Review

Mechanisms and Consequences of Oxygen and Carbon Dioxide Sensing in Mammals

Eoin P. Cummins

UCD Conway Institute, Systems Biology Ireland and the School of Medicine, University College Dublin, Belfield, Dublin, Ireland

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Moritz J. Strowitzki

UCD Conway Institute, Systems Biology Ireland and the School of Medicine, University College Dublin, Belfield, Dublin, Ireland

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, and

Cormac T. Taylor

UCD Conway Institute, Systems Biology Ireland and the School of Medicine, University College Dublin, Belfield, Dublin, Ireland

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Published Online:09 Dec 2019https://doi.org/10.1152/physrev.00003.2019

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Abstract

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Molecular oxygen (O₂) and carbon dioxide (CO₂) are the primary gaseous substrate and product of oxidative phosphorylation in respiring organisms, respectively. Variance in the levels of either of these gasses outside of the physiological range presents a serious threat to cell, tissue, and organism survival. Therefore, it is essential that endogenous levels are monitored and kept at appropriate concentrations to maintain a state of homeostasis. Higher organisms such as mammals have evolved mechanisms to sense O₂ and CO₂ both in the circulation and in individual cells and elicit appropriate corrective responses to promote adaptation to commonly encountered conditions such as hypoxia and hypercapnia. These can be acute and transient nontranscriptional responses, which typically occur at the level of whole animal physiology or more sustained transcriptional responses, which promote chronic adaptation. In this review, we discuss the mechanisms by which mammals sense changes in O₂ and CO₂ and elicit adaptive responses to maintain homeostasis. We also discuss crosstalk between these pathways and how they may represent targets for therapeutic intervention in a range of pathological states.

Oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively, in all human cells. Variation in the levels of these gasses outside the physiological range can lead to the pathological conditions such as hypoxia and hypercapnia which represent grave threats to health. Because of this, cells and tissues have evolved mechanisms to sense changes in microenvironmental oxygen and carbon dioxide levels and elicit adaptive responses to varying levels to maintain homeostasis. These responses can be rapid (nontranscriptional) or chronic (transcriptional) in nature and provide a pivotal point of homeostatic control. In this review, we discuss the nature of oxygen and carbon dioxide sensing in human cells and probe the potential of these pathways as new therapeutic targets.

I. INTRODUCTION

Molecular oxygen and carbon dioxide are two gasses that have played a vital role in physiology over the full course of evolution. Due to the pathological threat of conditions such as hypoxia and hypercapnia, it is vital that these gasses are constantly maintained within the physiological range. This occurs as a result of multiple oxygen and carbon dioxide sensing mechanisms in cells that elicit adaptive responses to maintain homeostasis. While our understanding of how oxygen is sensed in cells and elicits an adaptive response is more advanced, less is known about the nature of cellular CO₂ sensing or indeed crosstalk between O₂ and CO₂ sensing mechanisms. In this review, we discuss the mechanisms by which cells respond to altered levels of O₂ and CO₂ and elicit adaptive responses. Furthermore, we discuss how integrative signaling may account for crosstalk between the sensing mechanisms for these two important physiological gasses.

II. THE CONTRASTING NATURAL HISTORIES OF O₂ AND CO₂

The constituent gasses of the Earth’s atmosphere have played a key role in the evolution and expansion of life since the first living cells emerged from the primordial soup some 4 billion years ago (45). Over the course of geologic time, the constitution of the atmosphere has changed dramatically (201). The early atmosphere was dominated by high levels of carbon dioxide (CO₂) similar to the current atmospheres of lifeless planets such as Venus and Mars (~96%). Early life comprised largely prokaryotic microbes, which developed metabolic pathways that utilized molecules such as hydrogen sulfide and methane as electron donors (62). In contrast, the Earth’s present atmosphere is composed primarily of molecular nitrogen (N₂; 78%) and oxygen (O₂; 21%) with relatively low levels of CO₂ (0.04%). Despite (or perhaps because of) a dramatically changing and dynamic terrestrial atmosphere, life on Earth has continued and indeed flourished for almost 4 billion years. This success has been largely due to the capacity of living organisms to adapt to and thrive in changing atmospheres. This occurred through metabolic evolution towards processes such as oxidative phosphorylation, which utilizes atmospheric O₂ as a final electron acceptor for highly efficient metabolism. Evolutionary advantage for terrestrial life is conferred upon organisms using an atmospheric gas as the final electron acceptor in respiration, as the atmosphere (unlike soil or water for example) is instantly accessible almost anywhere on the planet surface. The evolution of oxidative phosphorylation as a metabolic strategy provided the bioenergetic boost needed for the evolution of multicellular animals (metazoans). This in turn relied upon the ability of living organisms to sense levels of atmospheric gasses and adapt accordingly. The mechanisms by which simple unicellular organisms sense changes in environmental gasses are an area of significant interest in terms of developing our understanding of microbial physiology as well as virulence and antibiotic resistance. However, in this review, we focus on mechanisms by which higher eukaryotic organisms such as mammals sense physiological gasses and adapt to changing levels accordingly.

Two key atmospheric gasses that have shaped evolution and will be the focus of this review are O₂ and CO₂. O₂ was absent from the early atmosphere until the appearance of carbon-fixing cyanobacteria in the early planet’s oceans (~3 billion years ago) which consumed CO₂ and generated O₂ during photosynthesis (62). As the levels of atmospheric O₂ started to rise, the initial effects on the planet’s biomass were devastating, with the vast majority of life on earth being eradicated in what has been termed the ‟great oxidation eventˮ (72). However, a subset of cells evolved the capacity to not only withstand the reactive and toxic chemistry of molecular oxygen but to utilize it as a fuel for highly efficient oxidative metabolism. CO₂ on the other hand played a more prominent role in early atmospheres where it was the dominant gas form but has decreased over geologic time (FIGURE 1). Current CO₂ levels are relatively low when compared with those previous levels outlined above but have recently exceeded 400 ppm (0.04%) due to anthropologic activity, a level which has clear and potentially severe implications for the planet’s climate (177).

**FIGURE 1.**Estimation models of the relative atmospheric oxygen and carbon dioxide levels in the Earth’s atmosphere over geologic time between the formation of the planet (~4,500 million years ago) and ~500 million years ago. While carbon dioxide was the dominant gas in the early history of the planet, levels have consistently decreased over time, and current levels are 400 ppm/0.04%. In contrast, oxygen concentrations became elevated during the “Great Oxidation Event” beginning at 175,000 million years ago and are currently at 21%. The concepts in this figure were inspired by References 4a, 187, 201.

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Interestingly, while atmospheric O₂ levels are relatively high and CO₂ levels low, the opposite is the case within respiring organisms where the consumption of O₂ and the production of CO₂ during oxidative phosphorylation leads to lower O₂ and higher CO₂ levels than found in the atmosphere. Therefore, opposing gradients of O₂ and CO₂ exist between respiring organisms and the atmosphere. This can have biological consequences for interactions between species. For example, the CO₂ gradient from mammals is the primary homing mechanism used by mosquitos which can sense and follow this gradient to their prey (151).

In higher organisms such as mammals, it is essential to maintain levels of O₂ and CO₂ in circulation and in tissues that remain within the physiological range. This is achieved largely through effective gas exchange mechanisms, which absorb oxygen from the atmosphere through the lungs into the bloodstream and release CO₂ back to the atmosphere. If oxygen levels are too low (hypoxia) or too high (hyperoxia) within the body, it can result in bioenergetic crisis or oxidative stress, respectively, both of which can lead to cell, tissue, and organism death. Similarly, if CO₂ levels drop too low (hypocapnia) or rise too high (hypercapnia), this can also lead to pathological changes in the cellular acid-base balance leading to severe pathological outcomes. Therefore, an essential evolutionary development has been that organisms have evolved the capacity to sense and respond to conditions where endogenous levels of O₂ and CO₂ change and adapt through rapid effector mechanisms to maintain homeostasis.

Under physiological conditions, the levels of O₂ and CO₂ in the blood remain remarkably consistent under disparate states ranging from deep sleep to vigorous exercise. The status quo is maintained through the concerted actions of central and peripheral chemosensing mechanisms. Interestingly, the chemoreception of CO₂ is more sensitive than that of O₂. A relatively small (~10 mmHg) increase in Pco₂ from normal circulating levels (45 mmHg) is sufficient to promote a marked change in ventilation (48). In contrast, a much greater Po₂ decrease (20–40 mmHg) from physiological levels is required to markedly change basal ventilation. Sensitivity of peripheral chemoreceptors to oxygen increases dramatically only when the Po₂ of the blood flowing through the carotid body falls from between 80 and 100 mmHg to 60 mmHg (214).

III. ACUTE VERSUS CHRONIC GAS SENSING

The maintenance of consistent levels of O₂ and CO₂ in the blood is vital for homeostasis and is maintained by peripheral chemoreceptors capable of detecting changes in the partial pressures of oxygen and carbon dioxide (Po₂/Pco₂) and rapidly transducing these signals into neuronal activity which leads to altered respiration through the regulation of pulmonary gas exchange. Typically, this acute response to altered circulating O₂ or CO₂ is mediated by molecular gas-sensing mechanisms that are linked to ion channels in chemoreceptor cells, which generate a neuronal signal, which in turn drives rapid changes in ventilatory function.

The acute physiological responses to altered O₂ and CO₂ levels are complimented by a second, slower and more sustained response, which occurs at the cellular level and compliments respiratory adaptation through the regulation of transcription factors and downstream gene expression (FIGURE 2). In combination, the acute and chronic responses complement each other to maintain O₂ and CO₂ homeostasis. In this review we discuss what is known about the mechanisms relating to both the acute and chronic sensing of O₂ and CO₂ and the nature of the adaptive responses induced.

**FIGURE 2.**Changes in the levels of oxygen and carbon dioxide detected by specialized central and peripheral chemoreceptor cells elicit rapid physiological changes in the rate and depth of breathing (depicted in red). Changes in levels of oxygen and carbon dioxide in all cells affect gene expression leading to more sustained physiological effects through the regulation of transcriptional factors (depicted in green).

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IV. ACUTE PHYSIOLOGICAL RESPONSES TO ALTERED O₂

A continuous supply of sufficient circulating O₂ to support metabolic demand is an absolute requirement for the survival of most mammals. However, some (rare) exceptions such as the naked mole rat demonstrate extreme resistance to low oxygen levels (144). Therefore, in the majority of cases, the condition that arises when circulating oxygen levels are pathologically diminished (hypoxemia) represents a serious threat to cell, tissue, and organism survival (20). Hypoxemia however is commonly encountered in a number of physiological states including ascent to high altitude and intense exercise. During fetal development, oxygen levels also drop as tissues expand and outgrow the local blood supply. Hypoxemia can also occur in pathological states including common diseases such as chronic obstructive pulmonary disease (COPD) and anemia. Because of the vital importance of a steady level of circulating O₂, multiple mechanisms have evolved in mammals to detect hypoxemia and to mitigate the risk posed through the activation of adaptive pathways directed towards increasing circulating oxygen levels (72, 114, 155, 157). Principal among the oxygen-responsive chemoreceptors are the carotid bodies, located at the bifurcation of the ascending carotid artery, which play a pivotal role in the maintenance of blood oxygen levels by detecting hypoxia in arterial blood and relaying neuronal messages to the sites in the central nervous system that control the rate and depth of breathing. Of note, oxygen-sensitive ion channels have also been described in other tissues reflecting the fact that acute oxygen sensing is a more widespread phenomenon (114). This occurs in tissues including pulmonary arteries, the adrenal medulla, and the ductus arteriosus (72). However, in this review, we focus on mechanisms in the carotid body as an example of acute oxygen-sensing pathways in mammals. The carotid body-mediated cardiorespiratory reflex is triggered by the ability of the constituent cells to sense changes in arterial oxygen levels and activate a rapid physiological response based on initiating a neuronal signal, which informs the central nervous system of the need to increase the rate and depth of respiration (105).

The carotid bodies are highly perfused organs situated in close proximity to the carotid arteries and as such are ideally situated to monitor arterial oxygen content before oxygen delivery to the brain (FIGURE 3). The functional unit of the carotid body consists of glomus (type I) cells that are neuronal in nature and type II cells that are more glial-like stem cells which facilitate carotid body expansion in chronic hypoxemia (114). It is the type I glomus cells that are primarily responsible for oxygen sensing. In addition to being highly vascularized, the carotid bodies are heavily innervated with both afferent and efferent fibers. The primary afferent fiber is the glossopharyngeal nerve (cranial nerve IX), which communicates signals generated in the carotid body with the respiratory centers in the pons and medulla oblongata at the base of the brain (FIGURE 3). Less is known about the efferent fibers from sympathetic and parasympathetic branches of the autonomic nervous system which mediate inhibitory signals in the carotid body (24). The activation of the carotid body when arterial oxygen levels drop induces a rapid physiological response, which leads to an increase in the rate and depth of breathing through the glossopharyngeal nerve/cranial nerve IX. Sensory discharge from the type I cells of the carotid body is low in physiological normoxia (arterial blood of ~100 mmHg); however, this is increased when blood oxygen levels drop even modestly (105, 155). The rapidly responding nature of the carotid body/respiratory reflex belies its reliance upon preexisting factors and its independence of the need for de novo protein synthesis or gene expression (157).

**FIGURE 3.**Schematic overview of the carotid body (CB). Type I (glomus) cells within the CB detect changes in diffused oxygen levels from the carotid artery. Changes in oxygen levels are sensed by type I cells that then relay a signal to afferent fibers of the glossopharyngeal (cranial nerve IX) nerve which propagate the signal (red arrows) from the carotid body to the respiratory center within the pons and medulla oblongata where a signal is generated that activates changes in the rate and depth of breathing.

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A. The Membrane Hypothesis for Arterial Chemotransduction

Because of the key role the carotid body plays in mediating the cardiorespiratory reflex response to hypoxemia, much attention has been directed towards understanding the mechanism(s) by which type I glomus cells sense hypoxia and transmit a signal to the glossopharyngeal nerve/cranial nerve IX to activate the central respiratory response. The “membrane hypothesis” for chemotransduction proposes a mechanism for this process (115). In this hypothesis, oxygen-sensitive potassium channels play a key role as the primary effectors in the activation of this pathway in response to hypoxia.

The membrane hypothesis model of chemotransduction implicates oxygen-sensitive potassium channel closure as the primary effector event for the type I glomus cell response to hypoxia. This is followed by membrane depolarization and the opening of voltage-gated calcium channels leading to calcium influx, which in turn promotes the release of neurotransmitters such as dopamine, acetylcholine (ACh), and ATP (66, 221) that stimulate afferent fibers of the glossopharyngeal nerve/cranial nerve IX leading to the initiation of a neuronal signal from the carotid sinus to the respiratory centers in the pons and medulla oblongata leading to altered respiration (65, 115).

While the key aspects of the membrane hypothesis of carotid body type I cell oxygen sensing (potassium channel closure, membrane depolarization, calcium entry, and downstream neuronal transmission) are generally well studied, a key question that remains controversial pertains to the nature of the oxygen sensor responsible for the conference of hypoxic sensitivity upon the oxygen-sensitive potassium channel in type I glomus cells. Current concepts regarding the putative mechanisms of carotid body oxygen sensing have been discussed in a series of excellent reviews to which readers are directed for an in-depth discussion of the topic (105, 114, 155, 157, 160).

The potassium channels responsible for mediating the carotid response to hypoxia do not act as direct oxygen sensors but rather rely on upstream sensors for the conferral of their oxygen dependence (114). In recent years, several candidates for the role of this carotid body oxygen sensor have been proposed. It should be noted in advance that these mechanisms are not necessarily mutually exclusive, and it is possible that a response of such physiological importance as the maintenance of blood oxygen levels may be under the control of multiple sensing and signaling mechanisms (152). The proposed mechanisms for carotid body O₂ sensing are summarized in FIGURE 4 and will be discussed separately below.

**FIGURE 4.**Proposed mechanisms of oxygen sensing in the carotid body. According to the “Membrane Hypothesis,” oxygen-sensitive potassium channels close within type I cells of the carotid body in response to hypoxia. This leads to membrane depolarization and the opening of voltage-gated calcium channels. The ensuing influx of calcium ions leads to neurotransmitter release. These neurotransmitters activate cognate receptors on the afferent fibers of the glossopharyngeal (cranial nerve IX) nerve leading to signal propagation to the respiratory center. Multiple oxygen sensors that link altered oxygen levels to the opening of potassium channels have been proposed and are each outlined in a different color. AMPK, AMP-activated kinase; HO-2, heme oxygenase-2; ROS, reactive oxygen species.

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B. A Metabolic Sensor

Multiple studies have identified a link between altered mitochondrial metabolism in hypoxia and carotid body activation. However, the nature of this link remains controversial. Furthermore, it requires that the mitochondria found in type I glomus cells are particularly sensitive to changes in O₂ levels in comparison with mitochondria from other cell types (56). This hypothesis proposes that under conditions of sufficiently severe hypoxia, mitochondrial oxidative phosphorylation is reduced due to the availability of the final electron acceptor of the mitochondrial electron transport chain (O₂) being limited. This results in reduced ATP production and an associated accumulation of its precursor AMP. Two separate hypotheses relating to how ATP depletion is linked to K⁺ channel closure in type I glomus cells have been proposed. First, the Twik-related acid-sensing K channel (TASK) is activated by ATP leading to its closure when ATP is depleted (208). This direct link between ATP depletion and K⁺ channel activity is elegantly simple; however, a key, missing piece of information in this model is the identity of the ATP sensor (160). Second, a role for AMPK (an enzyme which is activated when ATP is depleted and the AMP-to-ATP ratio is elevated as a result) has been proposed as a link between decreased ATP levels/increased AMP levels and K⁺ channel closure (61). Whether it is ATP depletion or AMP elevation within subcompartments of the oxygen-sensing cell that act as a triggering signal remains to be determined.

A key question, which remains to be answered with respect to the metabolic sensor hypothesis, is whether ATP levels are sufficiently depleted to activate a response when type I cells are exposed to the physiological or pathophysiological range of hypoxia in vivo (209). Furthermore, the nature of the unique difference in mitochondria of the type I cells in the carotid body which accounts for its high sensitivity to hypoxia has yet to be clarified. However, it has been proposed that the carotid body mitochondrial cytochrome c oxidase has a uniquely low affinity for molecular oxygen, making them more sensitive to inhibition in hypoxia (22, 128, 155).

In a development of the metabolic hypothesis, a recent theory of carotid body oxygen sensing was proposed that involves the activation by lactate of a G protein-coupled receptor (GPCR) olfactory receptor (Olfr78) that is highly expressed in carotid body glomus (28). In this theory, lactate levels are elevated in cells exposed to hypoxia as oxidative phosphorylation is reduced and lactate produced during glycolysis accumulates in cells rather than entering the Krebs cycle (28). While potentially of interest, some key questions remain to be answered in relation to this theory including the identity of the mechanism whereby Olfr78 binding to lactate leads to membrane depolarization, the affinity of Olfr78 for lactate, and the basis of the specificity of this response for type I glomus cells (160).

C. A Redox Sensor

An alternative theory linking mitochondrial oxygen sensing to potassium channel activity in type I glomus cells is the “redox hypothesis.” This hypothesis proposes that altered generation of reactive oxygen species (ROS) by mitochondria in response to hypoxia is a key event in carotid body oxygen sensing which links hypoxia to the closure of the potassium channel and subsequent membrane depolarization. It has been proposed that hypoxia elicits the production of ROS by complex I of the electron transport chain in type I cell mitochondria. This is supported by studies using both pharmacological and genetic blockage of complex I (64, 141).

However, key questions still remain in relation to the impact of hypoxia on mitochondrial ROS production and how altered ROS levels are linked to potassium channel open probability (114). An alternative source of altered ROS production in hypoxia that has been proposed is NADPH oxidase, although whether this is acting as an oxygen sensor in type I glomus cells of the carotid body remains to be determined (2). In a separate study, a role for NADPH oxidase in carotid body sensory plasticity in response to intermittent hypoxia has been described (147).

D. A Gasotransmitter Sensor

Gasotransmitters are physiological gasses that play signaling roles and include nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S). A number of lines of evidence implicate a role for gasotransmitters in mediating oxygen sensing in type I cells of the carotid body.

First, CO production by the constitutively expressed heme oxygenase-2 (HO-2) isoform is dependent on the availability of molecular oxygen, which facilitates HO-2-dependent conversion of heme to biliverdin and CO. Other studies demonstrated that HO-2 is physically associated with the oxygen-sensitive potassium channel complex (213). The O₂-dependent production of CO by HO-2 was proposed to play a role in carotid body oxygen sensing by Prabhakar et al. in 1995 (153), and subsequent studies supported this (220). Therefore, when oxygen levels drop, CO production is decreased. CO has been proposed to act as a potassium channel activator, and therefore, in hypoxia, decreased CO levels have been implicated in K⁺ channel closure (168). However, mice lacking the HO-2 gene demonstrate normal physiological responses to severe hypoxia, suggesting that HO-2 is not acting as a sole O₂ sensor in type I cells of the carotid body, at least in severe hypoxia, although this does not rule out the possibility of redundancy in acute O₂ sensing (142). In separate studies, however, HO-2 deficient mice showed enhanced sensory responsiveness in the carotid body in response to less severe hypoxia and an exaggerated ventilator response leading to sleep apnea (149, 220). Therefore, the potential role of HO-2 in acute oxygen sensing remains intriguing but requires further investigation.

In the context of all experiments examining the impact of hypoxia on acute signaling responses, it is important to take into account the degree of hypoxia to which the experimental model is exposed, and whether this reflects levels likely to be encountered in vivo.

More recently, it has been implicated that CO-mediated potassium channel closure is mediated through its regulation of the production of another gasotransmitter H₂S. Briefly, CO leads to activation of protein kinase G (PKG), which in turn phosphorylates and inactivates cystathionine γ-lysase (CSE), the primary cellular source of H₂S. In hypoxia therefore, reduced O₂ would lead to reduced CO, which in turn would decrease PKG activity with a resultant increase in CSE activity and H₂S production (220). Of interest, inherent differences in the CO/H₂S axis in the carotid body have been reported to be associated with hypertension and other pathologies such as pulmonary edema (148).

E. Summary of Acute O₂ Sensing in the Carotid Body

While it is clear that type I cells of the carotid body are key peripheral oxygen chemosensors, multiple oxygen-sensing mechanisms have been hypothesized to link hypoxia to the closure of membrane potassium channels. Several of these mechanisms center around a change in mitochondrial function in the type I cell as being important in mediating oxygen sensing in this cell type. This key oxygen-sensing event, which is critical to the maintenance of circulating oxygen levels within the physiological range, represents an important physiological pathway, which allows mammals to adapt to conditions of hypoxia at the systemic level. Of note, the existence of multiple sensors for this important physiological response is possible, so the proposed theories outlined above relating to the identity of the proposed sensor are not necessarily mutually exclusive. The existence of multiple sensors would allow redundancy to ensure a physiological response in the absence of one of the pathways being pathophysiologically compromised.

As noted above, the capacity for acute oxygen sensing is not exclusive to the carotid body. A number of other tissues also display acute oxygen sensitivity including the ductus arteriosus as well as pulmonary and feto-placental arterial tissue. The smooth muscle cells of these tissues are capable of intrinsic oxygen sensing through a redox-dependent mechanism in which reduced production of ROS by complexes I and III of the mitochondrial electron transport chain leads to regulation of oxygen-sensitive voltage-gated potassium channels which induce vasoconstriction through increased intracellular calcium-dependent signaling (57). Therefore, multiple acute oxygen-sensing mechanisms exist in distinct chemosensing cells in the body.

V. ACUTE PHYSIOLOGICAL RESPONSES TO ALTERED CO₂

CO₂ levels outside of the physiological range result in hypo- or hypercapnia, both serious conditions that can result in cell, tissue, and organ damage as well as organismal death. Conditions leading to alterations in circulating CO₂ levels are frequently encountered in both health (e.g., exposure to high altitude, extreme exercise) and disease [e.g., COPD, cystic fibrosis, obesity hypoventilation syndrome, and congenital central hypoventilation syndrome (CCHS)]. Therefore, similar to O₂, the capacity to sense changes in circulating CO₂ and respond when levels change to maintain homeostasis is essential. The fine-tuning of CO₂ chemosensation is a vital adaptive response to facilitate the control of acid-base balance in tissues.

CO₂ in solution has the potential to form carbonic acid, which in turn can dissociate into ${HCO}_{3}^{-}$ and H⁺ ions catalyzed by the enzyme carbonic anhydrase

{CO}_{2} + H_{2} O ⇄ H_{2} {CO}_{3} \overset{CA}{⇄} {HCO}_{3}^{-} + H^{+}

Increased blood Pco₂ can give rise to elevated Pco₂ in the cerebrospinal fluid (CSF), which in turn drives elevated H⁺ concentrations in the CSF and its acidification. This decreased pH in the CSF remains relatively unbuffered due to low protein content and absence of red blood cells.

Respiratory acidosis is the situation that occurs due to alveolar hypoventilation and insufficient removal of CO₂ from the blood. The pH-modulating effects of chronic respiratory acidosis (a feature of a range of disorders including COPD and obesity hypoventilation syndrome) can be attenuated by bicarbonate reabsorption by the kidneys (192). However, in acute respiratory acidosis (which occurs due to an abrupt impairment in ventilation such as occurs in airway obstruction, respiratory depression, and acute hypercapnic COPD), the buffering capacity of the blood is not sufficient to handle the excess CO₂ (38), resulting in acute respiratory acidosis (pH <7.35). This can result in a number of symptoms including headache, confusion, and anxiety, which can develop into more severe symptoms including delirium, shortness of breath, and coma if untreated. Therefore, several areas of the brain stem (which has a close anatomical relationship with the CSF) have been implicated in the chemosensation of changes in Pco₂, mostly via pH-sensitive mechanisms. The net result of an increase in Pco₂ is stimulation of ventilation. This is achieved through a communication network involving the central chemoreceptors (which detect the change in pH), dorsal and ventral respiratory neurons (which control the rhythm of respiration), lower respiratory motor neurons, phrenic and intercostal nerves, and the respiratory muscles. The coordinated increase in respiratory drive in response to elevated CO₂ is an adaptive response, which promotes exhalation of CO₂ and restores homeostasis. The opposite occurs during hyperventilation where excessive amounts of CO₂ are exhaled, leading to a relative increase in pH in the CSF. The net result of a decrease in Pco₂ is the feedback inhibition of ventilation.

The seminal work of Haldane and Priestley (80) revealed that ‟either deficiency of oxygen or excess of CO₂ increases the activity of the respiratory center.ˮ In this review, we will provide examples in support of this observation.

The CO₂ chemoreflex is also considered by many to be required for a tonic drive underpinning normal air breathing. This is thought to be at least in part regulated by a negative feedback mechanism whereby subtle fluctuations in arterial Pco₂, via the CO₂ chemoreflex, regulate control of CO₂ homeostasis at rest (78, 203). However, a recent review challenges this view citing examples of animals that have a significantly impaired CO₂ chemoreflex without significant impact on normal breathing, e.g., the bullfrog, toad, and Brown Norway rat (173). The focus of this section of the review is on the acute sensing and signaling mechanisms downstream of pathophysiologic CO₂ levels rather than on the role of CO₂ in normal breathing.

A. Regions of CO₂ Chemosensitivity in the Brain

Several neurons in the brain are capable of detecting changes in CO₂/pH, although some of these are not involved in chemosensory regulation of respiration due to their anatomical location. Indeed, in mice the amygdala [in conjunction with the bed nucleus of the stria terminalis (198)] has been identified as a CO₂-chemosensitive brain region linked to acidosis and elicitation of fear behavior (222). This chemosensitivity involves acid sensing ion channel 1a (ASIC1a) and is thought to have evolved to forewarn against suffocation to ensure organismal survival. The exact locations, nature, and mechanisms underpinning centrally controlled CO₂-dependent regulation of ventilation are an area of active investigation. However, several brain regions, particularly those in the brain stem, have been implicated. Much of the early work in this area was elegantly described by Hans Loeschke in a British Physiological Society Lecture in 1982 (113). Here we discuss key regions of the brain that are involved in CO₂ chemosensitivity. These regions are discussed below and summarized in FIGURE 5.

**FIGURE 5.**A: overview of carbon dioxide-sensitive respiratory centers within the pons, the medulla oblongata, and the cerebellum (sagittal plane). B: chemosensitive neurons have been detected within the retrotrapezoid nucleus (RTN), the nucleus of the solitary tract (NTS), and the medullary raphe (coronal plane) (1). Figure references: 1) Nattie (134), 2) Fu et al. (67), 3) Wu et al. (216), 4) Dean et al. (50), 5) Dubreuil et al. (55), 6) Mulkey et al. (131), 7) Gestreau et al. (74), 8) Kumar et al. (104), 9) Richerson et al. (167), 10) Gourine et al. (75), 11) Bayliss et al. (13).

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1. Medulla oblongata

a) retrotrapezoidnucleus.

A role for the ventral surface of the medulla oblongata (VMS) (FIGURE 5A) in CO₂ sensitivity (via pH) was originally proposed in the 1960s (129), but the identification of the pH-sensitive neurons in the VMS remained elusive until more recently. Mulkey et al. (131) investigated chemosensitive neurons close to the VMS in the retrotrapezoid nucleus (RTN). These neurons within the RTN (FIGURE 5B) are activated by CO₂ in vivo, and continue to function in the absence of carotid body input and in the presence of central pattern generator (CPG) blockade. Importantly, these glutamatergic neurons innervate respiratory nuclei with chemosensitivity underpinned by a pH-sensitive K⁺ current. Thus many years after the VMS was proposed as a site of CO₂ sensitivity, the neurons responsible were identified and characterized.

Further evidence in support of glutamatergic neurons in the RTN playing a key role in chemosensitivity comes from the work of Dubreuil et al. (55). This group modeled CCHS in mice by generating animals with a heterozygous mutation of the Phox2b transcription factor (Phox2b^27Ala/+). Strikingly, these animals were not capable of responding to hypercapnia and lacked a population of glutamatergic Phox2b-expressing neurons in the RTN/parafacial respiratory group (pFRG). The proper expression and functioning of these neurons is thought to be particularly important in the control of breathing in the critical neonatal period and may also play a role in the regulation of respiration in addition to their CO₂ chemosensing properties (161). Recently, the role of GPCRs in CO₂ sensing in the RTN has been described and is discussed below.

b) nucleusofthesolitarytract.

Chemosensitivity of neurons in the nucleus of the solitary tract (NTS) (FIGURE 5B) was initially identified in the 1980s (127). This work was subsequently supported by work illustrating that depolarization and stimulation of the neurons of the NTS by CO₂ do not require synaptic input (49), suggesting a role in cardiorespiratory central chemoreception. Coates et al. (31) confirmed the role for chemoreceptors in several locations within the brain stem that could modulate ventilatory response. Interestingly, gap junctions (containing connexin 26) between adjoining chemosensitive neurons within the NTS have been implicated as a key mechanism linking CO₂/H⁺ chemoreception to the regulation of breathing (50).

Recently, Phox2b expressing neurons were determined to be crucial for the hypercapnic ventilator response in the NTS (67).

2. Medullary raphe

The medullary raphe (FIGURE 5B) is known to contain two types of chemosensitive neuron that are 1) activated by low pH or 2) inhibited by low pH. Both neuron types are thought to affect respiratory output, possibly through serotonergic activation and inhibition, respectively (167). Those neurons activated by low pH are selectively serotonergic (similar to those found in the ventrolateral medulla) and are morphologically (large multipolar somata vs. smaller filiform somata), biochemically (different neurotransmitters), and neurologically (different firing patterns) distinct from those inhibited by low pH. Interestingly, the percentage of acidosis-stimulated neurons in this brain region increases during the first 12 days of life in rats (212), suggesting a transient role for chemosensitivity in the medullary raphe in the development of physiological chemosensory networks. Indeed, the emergence of 5-hydroxytryptamine (5-HT) neurons in this region of the brain (medullary raphe) during early development coincides with a switch in sensitivity of 5-HT neurons to CO₂ by postnatal day 12 (P12). 5-HT neurons in the medulla do not play a role in the hypercapnic ventilatory response in rodents until they reach 12 days old. Thus the maturation of medullary 5-HT neurons in the first few weeks of life of mice contributes to the development of respiratory CO₂/pH chemoreception (27).

3. Cerebellum

The role of the cerebellum (FIGURE 5A) in chemosensation has been recently reviewed (219). Experiments performed in the 1930s by Mansfeld and Tyukody (120) revealed the impact of cerebellectomy in the unanesthetized dog on the ventilatory response to both hypercapnia and hypoxia. In particular, the fastigial nucleus (FNr) of the cerebellum is implicated as a chemosensory region of the cerebellum (but not the interposed or lateral nucleus). Ablation of this nucleus does not affect normal (eupneic) breathing but does affect the respiratory response to hypercapnia. The lack of sensitivity under normal conditions is attributed to inhibitory inputs from Purkinje cells. The FNr contains CO₂/H⁺-sensitive neurons as indicated by sensitivity to microinjection of acetazolamide, a pharmacological carbonic anhydrase inhibitor that can produce focal tissue acidification (134).

B. Role of Glial Cells, Respiratory Neurons, and Postsynaptic Processing in Acute CO₂ Sensing

While several CO₂/H⁺-sensitive neurons have been characterized in a number of brain stem regions as outlined above, there is evidence to indicate that other non-neuronal mechanisms can contribute to CO₂-dependent respiratory control. Notably, Gourine et al. (75) propose a role for astrocytes as key chemosensors in the brain. The authors contend that these glial cells are acutely well positioned to serve as CO₂/pH sensors due to their intimate association with cerebral blood vessels. In response to physiological changes in CO₂, the astrocytes (through a currently unidentified mechanism) elicit a pH-triggered release of intracellular calcium that in turn is propagated by a sustained ATP release from the VMS.

Furthermore, additional levels of control on CO₂/H⁺-dependent ventilatory drive can potentially be exerted by chemosensitive respiratory neurons. Bayliss et al. (13) described the expression of TASK-1 K⁺-leak channels in brain stem respiratory neurons. These channels are inhibited by extracellular protons, which in turn enhance neuronal excitation. Thus, for a given input to promote respiratory drive, a direct effect of H⁺ on respiratory motor neurons could augment the response to altered CO₂/pH, providing an additional level of control on CO₂-dependent chemoreception linked to respiratory drive.

Further regulatory control of the respiratory response to CO₂/pH can be exerted at the level of postsynaptic processing of chemoreceptor-derived inputs (8). It is known that episodic hypoxia (but not continuous hypoxia) contributes to respiratory long-term facilitation, leading to a lasting increase in respiratory motor output (69). Conversely, continuous hypercapnia elicits the opposite effect, leading to a long-term depression of respiratory motor output, with episodic hypercapnia having a lesser effect (7).

C. Mechanisms of Central CO₂ Chemosensing

In response to an increase in Pco₂ in the blood and CSF, there are three potential molecular signals that can be detected to elicit a change in respiratory drive. As discussed above, CO₂ in solution can dissociate to form H⁺ and ${HCO}_{3}^{-}$ meaning that either molecular CO₂, H⁺, or ${HCO}_{3}^{-}$ have the potential to be direct molecular signals in the chemosensing response. Much of the evidence presented thus far supports the concept that CO₂-dependent changes in pH are a major effector of central chemosensation. This is summarized in FIGURE 5. Below, we discuss this and potential alternative molecular mechanisms of CO₂ sensing.

1. pH-sensitive ion channels

The role for pH-sensitive TASK channels in central respiratory chemoreception has recently been expertly reviewed (12). TASK channels are members of the background K_2P channel family that facilitate selective K⁺ leak and contribute to the negative resting membrane potential in cells. Based on expression levels in specific regions of the brain and sensitivity to pH, TASK channels 1–3 were postulated to play a role in CO₂-dependent regulation of breathing. TASK-1 and -3 are the most similar of these three channels with both displaying acid sensitivity and widespread expression in known chemosensing regions of the brain (107). However, despite TASK-1 and -3 appearing to be attractive candidates for mediating CO₂-dependent sensitivity, double gene deletion experiments failed to reveal a requirement for TASK-1 and -3 channel subtypes in the central respiratory chemoreflex (132).

In contrast to the TASK-1 and -3 channels discussed above, TASK-2 channels are alkaline sensing channels, with a broader pH sensitivity (135) and have a more restricted expression within the brain. Notably, TASK-2 expression within the hindbrain localized specifically to regions of the RTN where Phox2b neurons reside. Crucially, TASK-2 knockout mice demonstrated a blunted ventilatory CO₂ response curve in vivo (74). Taken together, these data indicate that the background K_2p channels TASK-1 and -3 are dispensable for normal regulation of breathing by CO₂, while TASK-2 channels are required.

Other types of pH-sensitive channels have also been implicated in the central chemosensitivity to CO₂. For example, several inwardly rectifying potassium channels (KiR) channels are inhibited by hypercapnic acidosis (e.g., KiR1.1, KiR2.3, and KiR 4.1), and mRNAs for these channels are expressed in several brain stem nuclei involved in cardiorespiratory control (e.g., ventrolateral medulla and locus coeruleus and solitary tract nucleus) (216).

Catecholaminergic neurons in the locus coeuruleus of the pons have also been proposed to contribute to the ventilatory response to hypercapnia (39). Specifically, transient receptor potential (TRP) channels have been implicated. Several of these channels are sensitive to pH, and TRPC5 in particular is enriched in chemosensory regions of the brain.

2. pH-sensitive G protein-coupled receptors

GPCRs are sufficient for chemosensation of CO₂ in Drosophila melanogaster via Gr21a and Gr63a GPCRs together (95). Kumar et al. (104) investigated whether a similar GPCR-dependent mechanism exists in mammals. By systematic genetic deletion of mammalian proton-activated GPCRs they identified a deficit in CO₂ sensitivity (but not hypoxic sensitivity) in mice lacking GPR4. With the use of hybridization techniques, GPR4 was strongly expressed in a large percentage of Phox2b-expressing neurons in the RTN (as well as some expression in raphe neurons). Interestingly, GPR4 loss ablated pH sensitivity only in a subset of RTN neurons, with residual pH dependence attributed to independent activity of TASK-2 expressing RTN neurons. In a rescue experiment, re-expression of GPR4 selectively in the RTN was sufficient to restore CO₂ sensitivity in GPR4-deficient mice. Taken together, these data illustrate the importance of CO₂-sensitive GPCRs and suggest the existence of independent pH sensors (GPR4 and TASK-2) in overlapping populations of RTN chemosensitive neurons.

3. CO₂-sensitive connexin proteins

As discussed above, the ventral surface of the brain stem has been implicated in the ventilatory response to hypercapnia. Huckstepp et al. (89) investigated ATP release from brain slices derived from the VMS in response to elevated Pco₂. They observed that Pco₂ affects ATP release in this region, and it is independent of extracellular acidification and extracellular Ca²⁺. Connexin hemi-channels including connexin-26 (Cx26) were identified as being responsible for the ATP release, with Cx26 expression localizing strongly with known chemosensory regions in the medulla oblongata. Subsequent studies in HeLa cells revealed a role for inward-rectifying K⁺ channels (89), which could result in hyperpolarization of excitable cells and thus contribute to CO₂-dependent inhibition during hypercapnia.

Importantly, in 2013, Meigh et al. (125) linked the chemosensitivity of Cx26 directly to a CO₂-dependent posttranslational modification of the channel, as opposed to a change in pH (which is a more dominant signaling mechanism in the regulation of central CO₂ chemosensitivity). CO₂ molecules can bind to Lys125 on Cx26 forming a carbamate bridge between Lys125 and a neighboring residue, Arg104. The net result of this CO₂-dependent modification is a structural change in the gap junction, which facilitates altered connexin-dependent signaling (e.g., ATP release). This study is significant in identifying that central chemosensitivity to CO₂ is not exclusively mediated by indirect changes in pH and can be affected by directly CO₂-dependent modifications. Further evidence in support of Cx26 channels being important for chemosensing came from the study of specific Cx26 mutations (e.g., A88V) that exist in the rare clinical condition Keratitis-Ichthyosis-Deafness (KID) syndrome. In a severe case of KID syndrome, there is evidence of respiratory dysfunction including difficulties in breathing spontaneously at birth. Meigh et al. (126) modeled the impact of specific channel mutations in vitro. Interestingly, while the A88V mutant formed functional gap junctions and hemi-channels, Cx26^A88V hemichannels could act in a dominant negative manner to remove CO₂ sensitivity from Cx26^WT (126). Taken together, these data highlight the importance of CO₂-sensitive hemi-channels in the regulation of respiration.

In summary, multiple sites within the central nervous system are capable of sensing and eliciting rapid adaptive responses to acute changes in local CO₂ concentrations. The balance of evidence points to a particularly strong contribution of acid/pH sensing being required for acute CO₂ sensing in the brain stem to modulate respiration. However, the work described above on Cx26 points to an alternative and direct role for CO₂ via formation of a carbamate bridge between key residues in gap junctional proteins to modulate gap junction function and the control of respiration.

While there is a limited amount of information available, ${HCO}_{3}^{-}$ , the third component of the CO₂, H⁺, ${HCO}_{3}^{-}$ -triumvirate has also been proposed as a modulator of CO₂-dependent activation of GC-D+ neurons of the murine olfactory subsystem. This is thought to be downstream of carbonic anhydrase II (86). ${HCO}_{3}^{-}$ has additionally been proposed as a means through which soluble adenylyl cyclases (sACs) are stimulated for sperm cell maturation (30). Thus all of the components in the critical chemical reaction underpinning acid-base balance have been implicated in ‟sensingˮ or transducing (carbonic anhydrases) CO₂-dependent signaling. Carbonic anhydrase inhibitors, e.g., acetazolamide, are used clinically in the context of COPD. These compounds can act as respiratory stimulants to improve oxygenation and may be of particular benefit in patients with mild to moderate COPD where there is sufficient opportunity for the drug to stimulate ventilation (3). Indeed, pharmacological inhibition of carbonic anhydrases has been informative both in determining the sensitivity of organisms to CO₂ (reviewed in Ref. 45) and in provoking debate of our fundamental understanding of the decarboxylation products of the Krebs cycle being CO₂ or H⁺ and ${HCO}_{3}^{-}$ (193).

D. Crosstalk Between the Central Nervous System and the Endocrine System with Respect to CO₂-Dependent Regulation of Respiration

Several hormones have been implicated in the regulation of breathing including sex steroid hormones (progesterone), corticotrophin-releasing hormone, leptin, somatostatin, dopamine, and neuropeptide Y (171).

In particular, altered leptin levels and leptin-dependent signaling are associated with an aberrant hypercapnic ventilatory response. Animal models have identified that leptin-deficient mice (ob/ob mice) exhibit a blunted ventilatory response to hypercapnia, suggesting that leptin can act as a respiratory stimulus (197). In subsequent studies, leptin infusion in obese leptin-deficient mice increased CO₂ sensitivity during sleep (137) and enhanced ventilatory responses to CO₂ when administered via microinjection into the ventrolateral medulla (10).

Interestingly, the authors propose that a paucity of leptin-dependent signaling in the central nervous system may account for hypoventilation in some obese human subjects. These data are supported by evidence linking hyperleptinemia and reduced respiratory drive and hypercapnic response to leptin resistance in the respiratory center (25). Therefore, the endocrine system may play an important role in modulating central responses to altered circulating CO₂ levels.

E. Crosstalk Between Central and Peripheral Nervous Systems with Respect to CO₂-Dependent Regulation of Respiration

As outlined above, central CO₂ chemosensitivity is a major driver of ventilatory control. However, the extent to which chemosensing within the brain is affected by signals emanating from peripheral chemosensory tissues, such as the carotid body, is an area of continuing controversy. Different studies have proposed a negative interaction (47), an additive interaction (18), and a hyperadditive (18) interaction between central and peripheral chemoreceptors during CO₂ sensing. It is known that an intersection point exists within the NTS and RTN for signals emanating from the carotid body and central chemoreceptors (146). Stornetta et al. (189) described the requirement for the transcription factor Phox2b for the proper assembly of the network of neurons linking peripheral and central chemosensory loci. Most of the controversy in this area relates to difficulties that exist in interpreting data obtained from different animals, in different models, some of which used anesthesia and some of which did not (146). Recently, Smith et al. (186) attempted to clarify this issue using an invasive, unanesthetized canine model, which permitted independent peripheral and central stimulation or inhibition. Thus the impact of hypocapnic, normocapnic, or hypercapnic perfusion of the carotid body could be monitored as the fractional inspired CO₂ was progressively increased. Smith et al. (186) demonstrated an increase of the slope of minute ventilation and inspiratory flow rate versus central Pco₂ when the isolated carotid body was exposed to hypercapnia versus hypocapnia. Thus, in agreement with previous work from the same group (18), the authors conclude that peripheral chemosensing of CO₂ had the ability to synergize (or work in a hyperadditive manner) with central chemoreceptors to modulate the ventilatory response to CO₂. Thus, rather than acting in isolation, the carotid body afferents linking it to the NTS and RTN are an important neural pathway for the physiological response to CO₂.

F. Acute CO₂ Chemosensing Summary

Acute chemosensing of CO₂ that results in altered respiration is a complex process involving integration of multiple brain regions and cells, effector channels, and sensing mechanisms. Nattie et al. (134) and Ballantyne et al. (9) argue that one region of the brain alone cannot account for the spectrum of sensitivity to CO₂. Indeed, different regions may be relatively more or less important depending on the context (e.g., arousal vs. sleep or infancy vs. adulthood). It is clear that the ability to acutely sense and respond to elevated CO₂ is a key physiological adaptation that is central to whole body acid/base balance. pH is clearly a major effector of CO₂-dependent signaling in the brain; however, the work on connexin hemi-channels has implicated a potential to direct CO₂-dependent protein modification as an additional mechanism (125). Furthermore, it is unlikely that under normal physiological conditions that the central chemoreception of CO₂ is isolated from peripheral sensing mechanisms in the carotid body. Recent evidence suggests an important crosstalk between the carotid body and central chemosensing regions of the brain that determines the respiratory response to altered CO₂ (186).

VI. TRANSCRIPTIONAL RESPONSES TO O₂ AND CO₂

The acute response to systemic hypoxia and hypercapnia has been discussed above. These sensor/effector pathways occur in specialized chemosensory cells and coordinate an effective rapid physiological response to altered O₂/CO₂ in the bloodstream activated within seconds, which results in altered gas exchange through changing the rate and depth of breathing. In addition to this physiological response, all cells have the capacity to respond to alterations in O₂ or CO₂ and induce an adaptive response, which is slower in nature and dependent on alterations in de novo gene expression. In the next section, we discuss what is known about the mechanisms involved in transcriptional responses to altered O₂ and CO_2.

VII. REGULATION OF GENE EXPRESSION BY O₂

The physiological response to hypoxia, as outlined above, is complemented by a second, slower and more sustained transcriptional response that occurs in all cells and involves a change in the transcription of genes that promote local adaptation to hypoxia. Transcriptomic studies have revealed that (depending on the cell type under investigation) the expression of between 200 and 1,000 genes are altered in response to hypoxia with approximately equal numbers of genes being activated and repressed (188). Furthermore, multiple transcription factors demonstrate sensitivity to hypoxia (42, 46). Primary among the transcription factors, which increase gene expression in hypoxia, is the hypoxia inducible factor (HIF). However, a number of other transcription factors have also been shown to display hypoxic sensitivity including nuclear factor (NF)-κB, cAMP response element binding protein (CREB), AP-1, ATF-4, SP1, Sp1/3, and p53 (42, 46). For the purpose of providing examples, in this review we focus on the best characterized of the oxygen-sensitive transcription factors.

The HIF pathway has been extensively reviewed elsewhere, and readers are directed towards a number of excellent reviews that cover this topic in detail (96, 156). A brief description of the key aspects of this pathway and its role in physiology and disease is provided here with a focus on recent developments in the area.

HIF is a heterodimeric transcription factor comprised of an oxygen-sensitive α subunit and a constitutively expressed β subunit (FIGURE 6). There are two primary transcriptionally active HIF α subunits described to date termed HIF-1α and HIF-2α which when combined with HIF-1β form HIF-1 and HIF-2, respectively. Whereas HIF-1α is ubiquitously expressed in mammalian cells, HIF-2α expression is limited to specific cell types and tissues (156). HIF-1α and HIF-2α share 48% amino acid identity (156, 205). While a cohort of genes are regulated by both HIF-1 and HIF-2, there are also a number of genes that are isoform specific. For example, genes such as adrenomedullin and carbonic anhydrase XII are regulated by either HIF-1α or HIF-2α, whereas BCL2 interacting protein 3 and hexokinase 1 are mainly HIF-1-dependent and erythropoietin (EPO) and transforming growth factor (TGF)-α are largely HIF-2-dependent (98). This, along with differential tissue expression profiles, gives rise to distinct physiological and pathophysiological roles for these two isoforms (98).

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The oxygen sensitivity of the HIF pathway is conferred by a family of 2-oxyglutarate-dependent dioxygenases termed HIF-hydroxylases, consisting of three prolyl hydroxylases (PHD1/EGLN2, PHD2/EGLN1, and PHD3/EGLN3) and one asparagine hydroxylase termed factor inhibiting HIF (FIH). These enzymes utilize molecular oxygen as a substrate to hydroxylate HIF-1α and HIF-2α. When hydroxylated on specific proline residues, HIF-α proteins become targets for ubiquitination by the von Hippel Lindau protein (pVHL), an E3 ubiquitin ligase which in turn targets them for proteasomal degradation. FIH hydroxylates an asparagine residue, which reduces the affinity of the HIF-α isoform for the transcriptional coactivator CBP/p300. Therefore, the HIF hydroxylases provide a repressive force against HIF signaling in normoxia (FIGURE 6). In hypoxia, HIF-α hydroxylation is reduced rendering the HIF-α molecule stable and with higher affinity for CBP/300. Stabilized HIF-α then translocates to the nucleus where it binds to HIF-1β to form a functional transcriptional complex capable of regulating the expression of hypoxia-responsive genes. HIF binds to the hypoxia response element (HRE) which contains the sequence 5′-CGTG-3′ (96) and is the primary driver of gene expression. There are a limited number of examples of HIF functioning as a repressor (156). HIF-1-dependent gene repression can occur through three mechanisms: 1) HIF-1 binds to transcriptional repressors (119); 2) HIF regulates microRNA expression, thereby inducing the degradation of specific mRNAs (37); and 3) HIF binds to “reverse” HRE sequences, thereby repressing gene expression (94, 106, 124, 133).

In addition to requiring O₂ as a substrate, the HIF hydroxylases are dependent on 2-oxyglutarate and iron as cofactors (FIGURE 6). Therefore, these enzymes can function more broadly as metabolic sensors. During metabolic stress, the intracellular concentrations of these cofactors can change dramatically, and other modulatory signals such as ROS may be induced. The increased amount of ROS leads to an oxidation of iron (II to III), thereby inhibiting the PHDs. Recent studies have demonstrated that HIF expression can also be regulated by a number of other factors including microRNAs (see Box 1), posttranslational protein modifications such as ubiquitination and SUMOylation, and phosphorylation (103). Therefore, the activation of HIF is under the influence of a number of signals, which can be dependent or independent of oxygen levels. As a result, the activation of HIF signaling is not a linear function, but a complex product of distinct signals that work together to regulate local oxygen hemostasis. A number of recent studies have provided evidence that the HIF hydroxylases may also regulate a number of non-HIF proteins through hydroxylation (190). Outlined below are several physiological and pathological conditions under which HIF signaling plays an important role (FIGURE 7).

Box 1.
HIF and microRNA

Noncoding RNA (ncRNA) is a superfamily including ribosomal RNAs, small nuclear RNAs, transfer RNA, small interfering RNAs, microRNA (miRNA), and long ncRNAs (90). ncRNAs play key roles in multiple physiological and pathological processes including cell growth, differentiation, metabolism, infection, and tumorigenesis (23). miRNAs are single-stranded ncRNA molecules of up to 22 nucleotides in length that regulate the expression of target genes by inhibiting their mRNA expression or increasing the cleavage of the target mRNA (207). So far, ~2,200 miRNAs have been identified within the human genome (90). The transcription of the genes encoding miRNAs and the further processing of the resulting primary transcripts by RNA polymerase II and the nuclear RNase III Drosha have been expertly reviewed (90, 178). Briefly, the mature miRNA is transported into the cytoplasm and incorporated into the RNA-induced silencing complex (RISC), which recognizes its target mRNA based on sequence complementarity of the target genes leading to their translation inhibition and/or mRNA degradation (53, 54). Of note, a perfect sequence complementarity is usually only required between a short, specific region, called the seed region, of a miRNA and the 3′ untranslated region of its target mRNA. Due to this lack of specificity, a single miRNA can theoretically regulate multiple mRNAs (often hundreds), which leads to a significant challenge to identify biologically relevant miRNA targets and functions (90).

To date, the role of miRNAs during physiological and pathological processes such as DNA repair, cell metabolism, apoptosis, cell cycle arrest, angiogenesis, and cancer development has been well characterized and specific targets identified (23, 90). Many solid cancers, for example, such as soft tissue sarcoma or pancreatic cancer, have specific miRNA signatures consistently showing that a high expression, for example, miR-210, is associated with a poor patient survival and an unfavorable prognosis (73, 90). Interestingly, the tumor microenvironment of many solid cancers is characterized by severe hypoxia (see sect. VIIE), and it is therefore not surprising that preclinical studies showed a strong induction of several miRNAs, such as miR-210 and -155, under hypoxia (88, 159). However, concerning malignant diseases, it is still a matter of debate whether high miR-210 only serves as an indicator of tumor hypoxia or actively promotes a more aggressive disease (88).

HIF-1 directly binds to a HRE at the proximal promoter region of the above-mentioned miRNAs and thereby induces their expression (87). Thus the expression of miR-210 is a reflection of HIF activity in vitro and in vivo (52, 63, 87). Recent work from our group showed that on the other hand HIF-1α, but not HIF-2α, is under the direct control of miR-155 in intestinal epithelial cells. Using a HRE-luciferase reporter assay, we found that exogenously applied miR-155 reduced hypoxia-induced HIF activity, which could be reversed by cotreating cells with neutralizing anti-miR-155. This negative-feedback loop fine tunes the hypoxic induction of HIF-1α and promotes its resolution during prolonged hypoxia (21). Comparable to the findings regarding miR-210, recent studies revealed that a high expression of miR-155 in tumors is correlated with aggressive tumor growth (159).

In summary, although the role of miRNAs in adaption to low oxygen levels is complex, there is strong evidence that they fine tune the expression of numerous specific target genes and HIF activity; thereby miRNAs strongly influence the pathogenesis of several diseases, such as cancer development, but also physiological processes, such as cell metabolism or DNA repair.

**FIGURE 7.**Overview of different physiological (green) or pathophysiological (red) conditions in which hypoxia plays a role through activation of the hypoxia inducible factor (HIF) pathway.

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A. Fetal Development and Tissue Maintenance

Although tissue hypoxia is often associated with pathological conditions, such as inflammation, cancer, and ischemia, hypoxia can also occur during physiological states. For example, during normal fetal development, certain regions of the growing embryo exist in a hypoxic microenvironment as the tissue outgrows the existing local blood supply. Stem cells, which reside in specific anatomic niches formed by a hypoxic microenvironment, are modulated by oxygen levels that can influence cell growth and tissue maintenance (130).

The embryonic development of the cardiovascular system is regulated by hypoxia through the HIF-dependent induction of multiple angiogenic factors including vascular endothelial growth factor (VEGF), TGF-β, platelet-derived growth factor (PDGF)-β, and angiopoetin-1/2 (184). Therefore, it is not surprising that inactivation of HIF-1α conveys profound developmental disorders and abnormalities within the cardiovascular system. Indeed, homozygous loss of HIF-1α gene function is lethal in embryos during development (91, 170). Loss of HIF-2α results in lethal bradycardia and insufficient erythropoiesis due to decreased catecholamine and EPO production, respectively (172, 204).

Of note, during embryonic development as well as under pathological conditions such as severe hypoxia or kidney failure in adults, liver cells (including hepatocytes and adventitial cells) are capable of sensing hypoxia and producing EPO (58). In mice lacking HIF-1β, it has been shown that a decrease in VEGF protein levels is deleterious, since VEGF is essential not only for angiogenesis, but also for vasculogenesis (118, 162, 184).

In conclusion, modulation of HIF activity affects a wide range of cell autonomous development pathways (FIGURE 7) (96).

B. Altitude Adaptation and Exercise

At high altitude, the body experiences decreasing partial pressure of circulating arterial oxygen resulting in systemic hypoxia, which in turn leads to physiological adaptation through the activation of acute oxygen sensing mechanisms (described above) resulting in increased ventilation (76). Furthermore, HIF-2-dependent activation of EPO complements acute responses to hypoxia to facilitate physiological adaptation.

Studies in high-altitude populations demonstrated that the relationship between arterial oxygen saturation and hemoglobin concentration show heritability. Tibetans have a significantly lower hemoglobin concentration compared with Aymaras although both live at similar altitudes (3,800–4,065 m) (14, 16). Subsequent genome-wide studies identified several key HIF-related genes to be involved in the Tibetan pattern of adaptation including EPAS1 (which encodes HIF-2α) and EGLN1 (which encodes PHD2) (16). Interestingly, HIF-1α^+/− mice display remarkable absence of ventilatory acclimatization and showed reduced hypoxic ventilatory stimulation following chronic hypoxia (102). In addition, chronic hypoxia alters the morphology and the sensory response of carotid bodies to hypoxia (17, 154). Inactivation of PHD2 in mice enhances hypoxic ventilatory responses and carotid body hyperplasia. This phenotype is strongly compensated for by concomitant inactivation of HIF-2α, but not HIF-1α (84). In line with these findings, Macias et al. (117) demonstrated that there is an absolute developmental requirement for HIF-2α for growth and survival of oxygen-sensitive glomus cells within the carotid body. The loss of these cells renders mice incapable of ventilatory responses to (acute) hypoxia with striking effects on arterial pressure regulation, exercise performance, and glucose homeostasis (117).

High-intensity exercise can result in systemic and tissue hypoxia through increased oxygen consumption. Therefore, the body needs to not only rapidly adapt the ventilatory response to increase the availability of oxygen within the circulation as illustrated above, but also change the way that peripheral oxygen is consumed by the skeletal muscle. This is mediated by reducing the oxygen consumption on a cellular level within the mitochondria, which occurs in a HIF-1α-dependent manner (111). Reduced HIF-1α activity through heterozygous genetic knockout leads to attenuated PDK-1 levels at rest and after exercise. This may explain the enhanced mitochondrial function and the reduced lactate accumulation seen after exercise in these mice (101). The reduction of HIF-1α activity within skeletal muscle of these mice led to a marked increase in performance including swimming and running endurance (122, 123). The role of HIF-2α during exercise remains less clear (111).

Therefore, HIF signaling is important for the maintenance of homeostasis during physiological conditions such as the embryonic development, high-altitude adaption, and exercise. Furthermore, physiological hypoxia is a feature at a number of tissues. For example, in the intestinal mucosa, a controlled oxygen gradient is sustained by the juxtaposition of the rich capillary network of the mucosal vasculature with the anoxic lumen of the gut (40, 70, 200). It is likely that at such sites, the HIF pathway plays a role in the maintenance of tissue homeostasis.

C. Inflammation

Key aspects of the mammalian immune response occur within different immunological niches that are influenced by the microenvironment including lymphoid tissues and mucosal surfaces. Hypoxia is frequently a feature of the microenvironment in these immunological niches and may be physiological or pathophysiological in nature depending on the degree and duration of exposure (200).

It is now recognized that HIF plays a key role in cell-type specific immune cell development and differentiation both in adaptive and innate immune responses (200). Circulating immune cells exist in the oxygen-rich microenvironment of the blood and are recruited to hypoxic immunological niches (200). During this process, immune cells must rapidly adapt to a hypoxic microenvironment. HIF activation has a strong regulatory impact upon immune cell function. For example, HIF increases the rate of glycolysis through the transcriptional upregulation of glycolytic enzyme expression (35). This, in turn, is associated with the activation of a number of immune cell types including macrophages, dendritic cells, T lymphocytes, and B lymphocytes (35). In macrophages, HIF regulates proinflammatory (M1) and immunomodulatory (M2) polarization, motility, and bactericidal activity (110, 200). Of interest, skewing the macrophage population to an M2 phenotype plays an important role during wound healing and tumor development (36, 81, 150, 191, 202). On the other hand, M1 macrophages arise from stimulation with the cytokine interferon-γ (IFN-γ) alone or in concert with bacterial ligands, such as lipopolysaccharide (LPS) or cytokines [for example, tumor necrosis factor-α (TNF-α)]. M1 macrophages are involved in the differentiation of Th1 cells, which improves antigen phagocytosis during acute inflammation (36, 71, 81). Interestingly, the M1- and M2-polarization in macrophages seem to rely on HIF-1α and HIF-2α, respectively (71).

One model example for “pathological hypoxia” defined by an inconsistent and unstructured oxygen gradient is the intestinal mucosa during inflammatory bowel disease (IBD) (217). IBD is characterized by a breakdown in the intestinal epithelial barrier with subsequent unregulated exposure of the mucosal immune system to luminal antigenic material leading to inflammation and further barrier breakdown (11, 199). Chronic hypoxia in IBD occurs due to an insufficient oxygen delivery due to damaged microvasculature as well as an increased oxygen consumption by infiltrating immune cells, in particular neutrophils (32, 176, 199).

Multiple studies have demonstrated that HIF elicits a barrier protective transcriptional program in the intestine during IBD (33, 60, 70, 194). Karhausen et al. (97) demonstrated that mice with intestinal epithelial-targeted expression of either mutant HIF-1α (constitutive repression of HIF-1) or mutant von Hippel Lindau gene (Vhl, constitutive overexpression of HIF-1/HIF-2) showed divergent clinical phenotypes with respect to experimental colitis. While the loss of epithelial HIF-1 correlated with more severe clinical symptoms, an increase in epithelial HIF-1 was protective (97).

Of note, HIF activity can be modulated by either pharmacological HIF inhibitors such as YC-1 (191, 218), metformin (77, 211), and rapamycin (218) or HIF activators such as HIF-prolyl hydroxylase inhibitors [PHI; for example, dimethyloxallylglycine (DMOG), FG-4497, and JNJ1935] (59, 169, 176, 218).

Preclinical studies have demonstrated that IBD can be attenuated by pharmacological interference with molecular oxygen-sensing pathways. In particular, pharmacological inhibition of HIF-prolyl hydroxylases (PHD1–3) leads to enhanced protection of the intestinal barrier, thus alleviating colitis in experimental animal models (41, 44, 176, 196). This is at least in part due to PHD1 inhibition in intestinal epithelial cells leading to decreased rates of apoptosis and subsequent enhancement of intestinal barrier function (44, 176, 196). In conclusion, there is now strong evidence that increased HIF signaling is protective in preclinical models of inflammation such as IBD.

D. Cancer

The role of HIF during tumor development has been expertly reviewed (96, 99, 163, 176). As the developing solid tumor outgrows the local oxygen supply, this results in an oxygen deficit and tumor hypoxia that induce tumor angiogenesis (181). However, the vascular system initiated by the oxygen-deprived tumor is chaotic and leaky and therefore inefficient in delivering oxygen (181). This leads to tumor hypoxia that induces regional HIF stabilization within the growing tumor (96). Increased HIF-α levels have been documented in many solid tumors, and high HIF-α levels are linked to a poor prognosis in cancer patients (181).

The role of HIF in tumor development is of clinical relevance since PHIs (which stabilize HIF) are currently under investigation for clinical application in patients suffering from anemia. However, little evidence presented to date implicates PHI treatment as promoting tumor development or growth (6, 29, 51, 79, 121).

In addition to hypoxia, several other stimuli have been reported to induce HIF accumulation within tumors: 1) Ras activation with resultant increased amounts of intracellular ROS, 2) mutations that activate mTOR, 3) suppressed HIF hydroxylation due to accumulation of succinate and fumarate, and 4) von Hippel-Lindau mutations impair the ability of pVHL to polyubiquitylate HIF-α (96). Collectively, pharmacological inhibition of HIF, or critical downstream HIF targets, might be useful to treat cancers that overexpress HIF (96).

E. Ischemia

Ischemia occurs when oxygen and nutrient supply abruptly exceeds demand and can be due to arterial stenosis or acute blockage rendering the tissue oxygen and nutrient deprived (180). For example, atherosclerotic involvement of major arteries in the legs causes peripheral arterial disease (PAD). PAD is a progressive vascular disorder, eventually leading to critical limb ischemia (CLI) associated with tissue necrosis (ulceration and gangrene); 1–2% of PAD patients older than 50 develop CLI with an overall poor prognosis (136). In experimental studies with mice using femoral artery ligation as a model of limb ischemia, wild-type mice recover without permanent disorders while mice with heterozygous HIF-1 deficiency (HIF-1α^+/−) demonstrate impaired recovery of blood flow to the ischemic limb and less tissue damage (19). Conversely, in a gain-of-function study, adenovirally expressed HIF-1α stimulated arterial remodeling and increased blood flow through the promotion of collateral vessels when injected into the ischemic limb following femoral artery occlusion (145). Interestingly, this effect was age dependent, and 13-mo-old mice only profited when DMOG-treated bone marrow-derived angiogenic cells (BMDACs) were additionally injected after intramuscular injection of AdCA5 (165). There seem to be two main reasons for this: 1) DMOG induced the HIF-dependent expression of β2 integrins on the cell surface, thus increasing the adherence of BMDACs to hypoxic endothelial cells, which overall facilitates the retention of BMDACs within the ischemic tissue (165); and 2) DMOG induced HIF-dependent metabolic reprogramming, thereby increasing BMDAC survival in the ischemic limb (166).

Preclinical work has indicated that cytoprotective effects are based in part on metabolic reprogramming (5, 68). For example, Aragonés et al. (5) could show that loss of PHD1 gene function protected mice, in a HIF-dependent manner, from muscle necrosis during limb ischemia. This was found to be due to an increase of PDK4 expression, which inhibits pyruvate from entering the Krebs cycle and thus switches ATP production from oxidative to anaerobic glycolysis. This markedly decreased the amount of oxygen consumption within the skeletal muscle and thereby the production of intracellular ROS (5).

In conclusion, HIF plays a major role in orchestrating the vascular response after a major insult, such as ischemia by reprogramming the expression profile if the tissue (induction of pro-angiogenic HIF-target genes) and the metabolic status being overall cytoprotective during ischemia.

VIII. REGULATION OF GENE EXPRESSION BY CO₂

The prolyl-hydroxylase/HIF regulatory axis discussed above is an elegantly simple, evolutionarily conserved process that transduces a decrease in available oxygen molecules into a transcriptional signal to elicit adaptive responses to hypoxia such as the upregulation of EPO and VEGF. In contrast, the molecular mechanisms downstream of alterations in cellular CO₂ levels are poorly understood. At present, no transcription factor has been identified that fulfills the same master regulator role for CO₂-dependent alterations in gene expression as HIF does for oxygen-dependent signaling (42). However, multiple studies have demonstrated that CO₂ levels do indeed regulate gene expression in cells.

Several studies have employed gene array technology to investigate the impact of altered CO₂ levels on transcription. The study by Li et al. (109) set out to investigate whether chronic hypercapnia could contribute to hypercapnia-mediated lung protection. To test this hypothesis, newborn mice were exposed to a range of CO₂ conditions (room air, 8% CO₂ or 12% CO₂) for 2 wk. Neonates exposed to 8% CO₂ demonstrated thinner-walled alveoli, a feature of mature lungs. Furthermore, there was a substantial alteration in the gene expression profile between mice exposed to room air and those exposed to 8% CO₂. Among the clusters of genes differentially expressed were genes associated with cell adhesion (e.g., CD72, Wisp2, and Sftp-A1), the immune response [e.g., chemokines (CCL5), interleukins (IL15) and Toll-like receptors (Tlr1)], cell growth/maintenance (e.g., Ctgf and Atp6v1c2), and signal transduction (Stat 1 and 2 and Per1). Thus distinct functional categories of genes were identified as being differentially expressed in mice exposed to 8% CO₂. Subsequent studies in Caenorhabditis elegans and Drosophila melanogaster exposed to a range of CO₂ concentrations again illustrated a distinct transcriptional profile. Sharabi et al. (182) observed striking phenotypic changes in C. elegans exposed to a range of CO₂ concentrations (up to 19%). Animals that developed in increased CO₂ environments demonstrated decreased fertility, motility, and muscle organization but increased lifespan. Underpinning these gross phenotypic changes were marked alterations in the C. elegans transcriptome between animals grown in normal air and those exposed to elevated CO₂. Similar to the findings of Li et al. (109), genes associated with the innate immune response were significantly altered in C. elegans, as were genes associated with protein degradation, ubiquitin signaling, nuclear hormone receptors, seven-transmembrane domain genes, sperm proteins, and carbonic anhydrase genes. The pattern of altered gene expression observed in C. elegans was distinct from that elicited by exposure to hypoxia, which is strongly suggestive of differential regulation. Helenius et al. (82) took a similar gene array approach to investigating the transcriptional changes in response to elevated CO₂ in Drosophila. D. melanogaster exposed to elevated CO₂, like C. elegans, displayed alterations in fertility with changes observed in egg hatching and laying. Strikingly, Drosophila exposed to elevated CO₂ were more susceptible to bacterial infections and demonstrated impaired immune signaling. Underpinning the phenotypic changes observed in Drosophila were marked changes in genes with metabolic gene ontology (GO) functions, immune GO functions, or fertility-related GO functions. In relation to the suppression of immune signaling, the authors reported CO₂-dependent suppression of several antimicrobial peptides (AMPs) downstream of the NF-κB family member Relish.

Recently, another study also identified the importance of CO₂ in immune regulation in differentiated normal human epithelial cells grown in 20% CO₂ for 24 h. The authors report significant alterations in gene networks associated with among others immune response, lipid metabolism, ion transport, oxidation/ reduction, transcription and nucleosome assembly. These data give additional information into the extent of the immune suppression that can occur under conditions of hypercapnia. It should be noted, however, that the experiment in this study was performed under conditions that permitted hypercapnic acidosis, and pH-dependent effects per se may be responsible for some of the observed changes in gene expression (26).

Taken together, the gene expression profiles in distinct animal species illustrate that exposure to elevated CO₂ can have marked effects on the expression of genes controlling metabolism, fertility, and immunity. These cohorts of genes appear to be specific to the CO₂ stimulus and not shared with other respiratory stresses such as hypoxia. While we now have a strong appreciation that CO₂ exposure is a consistent and specific modulator of transcription, the molecular mechanisms underpinning how the CO₂ is sensed on a cellular level, and which effectors (i.e., transcription factors) are responsible for eliciting the transcriptional responses remain poorly understood. We recently reviewed some of the main transcription factors that are involved in CO₂-dependent cellular signaling. These transcription factors can be largely divided into two main categories: 1) those that are central for the development of chemosensing neurons, e.g., Phox2b and EGR-2; and 2) those whose signaling is altered under conditions of hypercapnia [NF-κB, FoxO3a, CREB, heat shock factor 1 (HSF1)], or are involved in hypercapnia-dependent signaling (ZFHX3/4). These transcription factors are discussed below.

A. Phox2b

Phox2b is a transcription factor that is expressed by chemosensitive neurons in the RTN and is involved in the acute chemosensing of CO₂. Expression of Phox2b is required for the development of a population of glutamatergic neurons in this region of the brain and for normal sensitivity to hypercapnia (55). Thus this transcription factor is likely important in coding for elements of the chemosensitive apparatus in neurons. Whether the activity of this transcription factor is responsible for altered gene expression in hypercapnia has not been fully addressed experimentally to date.

B. Egr2

Early growth response 2 (Egr2) is a transcription factor that is important for the normal development of respiratory function in adult mice. Animals lacking this transcription factor typically die within the first day of life due to respiratory insufficiency (92). This is thought to be a consequence of the requirement of Egr2 to establish a population of brain stem neurons essential for normal breathing at birth (164). Whether the activity of Egr2 is responsible for altered gene expression in hypercapnia has not been fully addressed experimentally to date. Interestingly however, Egr2 is differentially expressed when comparing normocapnic ventilator induced lung injury versus hypercapnic ventilator induced lung injury (143).

C. NF-κB

NF-κB is a family of transcription factors [RelA (p65), RelB, cRel, p50, p52] involved in the regulation of hundreds of genes associated with inflammation, immunity, apoptosis, cell survival, cell cycle, and more. This pathway has been extensively reviewed elsewhere. NF-κB is a master regulator of immune homeostasis, the activation of which is classically induced by ligands such as TNF-α, interleukin (IL)-1, and lipopolysaccharide binding to distinct receptors (TNFR, IL-1R, and TLR4) in the cell membrane and transducing signals downstream to a convergence point at the level of the IKK complex. The IKK complex is a heterotrimeric aggregation of three proteins (IKKα, IKKβ, and NEMO). This complex then initiates a series of phosphorylation events culminating in the activation of specific transcription factor dimers (with p65/p50 dimers the most common). NF-κB can also be noncanonically activated through ligation of the LTβR. The alternative NF-κB pathway results in the activation of IKKα homodimers (as opposed to the IKK complex) and preferentially activates the RelB/p52 heterodimer.

Given the evidence to date for CO₂ altering the expression of genes associated with inflammation and immunity, and the association between protective ventilation strategies and patient survival in the intensive care unit, it is not surprising that several groups have focused on the NF-κB pathway for evidence of CO₂ sensitivity. One of the first groups to report altered NF-κB signaling in conditions of elevated CO₂ (in this case hypercapnic acidosis) was Takeshita et al. (195). This study described suppressed proinflammatory cytokine production, which was associated with decreased p65 binding and increased expression of the inhibitory protein IκBα (195). Several other groups subsequently reported altered NF-κB signaling in vitro and in vivo in response to hypercapnia or hypercapnic acidosis (43, 108, 138). Interestingly, the experiments of Helenius et al. (83) exposing Drosophila to elevated CO₂ illustrated a marked change in Rel (Relish)-dependent antimicrobial peptide production, e.g., Diptericin. Thus it is attractive to speculate that the CO₂-sensing mechanism that results in altered Rel/NF-κB activation is conserved between insects and mammals. Helenius et al. (83) suggest that the node of sensitivity is at the level of or downstream of Relish activation. This conclusion is based on the fact that hypercapnia suppressed AMP production but did not alter Relish cleavage in response to peptidoglycan. We and others have further pursued the locus of sensitivity within the NF-κB pathway to CO_2. The Laffey group have published several studies outlining a role for altered canonical NF-κB signaling (increased IκBα and decreased p65) in response hypercapnia against a background of challenges such as epithelial damage (138), ventilation induced lung injury (34), and pulmonary epithelial stretch (85). These data are supported by evidence of altered canonical NF-κB activation against the background of a stimulus or challenge (43, 108, 195). However, in the basal state and in the absence of a proinflammatory challenge, members of the noncanonical NF-κB family appear to be particularly sensitive to changes in CO₂. In response to elevated CO₂, p100 (100), IKKα (43), and RelB (100, 139) all alter the cellular localization and are more abundant in the nuclear fraction. These effects appear to be independent of changes in pH. RelB additionally undergoes processing of its COOH-terminal region in hypercapnia, which results in cleaved and parental forms of the protein accumulating in conditions with high CO₂. These changes in RelB are associated with marked changes in the protein’s interactome between low and high CO₂ with p100 expression required for normal CO₂ sensitivity of RelB (100).

Thus, in summary, there is significant evidence documenting changes in the NF-κB pathway in response to altered CO₂. Whether these changes are a direct cause or a consequence of cellular CO₂ sensing is an important question and one that is under active investigation. A better understanding of how changes in CO₂ can affect immune and inflammatory signaling is crucial to allow us to determine what clinical circumstances hypercapnia might be tolerated and indeed employed therapeutically. Because of its immunomodulatory roles, hypercapnia may be of benefit in conditions of uncontrolled inflammation but may be detrimental against a background of bacterial infection.

D. FoxO3a

Forkhead box O3a is a transcription factor involved in regulation of proliferation and cell survival. In response to elevated CO₂, FoxO3a translocates to the nucleus of myotubes downstream of the energy sensor AMPKa2 (93). Myotubes exposed to CO₂ demonstrated evidence of atrophy in the form of decreased myotube diameter. Jaitovich et al. (93) propose a mechanism whereby in hypercapnia, phopho-FoxO3a promotes the expression of the ring finger protein MuRF1 which in turn leads to muscle atrophy. Thus FoxO3a indirectly modulates CO₂-dependent gene expression in skeletal muscle.

E. CREB

The CREB transcription factor regulated through cAMP and Ca²⁺ signaling (15) can function as both an activator and as repressor of gene expression (42). Phosphorylation of CREB on S133 can be modulated by several kinases.

Townsend et al. (206) identified CO₂-dependent regulation of G protein-regulated adenylyl cyclases, which was associated with increased CREB phosphorylation on S133. Notably, these G protein-coupled adenylyl cyclases displayed specific sensitivity to CO₂ (206), which is in contrast to soluble adenylyl cyclases, which have sensitivity to both CO₂ and ${HCO}_{3}^{-}$ (206).

F. HSF1

HSF1 is a transcription factor important in maintaining proteostasis (proteome homeostasis) during stress. Recently, Lu et al. (116) found that hypercapnia induced the protein expression and nuclear accumulation of HSF1 in immune cells. Intriguingly, mice that were heterozygous for HSF1 did not demonstrate hypercapnia-induced inhibition of IL-6 and TNF in vivo (116). HSF1 has previously been shown to negatively impact NF-κB activity (185, 215), and both IL-6 and TNF are NF-κB-regulated genes. Thus the authors propose that hypercapnia-mediated inhibition of NF-κB-dependent cytokine production requires HSF1 expression and/or activity. The mechanisms through which HSF1 directly responds to CO₂ and elicits its repressive effect on NF-κB activity in hypercapnia remain to be fully elucidated; however, the authors contend that it is likely independent of acidosis.

G. Other CO₂-Sensitive Regulators of Transcription

Zfh2 is a Drosophila gene encoding a conserved zinc finger transcription factor in immune tissues. Deletion of this gene prevented hypercapnic immune suppression in Drosophila (82). Given the conserved nature of this gene, it will be of great interest to determine whether the mammalian orthologues ZFHX3/4 are similarly involved in CO₂-dependent modulation inflammatory signaling. Additional transcription factors have been identified from microarray studies as being differentially expressed on the mRNA level (e.g., STAT1 and STAT2) (109).

While clearly of central importance, transcription factors are likely just one component of the regulatory network that governs the transcriptional response to hypercapnia. Epigenetic modifications, transcriptional coactivators/repressors, and regulatory RNAs likely also contribute to the transcriptional changes elicited in hypercapnia, although at present there is little known about this and more research is required. miR183 has been proposed as a CO₂-dependent miRNA (210). Levels of miR183 increase in response to hypercapnia, which in turn leads to a suppression of the mitochondrial protein isocitrate dehydrogenase 2 (IDH2). This effect is independent of acidosis, and the mitochondrial dysfunction is associated with reduced cell proliferation. Recently, miR133a has been implicated in the involvement of hypercapnia-induced smooth muscle contractility. In this study, airway smooth muscle cells demonstrated a reduced expression of miR133a in hypercapnia due to caspase-7 activity (183). Further work is required to define the role of alternative regulators of transcription in response to altered CO₂ levels.

H. Crosstalk Between O₂ and CO₂ Sensing: CO₂-Dependent Modulation of HIF

Several of the CO₂-sensitive transcription factors described above are reported to be sensitive to both changes in O₂ and changes in CO₂. This is true of NF-κB, Foxo3a, CREB, and HIF-1α (42). While hypoxia and hypercapnia are frequently coincidental features in a range of pathophysiological states, there have been relatively few studies looking at the impact of altered O₂ and CO₂ in combination with respect to transcriptional regulation. However, we have performed some studies to examine CO₂-dependent modulation of HIF (179).

HIF is discussed in detail elsewhere. During aerobic metabolism, the mitochondria of cells use oxygen as a substrate to produce ATP and CO₂. Thus the levels of O₂ and CO₂ are inextricably linked with several pathologies (e.g., respiratory disease) exhibiting concomitant hypoxia and hypercapnia. Given the close relationship between these two key physiological gasses, we investigated the impact of elevated CO₂ on HIF protein expression and HIF-dependent gene expression. Selfridge et al. (179) reported a marked suppression of DMOG-induced HIF-1α stabilization in vitro and in vivo. This degradation was independent of canonical hydroxylase-dependent HIF-1α degradation, with the authors proposing a role for lysosomal-dependent degradation of HIF-1α based on the ability of the compound bafilomycin A1 (a vacuolar ATPase inhibitor) to prevent CO₂-dependent suppression of HIF. Thus hypercapnia has the ability to alter the transcriptional profile downstream of HIF stabilization. For example, serum EPO levels were significantly suppressed in mice exposed to elevated CO₂ (179).

I. Regulation of Gene Expression by CO₂ Summary

Hypercapnia causes significant alterations in transcription in a variety of organisms and cells. The transcriptional profile elicited appears to be distinct for CO₂ and not shared with other respiratory stresses such as hypoxia. These transcriptional responses appear to be at least in part independent of changes in pH and potentially involve multiple transcription factors. Unlike the hypoxia field, which has HIF, at present there does not appear to be a master regulator of CO₂-dependent signaling. Clusters of genes involved in metabolism, fertility, and immunity appear to be consistently sensitive to alterations in CO₂ across several species, suggesting evolutionary conservation of sensing. The CO₂-dependent regulation of immune signaling is of particular interest, and several avenues of research implicate alterations in NF-κB-dependent signaling as being important. However, several key questions remain with respect to how hypercapnia-dependent transcription factors are sensing elevated CO₂ and whether they act alone or in combination to achieve transcriptional change.

IX. SUMMARY AND PERSPECTIVE

O₂ and CO₂ are the primary gaseous substrate and product of oxidative phosphorylation, respectively, and as such are important physiological gasses. In this review, we have discussed the mechanisms evolved by mammals to maintain homeostatic levels of oxygen and carbon dioxide within the compartments of the body. That this essential capacity for homeostatic control relies on multiple distinct mechanisms is not surprising given the importance of the regulation of levels of these key physiological gasses. However, a number of unanswered questions remain that are the topic of ongoing investigations.

A. What Is the Future for Therapeutic Intervention in the HIF Pathway?

A number of clinical trials are already ongoing for the use of HIF activators in the treatment of anemia and renal disease. It will be very interesting to see what other conditions these HIF activators become clinically indicated for, e.g., inflammatory diseases. Furthermore, there are a number of lines of evidence that the engagement of the hypoxia-induced transcriptional responses may be protective in ischemia-reperfusion injury including the demonstration that genetic or pharmacological PHD inhibition is protective (4, 140, 158, 175). Similarly, there is significant pharmaceutical interest in the development of specific HIF-1α isoform inhibitors. The emergence of these drugs could be very important in trying to inhibit potentially deleterious components of the HIF response while preserving the adaptive advantageous components.

B. Does a True Molecular CO₂ ‟Sensor” Exist?

While many responses are elicited downstream of a change in CO₂ levels, several of these responses can be attributed to alterations in pH. For those hypercapnic responses that appear to be refractory to changes in pH, it is of significant interest to determine how CO₂ is eliciting its effect. A direct modification of target proteins by CO₂ would be one way of supporting the idea of a CO₂ sensor. Detection of such labile modifications is challenging and may benefit from the development of new methodologies for the identification of carbon dioxide-mediated protein posttranslational modifications as recently published (112).

GRANTS

E. P. Cummins is funded by Science Foundation Ireland Career Development Award 15/CDA/3490. C. T. Taylor is funded by grants from the European Union (ERACoSys Med) and Science Foundation Ireland. M. J. Strowitzki receives funding from the German Research Foundation (DFG; STR 1570/1-1) and the Braun Foundation (Braun; BBST-D-18-00018).

DISCLOSURES

C. T. Taylor is on the Scientific Advisory Board of Akebia Therapeutics. No conflicts of interest, financial or otherwise, are declared by the other authors.

ACKNOWLEDGMENTS

Address for reprint requests and other correspondence: C. T. Taylor, UCD Conway Institute School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland (e-mail: [email protected]).

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Volume 100Issue 1January 2020Pages 463-488

Copyright & Permissions

History

Received 15 January 2019

Accepted 31 August 2019

Published online 9 December 2019

Published in print 1 January 2020

Keywords

Mechanisms and Consequences of Oxygen and Carbon Dioxide Sensing in Mammals

Abstract

I. INTRODUCTION

II. THE CONTRASTING NATURAL HISTORIES OF O2 AND CO2

III. ACUTE VERSUS CHRONIC GAS SENSING

IV. ACUTE PHYSIOLOGICAL RESPONSES TO ALTERED O2

A. The Membrane Hypothesis for Arterial Chemotransduction

B. A Metabolic Sensor

C. A Redox Sensor

D. A Gasotransmitter Sensor

E. Summary of Acute O2 Sensing in the Carotid Body

V. ACUTE PHYSIOLOGICAL RESPONSES TO ALTERED CO2

A. Regions of CO2 Chemosensitivity in the Brain

1. Medulla oblongata

a) retrotrapezoidnucleus.

b) nucleusofthesolitarytract.

2. Medullary raphe

3. Cerebellum

B. Role of Glial Cells, Respiratory Neurons, and Postsynaptic Processing in Acute CO2 Sensing

C. Mechanisms of Central CO2 Chemosensing

1. pH-sensitive ion channels

2. pH-sensitive G protein-coupled receptors

3. CO2-sensitive connexin proteins

D. Crosstalk Between the Central Nervous System and the Endocrine System with Respect to CO2-Dependent Regulation of Respiration

E. Crosstalk Between Central and Peripheral Nervous Systems with Respect to CO2-Dependent Regulation of Respiration

F. Acute CO2 Chemosensing Summary

VI. TRANSCRIPTIONAL RESPONSES TO O2 AND CO2

VII. REGULATION OF GENE EXPRESSION BY O2

A. Fetal Development and Tissue Maintenance

B. Altitude Adaptation and Exercise

C. Inflammation

D. Cancer

E. Ischemia

VIII. REGULATION OF GENE EXPRESSION BY CO2

A. Phox2b

B. Egr2

C. NF-κB

D. FoxO3a

E. CREB

F. HSF1

G. Other CO2-Sensitive Regulators of Transcription

H. Crosstalk Between O2 and CO2 Sensing: CO2-Dependent Modulation of HIF

I. Regulation of Gene Expression by CO2 Summary

IX. SUMMARY AND PERSPECTIVE

A. What Is the Future for Therapeutic Intervention in the HIF Pathway?

B. Does a True Molecular CO2 ‟Sensor” Exist?

GRANTS

DISCLOSURES

ACKNOWLEDGMENTS

REFERENCES

More from this issue >

Metrics

II. THE CONTRASTING NATURAL HISTORIES OF O₂ AND CO₂

IV. ACUTE PHYSIOLOGICAL RESPONSES TO ALTERED O₂

E. Summary of Acute O₂ Sensing in the Carotid Body

V. ACUTE PHYSIOLOGICAL RESPONSES TO ALTERED CO₂

A. Regions of CO₂ Chemosensitivity in the Brain

B. Role of Glial Cells, Respiratory Neurons, and Postsynaptic Processing in Acute CO₂ Sensing

C. Mechanisms of Central CO₂ Chemosensing

3. CO₂-sensitive connexin proteins

D. Crosstalk Between the Central Nervous System and the Endocrine System with Respect to CO₂-Dependent Regulation of Respiration

E. Crosstalk Between Central and Peripheral Nervous Systems with Respect to CO₂-Dependent Regulation of Respiration

F. Acute CO₂ Chemosensing Summary

VI. TRANSCRIPTIONAL RESPONSES TO O₂ AND CO₂

VII. REGULATION OF GENE EXPRESSION BY O₂

VIII. REGULATION OF GENE EXPRESSION BY CO₂

G. Other CO₂-Sensitive Regulators of Transcription

H. Crosstalk Between O₂ and CO₂ Sensing: CO₂-Dependent Modulation of HIF

I. Regulation of Gene Expression by CO₂ Summary

B. Does a True Molecular CO₂ ‟Sensor” Exist?