The purine nucleotide ATP mediates several distinct forms of sensory transduction in both the peripheral and central nervous systems. These processes share common mechanisms that involve the release of ATP to activate ionotropic P2X and/or metabotropic P2Y receptors. Extracellular ATP signalling plays an important role in ventilatory control, mediating both peripheral and central chemosensory transduction to changes in arterial levels of oxygen and carbon dioxide. New data also suggest that extracellular ATP may play an important role in mediating certain neurophysiological responses to systemic inflammation. Here, we propose the novel concept that both peripheral and central neurophysiological effects of ATP may contribute to alterations in ventilatory control during inflammatory pathophysiological states.

Introduction

Homoeostasis is critically dependent on afferent (sensory) mechanisms to enable adaptive behavioural and physiological responses. Many peripheral sensory processes share a common mechanism that involves the release of ATP to excite afferent fibres via activation of ligand-gated (P2X) and/or G-protein-coupled (P2Y) cell-surface receptors [1]. ATP has emerged as a critical mediator in several physiological processes, including the peripheral and central chemosensory control of ventilation [2]. ATP and its metabolite adenosine also play important roles in the peripheral and central inflammatory responses, through modulation of both immune and neural responses to acute inflammation [3]. It is well known that alterations in ventilatory control are common in many disparate pathophysiological states. In heart failure, the peripheral carotid body chemoreceptors, which serve to increase ventilation through detection of low levels of pO2 (partial pressure of oxygen) (hypoxia) and other blood-borne stimuli [4], exhibit much higher basal activity under normoxic conditions. This enhanced peripheral chemoreflex contributes to the tonic increase in overall sympathetic activity, which is associated with poorer clinical outcome [5]. Similarly, functional studies in humans with established and borderline essential hypertension [6,7], and experimental studies in spontaneously hypertensive rats, demonstrated higher basal levels of ventilatory drive and enhanced respiratory and sympathetic activities under hypoxic conditions [8]. The carotid chemoreceptor response to hypoxia was found to be markedly exaggerated in spontaneously hypertensive rats [9]. In acute inflammation, for example during bacterial sepsis, marked increases in ventilatory drive in critically ill patients occur often despite normal arterial pO2, relative hypocapnia and absence of metabolic acidosis. These clinical observations have been confirmed by experimental studies investigating the effects of the bacterial endotoxin, lipopolysaccharide, on ventilation and breath variability in humans [10]. Ongoing inflammation and the release of key inflammatory mediators, such as cytokines and prostaglandins, may provide a common basis for these conditions. In this brief review, we first consider the role of ATP in the development of inflammatory response. Through preliminary results, we speculate as to whether ATP extends its immunological role during pathophysiological states as a mediator between ventilatory control and activity of the immune system. We propose the novel concept that both peripheral and central neurophysiological effects of ATP may contribute to alterations in ventilatory control during inflammatory pathophysiological states.

ATP and inflammation

Extracellular ATP plays an important role in the activity of the immune system. Acting through P2X7 receptors, ATP may cause a variety of effects, including permeabilization of the plasma membrane, cell death, cell proliferation, shedding of cell-adhesion molecules, killing of intracellular pathogens or secretion of various inflammatory cytokines, including IL-1β (interleukin-1β) and tumour necrosis factor α [3]. Extracellular ATP also causes the generation of reactive oxygen species when applied to macrophages [11]. Peripheral blockade of P2X receptors during systemic inflammation reduces fever and decreases plasma levels of major inflammatory cytokines [12]. During systemic inflammation P2X7 receptors are markedly up-regulated in the CNS (central nervous system) where extracellular ATP triggers cytokine release from activated microglia [13]. Most importantly, there is evidence that activated immune cells such as lymphocytes and macrophages release large amounts of ATP into the extracellular space [1416]. In conscious rabbits, using amperometric ATP biosensors placed in the third brain ventricle, we detected significant increases in ATP concentration in the cerebrospinal fluid following endotoxin challenge (Figure 1A).

Role of ATP in mediating CNS response to systemic inflammation

Figure 1
Role of ATP in mediating CNS response to systemic inflammation

(A) Increase in ATP concentration in the cerebrospinal fluid of the third ventricle during the development of the systemic inflammatory response in conscious rabbits. The graph shows representative raw data illustrating changes in ATP level (measured in real time using amperometric ATP biosensors) and development of fever [increase in core body temperature (Tb)] following intravenous administration of Escherichia coli endotoxin (0.5 μg/kg). The arrow indicates time of endotoxin injection. (B) ATP-induced increases in intracellular Ca2+ in Rhod-2-loaded transverse slices of the rat medulla oblongata. Fluorescent sequential pseudocoloured images of a slice at the level of the rostral ventrolateral medulla in control (arrow 1) and after the application of ATP (arrow 2). The trace represents relative changes in intensity of fluorescence over time in the corresponding images.

Figure 1
Role of ATP in mediating CNS response to systemic inflammation

(A) Increase in ATP concentration in the cerebrospinal fluid of the third ventricle during the development of the systemic inflammatory response in conscious rabbits. The graph shows representative raw data illustrating changes in ATP level (measured in real time using amperometric ATP biosensors) and development of fever [increase in core body temperature (Tb)] following intravenous administration of Escherichia coli endotoxin (0.5 μg/kg). The arrow indicates time of endotoxin injection. (B) ATP-induced increases in intracellular Ca2+ in Rhod-2-loaded transverse slices of the rat medulla oblongata. Fluorescent sequential pseudocoloured images of a slice at the level of the rostral ventrolateral medulla in control (arrow 1) and after the application of ATP (arrow 2). The trace represents relative changes in intensity of fluorescence over time in the corresponding images.

Thus it appears that during inflammatory pathophysiological states, extracellular concentrations of ATP increase both in the periphery and in the CNS. Below, we discuss recent results from our laboratory demonstrating the importance of ATP-mediated purinergic signalling in central and peripheral chemosensory control of breathing and how this control may be affected by extra ATP released under pathological conditions.

ATP and peripheral chemoreceptors

In adult mammals, type I (glomus) cells of the carotid body are the main peripheral O2 sensors. A variety of stimuli, but most importantly hypercapnia [high pCO2 (partial pressure of carbon dioxide)], acidosis (low pH) and hypoxia (low pO2), trigger glomus cells to release neurotransmitters that activate afferent nerve fibres of the carotid sinus nerve, thereby transducing chemosensory information to the respiratory centres in order to evoke adaptive changes in breathing [4]. Mitochondrial cytochrome aa3, which has very low oxygen affinity [17], and non-mitochondrial cytochromes a592 [18] and cytochromes b558 [19] have been implicated in the glomus cell's chemosensory mechanism. While the exact mechanism of chemosensory transduction still remains incompletely understood, two important players that may link the activity of the immune systems with respiratory control have to be considered in the context of the present review. First, increased generation of reactive oxygen species has been implicated in chronic intermittent hypoxia [20], which results in increased chemosensitivity and sympathetic drive across species including humans [21]. Secondly, ATP has recently been identified as a key mediator of carotid body chemosensory transduction [22]. ATP receptors have been detected on the afferent terminals of the carotid sinus nerve surrounding individual glomus cells or their clusters [22]. ATP evoked a dramatic increase in the carotid sinus nerve chemoafferent discharge in a superfused in vitro murine carotid body–carotid sinus nerve preparations. P2 receptor antagonists dose-dependently reduced hypoxia-evoked activation of carotid chemoafferents. Critically, P2X2 receptorknockout mice demonstrated a markedly decreased hypoxic ventilatory responses and up to 80% reduction in baseline and hypoxia-stimulated carotid sinus nerve discharge. Given that CO2-evoked carotid chemoreceptor discharge is similarly reduced in P2X2-knockout mice (A.V. Gourine, unpublished work), ATP clearly plays a key role in the carotid body process of conveying information about arterial pO2, pCO2 and pH to the CNS.

How could extracellular ATP link inflammation with changes in ventilatory control at the level of the carotid body?

There are striking immunological features of the carotid body that merit consideration. The carotid body is a rich, although previously unrecognized, abundant site of monocytes and macrophages within its perivascular and connective tissue spaces [23]. Spectrophotometric recordings reveal that monocytes/macrophages represent the dominating cell type through cytochrome b558 activity, which generates superoxide anions (O2) through the NADPH oxidase system. Hypoxia-induced up-regulation of several inflammatory and hypoxia-related genes, including hypoxia-inducible factors, in macrophages [24] in the vicinity of the carotid body glomus cells may provide several stimuli (in addition to superoxide anions) that could increase carotid sinus nerve discharge. Both IL-1 [25] and IL-6 [26] receptors have been detected in the rat carotid body, both of which are pivotal cytokines responsible for shaping the inflammatory response and mediating adaptive autonomic and behavioural responses during infection.

Preliminary work from our laboratory, using superfused ex vivo murine carotid body–carotid sinus nerve preparations, supports numerous clinical observations that systemic inflammation results in an increase in respiratory activity. After mice had been subjected to systemic inflammation (peritonitis) for 4 h, both baseline carotid sinus discharge and chemosensory responses to hypoxia were dramatically increased (Figure 2). This occurs in the absence of circulating inflammatory mediators or acidosis but in the presence of hyperoxia, which would normally minimize carotid sinus discharge. These observations are consistent with the concept that cellular dysoxia [27] occurs during inflammation through several separate cellular mechanisms including mitochondrial dysfunction and generation of free radicals.

Whole carotid sinus chemoafferent nerve responses to hypoxia in the isolated carotid body–sinus nerve preparations excised from mice treated with either intraperitoneal injections of sterile saline (control) or zymosan (500 mg/kg; sepsis)

Figure 2
Whole carotid sinus chemoafferent nerve responses to hypoxia in the isolated carotid body–sinus nerve preparations excised from mice treated with either intraperitoneal injections of sterile saline (control) or zymosan (500 mg/kg; sepsis)

Zymosan elicits a profound systemic inflammatory response characterized by release of cytokines and other inflammatory mediators. Basal carotid sinus nerve discharge (normoxia 95% oxygen/5% carbon dioxide) in preparations taken from the zymosan-treated mouse is substantially higher compared with that in the controls. Chemosensory response to hypoxia (95% nitrogen/5% carbon dioxide for 3 min) has been found to be dramatically potentiated during zymosan-induced sepsis.

Figure 2
Whole carotid sinus chemoafferent nerve responses to hypoxia in the isolated carotid body–sinus nerve preparations excised from mice treated with either intraperitoneal injections of sterile saline (control) or zymosan (500 mg/kg; sepsis)

Zymosan elicits a profound systemic inflammatory response characterized by release of cytokines and other inflammatory mediators. Basal carotid sinus nerve discharge (normoxia 95% oxygen/5% carbon dioxide) in preparations taken from the zymosan-treated mouse is substantially higher compared with that in the controls. Chemosensory response to hypoxia (95% nitrogen/5% carbon dioxide for 3 min) has been found to be dramatically potentiated during zymosan-induced sepsis.

Several potential mechanisms exist that may explain how immune activation may affect carotid body function. First, local and/or circulating mediators of inflammation may induce transcriptional changes in the glomus cells or directly stimulate peripheral terminals of the carotid sinus nerve. A precedent already exists for cytokines (e.g. IL-1β) that are able to trigger increases in afferent vagal nerve activity, via activation of macrophages and dendritic cells that have been detected around vagal abdominal paraganglia of the rat [28]. This is one mechanism through which sickness behaviour may be induced during compartmentalized inflammation.

Secondly, generation of superoxide anions contributes to enhancing peripheral chemosensitivity in pathophysiological states. For example, in pacing-induced heart failure, the expression of NADPH oxidase, production of superoxide anion and carotid sinus nerve discharge are all elevated [29].

Finally, taking into the account the key role played by ATP in mediating carotid body chemosensory transduction we propose that ATP may be responsible for increases in baseline carotid sinus discharge, augmented responses to chemosensory stimulation and high respiratory drive under pathological conditions. Indeed, as discussed above, during development of the systemic inflammatory response, activated immune cells release large amounts of ATP, resulting in increases in tissue and plasma levels [30]. If this extra ATP reaches peripheral terminals of the carotid sinus nerve chemoafferent fibres the activities of the latter would undoubtedly increase via interaction of ATP with P2X2, P2X3 and P2X2/P2X3 receptors [22]. Interestingly, plasma levels of the ATP breakdown product adenosine have also been shown to be elevated during sepsis [31]. Adenosine not only exhibits powerful immunosuppressive effects, but also directly stimulates carotid chemoreceptors through postsynaptic A2a adenosine receptors [32,33] and presynaptic A2b adenosine receptors [33]. Some other key mediators in systemic inflammation such as nitric oxide, which is increased markedly during sepsis [34], interestingly reduce carotid body chemosensitivity [35].

ATP, central chemosensitivity and inflammation (Figure 3)

The brainstem respiratory network, which generates respiratory activity, is located just above the classical CO2/[H+] chemosensitive areas that were identified by Hans Loeschcke and Robert Mitchell on the ventral surface of the medulla oblongata. Compelling data now suggest that ATP also plays an important role in central chemosensory transduction, mediating the effects of increased arterial pCO2 on breathing [36]. Blockade of ATP receptors within the ventral respiratory network decreases resting respiratory activity and attenuates the increase in ventilation induced by CO2. At the cellular level, blockade of ATP receptors reduces baseline firing as well as CO2-induced increases in the discharge of pre-inspiratory and inspiratory neurons of the medullary respiratory network. Experiments, in which ATP was applied exogenously demonstrated marked increases in intracellular calcium on the ventral surface and adjacent areas of the medulla oblongata (Figure 1B) as well as augmenting central respiratory drive both in neonatal [37] and adult [36] experimental animals. Furthermore, experiments using amperometric ATP biosensors sited on the ventral medullary surface CO2/[H+] chemosensitive areas revealed a strong temporal and quantitative correlation between ATP release and resulting changes in breathing. CO2-evoked ATP release from the ventral surface of the medulla is site-specific (no ATP release was detected on the dorsal surface of the medulla) and does not require inputs from the peripheral chemoreceptors.

Hypothetical scheme illustrating potential interactive sites where direct or indirect release of ATP by the cells of the immune system may act to increase ventilatory drive

Figure 3
Hypothetical scheme illustrating potential interactive sites where direct or indirect release of ATP by the cells of the immune system may act to increase ventilatory drive

In the carotid body, a decrease in pO2 or an increase in pCO2/[H+] activates glomus cells, which release ATP as the main transmitter to stimulate afferent terminals of the carotid sinus nerve via interaction with P2X receptors that contain the P2X2 subunit, with or without P2X3 subunit. Local release of extracellular ATP, other inflammatory factors and endothelial-derived mediators increases carotid sinus nerve chemoafferent discharge either directly or via cellular/genomic changes within the glomus cells of the carotid body. On the ventral surface of the medulla, an increase in pCO2/[H+] activates primary chemosensors, which release ATP to act via P2 receptors on ventrally projecting dendrites of more dorsally located secondary chemosensitive neurons and/or respiratory neurons. The activity of these neurons feeds into the respiratory network and evokes adaptive increases in breathing. Release of ATP in the CNS during systemic inflammation may increase ventilation directly, through activation of the medullary respiratory network. Descending excitatory projections to the respiratory centre from the warm-sensitive neurons of the anterior hypothalamus may further contribute to an increase in respiratory drive to meet metabolic demands of the developing febrile response.

Figure 3
Hypothetical scheme illustrating potential interactive sites where direct or indirect release of ATP by the cells of the immune system may act to increase ventilatory drive

In the carotid body, a decrease in pO2 or an increase in pCO2/[H+] activates glomus cells, which release ATP as the main transmitter to stimulate afferent terminals of the carotid sinus nerve via interaction with P2X receptors that contain the P2X2 subunit, with or without P2X3 subunit. Local release of extracellular ATP, other inflammatory factors and endothelial-derived mediators increases carotid sinus nerve chemoafferent discharge either directly or via cellular/genomic changes within the glomus cells of the carotid body. On the ventral surface of the medulla, an increase in pCO2/[H+] activates primary chemosensors, which release ATP to act via P2 receptors on ventrally projecting dendrites of more dorsally located secondary chemosensitive neurons and/or respiratory neurons. The activity of these neurons feeds into the respiratory network and evokes adaptive increases in breathing. Release of ATP in the CNS during systemic inflammation may increase ventilation directly, through activation of the medullary respiratory network. Descending excitatory projections to the respiratory centre from the warm-sensitive neurons of the anterior hypothalamus may further contribute to an increase in respiratory drive to meet metabolic demands of the developing febrile response.

These results suggest a second pathway through which ATP can increase respiratory activity during inflammatory pathophysiological states. Indeed, we have shown that during systemic inflammation the level of ATP in circulating cerebrospinal fluid increases, at a similar level to that detected by amperometric ATP biosensors on the ventral medullary surface chemosensitive areas (Figure 1). Therefore the ventral surface chemosensitive areas are likely to be exposed to elevated levels of extracellular ATP even when arterial and brain pCO2 and pH remain normal. We suggest that this may contribute to the increases in ventilation often observed in many disparate pathophysiological states that include an inflammatory component. Whether an increase in cerebrospinal ATP concentration of this magnitude is indeed responsible for changes in central respiratory drive remains to be determined.

A third pathway responsible for increases in ventilation during systemic inflammation may originate directly from the thermosensitive regions of the hypothalamus. We have recorded a marked increase in extracellular ATP in the preoptic area/anterior hypothalamus during systemic inflammation induced in rabbits by small amounts of endotoxin (A.V. Gourine, unpublished work). In our early in vitro experiments, we observed profound excitatory effects of ATP on the activity of hypothalamic warm-sensitive neurons [38]. The preoptic area also mediates additional respiratory drive, observed at raised body temperature in anaesthetized rats [39]. During systemic inflammation, this pathway may play a similar role and contribute to an increase in respiratory activity to meet metabolic demands of the developing febrile response.

Conclusion

ATP is a ubiquitous cellular energy source and intercellular messenger molecule that plays an important role in co-ordinating many homoeostatic mechanisms, potentially linking ventilatory control with the activity of the immune system. We propose the novel concept that peripheral and/or central neurophysiological effects of ATP, released by activated cells of the immune system in the brain and the periphery, may contribute to increases in ventilation during inflammatory pathophysiological states.

Central Nervous System: A Focus Topic at Life Sciences 2007, held at SECC Glasgow, U.K., 9–12 July 2007. Edited by C. Dart (Liverpool, U.K.), M. Houslay (Glasgow, U.K.), M. Ludwig (Edinburgh, U.K.), R. Porter (Trinity College Dublin, Ireland) and J. Potts (Misouri-Columbia, U.S.A.).

Abbreviations

     
  • CNS

    central nervous system

  •  
  • IL-1β

    interleukin-1β

A.V.G. is a Wellcome Trust Senior Research Fellow. Our experimental work described in this review has been supported by The Wellcome Trust, BBSRC (Biotechnology and Biological Sciences Research Council) and a Young Investigator Award from the Intensive Care Society to G.L.A.

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Author notes

1

Owing to exceptional unforeseen circumstances, this speaker was unable to give this presentation at the meeting. This paper is included in the interest of completeness of the session.