may provide an exquisitely sensitive, yet simple, O2 sensor in a variety of tissues.

Hydrogen sulfide (H(2)S) has been proposed to mediate hypoxic vasoconstriction (HVC), however, other studies suggest the vasoconstrictory effect indirectly results from an oxidation product of H(2)S. Here we examined the relationship between H(2)S and O(2) in isolated hagfish and lamprey vessels that exhibit profound hypoxic vasoconstriction. In myographic studies, H(2)S (Na(2)S) dose-dependently constricted dorsal aortas (DA) and efferent branchial arteries (EBA) but did not affect ventral aortas or afferent branchial arteries; effects similar to those produced by hypoxia. Sensitivity of H(2)S-mediated contraction in hagfish and lamprey DA was enhanced by hypoxia. HVC in hagfish DA was enhanced by the H(2)S precursor cysteine and inhibited by amino-oxyacetate, an inhibitor of the H(2)S-synthesizing enzyme, cystathionine beta-synthase. HVC was unaffected by propargyl glycine, an inhibitor of cystathionine lambda-lyase. Oxygen consumption (M(O(2))) of hagfish DA was constant between 15 and 115 mmHg P(O(2)) (1 mmHg=0.133 kPa), decreased when P(O(2)) <15 mmHg, and increased after P(O(2)) exceeded 115 mmHg. 10 micromol l(-1) H(2)S increased and > or =100 micromol l(-1) H(2)S decreased M(O(2)). Consistent with the effects on HVC, cysteine increased and amino-oxyacetate decreased M(O(2)). These results show that H(2)S is a monophasic vasoconstrictor of specific cyclostome vessels and because hagfish lack vascular NO, and vascular sensitivity to H(2)S was enhanced at low P(O(2)), it is unlikely that H(2)S contractions are mediated by either H(2)S-NO interaction or an oxidation product of H(2)S. These experiments also provide additional support for the hypothesis that the metabolism of H(2)S is involved in oxygen sensing/signal transduction in vertebrate vascular smooth muscle.

How vertebrate blood vessels sense acute hypoxia and respond either by constricting (hypoxic vasoconstriction) or dilating (hypoxic vasodilation) has not been resolved. In the present study we compared the mechanical and electrical responses of select blood vessels to hypoxia and H2S, measured vascular H2S production, and evaluated the effects of inhibitors of H2S synthesis and addition of the H2S precursor, cysteine, on hypoxic vasoconstriction and hypoxic vasodilation. We found that: (1) in all vertebrate vessels examined to date, hypoxia and H2S produce temporally and quantitatively identical responses even though the responses vary from constriction (lamprey dorsal aorta; lDA), to dilation (rat aorta; rA), to multi-phasic (rat and bovine pulmonary arteries; rPA and bPA, respectively). (2) The responses of lDA, rA and bPA to hypoxia and H2S appear competitive; in the presence of one stimulus, the response to the other stimulus is substantially or completely eliminated. (3) Hypoxia and H2S produce the same degree of cell depolarization in bPA. (4) H2S is constitutively synthesized by lDA and bPA vascular smooth muscle. (5) Inhibition of H2S synthesis inhibits the hypoxic response of lDA, rA, rPA and bPA. (6) Addition of the H2S precursor, cysteine, doubles hypoxic contraction in lDA, prolongs contraction in bPA and alters the re-oxygenation response of rA. These studies suggest that H2S may serve as an O2 sensor/transducer in the vascular responses to hypoxia. In this model, the concentration of vasoactive H2S in the vessel is governed by the balance between endogenous H2S production and its oxidation by available O2.

The ability to detect oxygen availability is a ubiquitous attribute of aerobic organisms. However, the mechanism(s) that transduce oxygen concentration or availability into appropriate physiological responses is less clear and often controversial. This review will make the case for oxygen-dependent metabolism of hydrogen sulfide (H2S) and polysulfides, collectively referred to as reactive sulfur species (RSS) as a physiologically relevant O2 sensing mechanism. This hypothesis is based on observations that H2S and RSS metabolism is inversely correlated with O2 tension, exogenous H2S elicits physiological responses identical to those produced by hypoxia, factors that affect H2S production or catabolism also affect tissue responses to hypoxia, and that RSS efficiently regulate downstream effectors of the hypoxic response in a manner consistent with a decrease in O2. H2S-mediated O2 sensing is then compared to the more generally accepted reactive oxygen species (ROS) mediated O2 sensing mechanism and a number of reasons are offered to resolve some of the confusion between the two. [ABSTRACT FROM AUTHOR]