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Themed Issue Papers |
1 Department of Comparative Biosciences, University of Wisconsin Madison, 2015 Linden Drive, Madison, WI 53706, USA
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Abstract |
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(Received 9 October 2006;
accepted after revision 6 November 2006; first published online 10 November 2006)
Corresponding author G. S. Mitchell: Department of Comparative Biosciences, University of Wisconsin Madison, 2015 Linden Drive, Madison, WI 53706, USA. Email: mitchell{at}svm.vetmed.wisc.edu
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Introduction |
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TopAbstractIntroductionReferences |
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Apart from any discussion of possible relationships between LTF and OSA, an additional goal of this paper is to suggest new therapeutic strategies to harness the capacity for LTF within specific motor pools that may increase respiratory muscle activity and upper airway tone during sleep. Thus, a detailed understanding of cellular and synaptic mechanisms contributing to LTF may allow us to target key molecules that may offset the tendency for airway collapse, regardless of any intrinsic relationships between LTF and OSA.
Intermittent hypoxia causes respiratory LTF
Although published under a different name, LTF was first described by Millhorn et al.,, (1980a,b; Millhorn & Eldridge, 1986). In pioneering studies on anaesthetized cats, these investigators electrically stimulated the carotid sinus nerve in an episodic pattern and observed that integrated phrenic activity was increased above baseline levels for at least 90 min post-stimulation. Similar post-stimulus facilitation of respiratory activity is observed following intermittent hypoxia, and this effect was called respiratory long-term facilitation or LTF (Hayashi et al. 1993; Fregosi & Mitchell, 1994; Bach & Mitchell, 1996; Powell et al. 1998). Long-term facilitation has now been reported in respiratory nerve activity in anaesthetized rats (Hayashi et al. 1993; Bach & Mitchell, 1996; Peng et al. 2003) and cats (Fregosi & Mitchell, 1994; Morris et al. 2000, 2003), as well as ventilation in unanaesthetized rats (Olson et al. 2001; McGuire et al. 2003a,b), mice (Kline et al. 2002), dogs (Cao et al. 1992), goats (Turner & Mitchell, 1997), ducks (Mitchell et al. 2001b), sleeping humans (Babcock et al. 2003; Aboubakr et al. 2001) and awake humans, but only when maintained under conditions of modest hypercapnia (Harris et al. 2006). In general, LTF is predominantly observed in phrenic burst amplitude when anaesthetized and vagotomized animals are studied, with only small and variable effects on burst frequency (Powell et al. 1998; Mitchell et al. 2001a). In contrast, LTF is expressed as an increased breathing frequency, with small or variable effects on tidal volume in awake animals (Mitchell et al. 2001a). Factors contributing to this difference may include: (1) species, arousal state, or experimental preparation (i.e. anaesthetized versus unanaesthetized; vagotomized versus vagally intact; artificially ventilated versus spontaneously breathing); and (2) LTF may arise from multiple mechanisms at multiple loci with different influences on respiratory amplitude versus timing. Arousal state may play a prominent role, since unanaesthetized rats exhibit tidal volume LTF following intermittent hypoxia while in documented NREM sleep, but not when awake (Nakamura et al. 2005, 2006). Hypocapnia attendant to LTF in spontaneously breathing rats also changes the apparent breathing pattern, since chemoreceptor feedback constrains LTF, mainly by reducing the tidal volume (Olson et al. 2001).
Long-term facilitaion is also expressed in upper airway muscle activity
Long-term facilitaion in motor outputs innervating respiratory pump muscles increases ventilation. However, when LTF is expressed in hypoglossal motor neurones that innervate protrussor and retrussor muscles of the tongue (Bach & Mitchell, 1996; Fuller, 2005), it will be expressed as a change in airway resistance. The magnitude of XII nerve LTF varies considerably more than phrenic LTF among Sprague–Dawley rat substrains (Fuller et al. 2000, 2001a), thereby implying that upper airway and respiratory pump muscle LTF are differentially regulated. The concept of differential and local regulation of the respective motor nuclei during LTF is reinforced by the observation that midcervical injections of either serotonin receptor antagonists or protein synthesis inhibitors block phrenic, but not XII nerve, LTF following intermittent hypoxia (Baker & Mitchell, 2002). When the same drugs are delivered systemically, both phrenic and XII nerve LTF are blocked. Localized effects on different respiratory motor outputs are consistent with our hypothesis that LTF results from synaptic facilitation between medullary premotor neurones and individual populations of respiratory motor neurones (Mitchell et al. 2001a; Feldman et al. 2003). Differential regulation of upper airway motor output (versus pump muscle) may arise from differences in premotor input (Woch et al. 2000; Peever et al. 2002; Gestreau et al. 2005), reflex activation of serotonergic pathways (Sood et al. 2005) or susceptibity to modulatory influences, such as circulating sex hormone levels (Behan et al. 2002, 2003). An important implication of differential regulation is the potential to selectively target key molecules in upper airway motor pools in an attempt to harness LTF as a potential treatment for OSA.
Factors that affect LTF (and OSA)
Multiple factors have been identified that are relevant to potential interactions between LTF and OSA. Caution must certainly be exercised when interpreting similarities between LTF in anaesthetized rats and OSA in sleeping human subjects, yet the patterns are sometimes similar enough to raise important questions.
Long-term facilitation results from many protocols of intermittent hypoxia. Long-term facilitation is pattern sensitive, and is relatively insensitive to the severity or duration of hypoxia used as an inducing stimulus, as long as it is intermittent. The most frequently studied protocols of intermittent hypoxia in our laboratory involve 3–5 min isocapnic hypoxic episodes, with 5 min intervals (see Mitchell et al. 2001a). If a similar, cumulative duration of sustained hypoxia is presented, LTF does not occur (Baker & Mitchell, 2000).
Although there are some similarities between these experimental protocols used to study LTF and the intermittent hypoxia expected during sleep apnoeas, there are also significant differences. For example, it would certainly be rare to experience repetitive 5 min episodes. This protocol was not in fact intended to simulate sleep apnoea episodes, and differs in important characteristics from patterns expected during OSA, such as the lack of simultaneous hypoxia and hypercapnia (i.e. asphyxia), mechanofeedback induced by breathing efforts against an obstructed airway, and a regular clustering of apnoeas versus the more erratic exposures expected during OSA. Our use of 5 min hypoxic episodes was intended as a tool to enable study of respiratory plasticity in general, and was not meant to be a simulation of sleep apnoea per se. However, the details of intermittent hypoxia protocols used may not be as relevant to LTF as the fact that oxygen oscillates into and out of hypoxaemia. For example, LTF is insensitive to hypoxaemia levels between 28 and 60 mmHg during three 5 min hypoxic episodes (Fuller et al. 2000). Furthermore, 15 s exposures to 12% oxygen elicit phrenic LTF (Peng & Prabhakar, 2003) and three or six 25 s ventilator apnoeas are equally effective at inducing phrenic and XII nerve LTF as three 5 min hypoxic episodes in anaesthetized, paralysed and vagotomized rats (see Fig. 1; Mahamed & Mitchell, 2006,). Thus, LTF is insensitive to the intermittent hypoxia protocol, since the maximal arterial desaturation is only about 90% during 25 s ventilator apnoeas (ca 70 mmHg), and arterial CO2 increases by as much as 15 mmHg. At the other extreme, when 5 min hypoxic episodes are interspersed with 30 min intervals, LTF is not induced in this same preparation (Bach et al. 1999). The sensitivity of LTF to the specific temporal pattern of hypoxia makes it a likely influence on breathing after clustered apnoeas in human subjects, particularly in mild or preclinical cases of OSA (i.e. AHI < 10). Still it is difficult to extrapolate from studies on rats to humans, since rats do not exhibit spontaneous sleep-disordered breathing, except possibly in genetically obese Zucker rats (Radulovacki et al. 1996; Nakano et al. 2001).
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The prevalence of OSA in humans mirrors the decline of LTF in ageing rats. For example, OSA prevalence is low in young men (ca 1%), and reaches 5–6% between 40 and 70 years old (Bixler et al. 1998). The prevalence of OSA remains low in women until menopause, and then increases to levels between 3 and 4%, unless they are taking hormone replacement therapy. Although there is no link between rat LTF and human OSA, the striking inverse relationships of age and sex-hormone dependence in LTF and OSA lead to some interesting questions. One possibility is that the disappearance of upper airway LTF with age in human males (and postmenopausal females) accelerates the appearance of OSA owing to the loss of an important compensatory mechanism.
Genetic determinants of LTF. The magnitude of LTF appears to be influenced by genetics, since it varies in magnitude between inbred rat strains (Bavis et al. 2003) and even between substrains (vendor/colony) of Sprague–Dawley rats (Fuller et al. 2001a). If there is indeed a link between inadequate LTF and the onset of OSA, then the greater genetic variability characteristic of human populations suggests similar variability in the predisposition to OSA.
Metaplasticity in LTF: chronic intermittent hypoxia. Although phrenic LTF normally lasts for several hours postacute intermittent hypoxia (AIH), chronic intermittent hypoxia (CIH, e.g. 5 min episodes at 5 min intervals, 12 h per day for 7 days) elicits longer lasting forms of respiratory plasticity, including a serotonin-dependent enhancement of phrenic LTF (Ling et al. 2001; Peng & Prabhakar, 2003; McGuire et al. 2004). These effects, which can last for many days to weeks (Fuller et al. 2001b), may arise through amplification in central neural integration of chemoafferent neurone activity (Ling et al. 2001; Fuller et al. 2003) or increased carotid chemoafferent activity (Peng et al. 2003). However, sensory LTF in chemoafferent neurone activity is expressed uniquely in rats exposed to CIH and is not observed in naïve rats exposed only to acute intermittent hypoxia (Peng et al. 2003). The enhancement of LTF by CIH, whether owing to amplifications in central neural mechanisms or peripheral chemoreceptor function, may play an important role in OSA, since prior nights of intermittent hypoxia may increase the inherent capacity for compensation, or exaggerate pathological consequences.
Chronic intermittent hypoxia elicits additional forms of respiratory plasticity, including increased baseline ventilatory drive (which may reflect a long-lasting manifestation of LTF; Ling et al. 2001; McGuire et al. 2003b; Peng et al. 2003; Reeves & Gozal, 2005), as well as an amplification of the hypoxic ventilatory response (Ling et al. 2001; McGuire et al. 2003b; Peng et al. 2003; Reeves & Gozal, 2005). Each of these effects appears to be serotonin dependent, suggesting that serotonin has the potential to elicit respiratory plasticity in multiple time domains (Ling et al. 2001; McGuire et al. 2004).
The effects of CIH on the phrenic motor system may vary with age. For example, if cyclical hypoxia is administered from early pregnancy to birth, rats exhibit elevated ventilation under normoxic conditions from the 5th postnatal day until adulthood (Gozal et al. 2003). If CIH is administered for 30 days, starting at various postnatal ages, significant changes in ventilation are observed in all but the oldest rats; the greatest changes occur in rats exposed between 1 and 50 days postnatally (Reeves & Gozal, 2005). Thus, a critical developmental window exists in which chronic intermittent hypoxia induces life-long ventilatory effects. At the opposite extreme, geriatric female rats do not exhibit LTF after three 5 min episodes of hypoxia (Zabka et al. 2003). Nevertheless, chronic intermittent hypoxia restores the capacity for LTF on subsequent exposure to acute intermittent hypoxia in these animals (Zabka et al. 2003).
Several reports suggest that CIH can be used to harness respiratory plasticity as a means of reversing functional deficits (Fuller et al. 2001b; 2003,). However, CIH is also associated with considerable risk of morbidity, such as systemic hypertension, hippocampal apoptosis and learning disabilities (Gozal, 2001). Subtler protocols of chronic intermittent hypoxia (ten 5 min episodes per day for 7 days) enhance LTF (particularly XII nerve LTF) without evidence of systemic hypertension (Wilkerson et al. 2005b). We hypothesize that even modest intermittent hypoxia resulting from subclinical manifestations of sleep apnoea has the potential to enhance respiratory LTF, possibly providing relief from subsequent apnoeic episodes.
State dependence of LTF. Although ventilatory LTF has been reported in multiple species when awake (Mitchell et al. 2001a), the magnitude and duration appear limited in comparison with studies on anaesthetized, paralysed, vagotomized and ventilated animals. A portion of this difference may relate to LTF-induced hypocapnia, which limits the expression of LTF in spontaneously breathing animals (Olson et al. 2001). Recent studies demonstrated robust ventilatory LTF during non-rapid eye movement (NREM) sleep in Lewis rats, largely through increased tidal volume (Nakamura et al. 2005, 2006). Ventilatory LTF was not observed in a comparison of awake baseline posthypoxia measurements. Thus, it appears that sleep exerts a powerful influence on LTF, a property that increases its potential relevance to OSA. Although the basis for the distinction between wakefulness and NREM sleep is not clear, it may relate to the fact that medullary serotonergic neurone activity is decreased during NREM sleep, and discharges at higher, nearly maximal levels during wakefulness (Heym et al. 1982; Jacobs & Fornal, 1993, 1997; Veasey et al. 1995). Thus, episodic hypoxia may stimulate caudal raphe neurones through a greater dynamic range during NREM sleep than during wakefulness.
A progression from occasional apnoeas to OSA?
Clinically, an apnoea is commonly defined as near absent ventilation lasting greater than 10 s and resulting in an arterial desaturation of at least 4% (Rechtschaffen & Kales, 1968). In a random sampling of 602 men and women between 30 and 60 years old (the ‘Wisconsin Cohort’), 24% of men and 9% of women had five apnoeas or hypopnoeas per hour of sleep, or more (Young et al. 2002). To prevent pathophysiological consequences of OSA, compensations and/or compromises in the control of breathing are needed, possibly in the form of respiratory LTF. Long-term facilitation may stabilize the upper airway and minimize future obstructive apnoeas during sleep, thereby delaying the onset of clinical OSA. The functional significance of LTF in respiratory pump muscles is less clear, although it may improve ventilatory stability by decreasing the CO2 apnoeic threshold (Morris & Gozal, 2004; Dempsey, 2005; Mahamed & Mitchell, 2006a,b) or destabilize breathing owing to increased feedback loop gain (Khoo, 2000; Mahamed & Mitchell, 2006a,b).
Many individuals with high airway resistance do not reach the clinical criteria for OSA. For example, approximately 18% of men and 7% of women in the Swedish population snore (Larsson et al. 2003). Such individuals commonly experience sporadic apnoeas and/or hypopnoeas, with a frequency capable of eliciting LTF. In the ‘Wisconsin Sleep Cohort’, the average AHIs increased from 2.5 to 5.1 events h–1 in an 8 year follow-up study (Young et al. 2002). Although that difference was not statistically significant, individuals who snored habitually did increase their AHI by 6.3 events h–1 (Young et al. 2002). This frequency of apnoeas is in a range characteristic of LTF-inducing protocols, thus suggesting the possibility that LTF is relevant to OSA. If a compensatory relationship exists, then diminishing capacity to express LTF, whether as a result of age, sex or genetics, would minimize compensation, thereby increasing the AHI and accelerating progression towards clinically diagnosed OSA. Another common feature of OSA is that long periods of stable breathing are observed in 80% of OSA patients (Younes, 2003); LTF may enforce stable breathing in these patients. The remaining 20% of patients without consolidated stable breathing periods may lack upper airway LTF or have sufficient mechanical limitation that subtle neural mechanisms like LTF are inadequate. Although there is little direct evidence concerning the relationship between LTF and OSA in humans, if any, it is a promising area that warrants further investigation.
Evidence for and against LTF in humans
Ventilatory LTF has not been found in normal, male or female human subjects when awake (McEvoy et al. 1996; Jordan et al. 2002; Morris & Gozal. 2004) when using stimulus protocols that elicit at least some degree of ventilatory LTF in other species (goats, Turner & Mitchell, 1997; ducks, Mitchell et al. 2001b; and rats, Olson et al. 2001; McGuire et al. 2002). In contrast, when similar studies were performed on human subjects during NREM sleep, ventilatory LTF was observed when subjects had upper airway flow limitation, but not in normal subjects or subjects with OSA whose airflow limitation was relieved by CPAP(Babcock & Badr, 1998; Babcock et al. 2005). This observation led to the concept that humans exhibit LTF in upper airway resistance muscles, but not in the thoracic respiratory pump muscles (Aboubakr et al. 2001; Shkoukani et al. 2002). Thus, ventilatory LTF is expressed only when inspiratory flow resistance is relieved by upper airway dilatation; in normal subjects, no flow limitation is relieved and tidal volume is not increased (Babcock et al. 2003). In OSA patients, the mechanical limitations to flow may be too severe unless they are normalized with continuous positive airway pressure (CPAP; Aboubakr et al. 2001; Babcock et al. 2003). Heterogeneity in phrenic versus XII nerve LTF has been observed in rodent strains (Bavis et al. 2003) and even substrains; some colonies of Sprague–Dawley rats express XII nerve LTF while others do not (Fuller et al. 2001a). Thus, the species peculiarities of humans are well within the intraspecies variation of rodents. Recent evidence suggests that when slightly hypercapnic conditions are maintained in awake human subjects, ventilatory LTF is observed (Mateika et al. 2004; Harris et al. 2006). Furthermore, genioglossus LTF is exaggerated during constant, moderate hypercapnia in sleeping human subjects (Harris et al. 2006). At least some differences between humans and other species may be related to details such as the prevailing background level of CO2 or a shift towards greater plasticity in upper airway muscles. The emphasis on upper airway LTF in humans during sleep is particularly relevant in the context of OSA, and suggests that LTF is capable of influencing the expression of apnoeas during human sleep.
Cellular and synaptic mechanisms of phrenic LTF
Mechanisms of phrenic LTF have been studied most frequently in anaesthetized, vagotomized and ventilated rats (Mitchell et al. 2001a; Feldman et al. 2003; Baker-Herman et al. 2004). Our working model (Fig. 2) is that intermittent hypoxia triggers spinal serotonin release and serotonin receptor activation, thereby stimulating spinal protein synthesis that subsequently maintains phrenic LTF (Fuller et al. 2001c; Baker-Herman & Mitchell, 2002). New synthesis of Brain-derived neurotrophic factor (BDNF) protein is necessary for phrenic LTF, since RNA interference with small, interfering RNAs (siRNAs) targeting BDNF mRNA abolishes phrenic LTF (Baker-Herman et al. 2004). Brain-derived neurotrophic factor is sufficient to elicit phrenic LTF, since intrathecal BDNF administration elicits a long-lasting facilitation of phrenic nerve activity with a magnitude and time course consistent with hypoxia-induced phrenic LTF (Baker-Herman et al. 2004). Both phrenic LTF following intermittent hypoxia and BDNF-induced LTF require activation of the high-affinity tyrosine kinase receptor (TrkB). Tyrosine kinase receptor activation subsequently strengthens short-latency synaptic inputs from glutamatergic respiratory premotor neurones onto phrenic motor neurones (Golder F. J. & G. S. Mitchell, unpublished observations).
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), phospholipase C and protein kinase C (PKC). Activation of PKC subsequently initiates new BDNF synthesis via (direct or indirect) phosphorylation of relevant translation initiation factors (e.g. eukaryotic translation initiation factor 4E (eIF-4E); Whalen et al. 1996; Wang et al. 2003). After its synthesis, we propose that BDNF is released from phrenic motor neurone dendrites, activating pre- and/or postsynaptic TrkB receptors. Brain-derived neurotrophic factor activates TrkB receptors on (or in) phrenic motor neurones, activating further signalling cascades that establish phrenic LTF, possibly via the activation of extracellular regulated mitogen-activated protein (MAP) kinases 1/2 (ERK1/2) and/or protein kinase B (Akt). Phosphorylation of ERK1/2 is increased following intermittent hypoxia (Wilkerson et al. 2005a). Similarly, Akt is activated in the phrenic motor nucleus following trans-activation of TrkB receptors with an adenosine (A2A) receptor agonist (Golder F.J. & G. S. Mitchell, unpublished observations). We postulate that these kinases subsequently regulate the phosphorylation and trafficking of glutamate receptor subunits, increasing their synaptic density and/or current per glutamate receptor and strengthening the synapse between medullary premotor neurones and phrenic motor neurones. Intermittent serotonin receptor activation is sufficient to elicit phrenic (Lovett-Barr et al. 2006) and XII nerve LTF without hypoxia in in vitro preparations from neonatal rats (Bocchiaro & Feldman, 2004). In the in vitro brainstem slice from neonatal rats, XII nerve in vitro LTF induced by intermittent serotonin receptor activation is associated with amplification of AMPA-mediated currents (Bocchiaro & Feldman, 2004). In adult rats, NMDA receptors may play a more prominent role (McGuire et al. 2005).
Phrenic LTF is constrained by phosphatase activity, since phrenic LTF is revealed following 25 min of sustained hypoxia (a stimulus that does not normally elicit phrenic LTF) when spinal serine/threonine phosphatases are inhibited by intrathecal okadaic acid (Wilkerson et al. 2006). Phrenic LTF following intermittent hypoxia requires reactive oxygen species, most likely for their inhibitory actions on spinal protein phosphatase activity (Macfarlane & Mitchell, 2006).
Although a strong case is emerging that spinal mechanisms underlie phrenic LTF, other potential mechanisms must be considered, such as the possibility that intermittent hypoxia elicits additional plasticity in the carotid body or medullary premotor neurones. Peng et al. (2003) reported that intermittent hypoxia, when applied in a pattern that elicits phrenic LTF, does not elicit sensory facilitation in the carotid sinus nerve unless the animal has been preconditioned with chronic intermittent hypoxia. Thus, carotid body plasticity may play a role in enhanced phrenic LTF (Mitchell et al. 2001a; Mitchell & Johnson, 2003; Peng & Prabhakar, 2003), but is not a major contributor to phrenic LTF in normal rats. Morris et al. (2000, 2003) reported that some brainstem respiratory neurones exhibit persistent activation and synchronization 10 min postintermittent carotid chemoreceptor stimulation. However, the role of this activation in phrenic LTF remains unclear, since observations have not been made beyond 10 min. Since spinal mechanisms appear to account for most, if not all, phrenic LTF (Baker-Herman & Mitchell, 2002; Fuller et al. 2003; Baker-Herman et al. 2004), the persistent facilitation of medullary neurones reported by Morris et al. (2000, 2003) may reflect a distinct mechanism, possibly contributing in more limited time domains (Powell et al. 1998) or to respiratory frequency LTF. Regardless of the mechanism or mechanisms contributing to LTF, it remains a good candidate to compensate for and to minimize apnoeas during sleep.
Chronic intermittent hypoxia may fundamentally alter LTF mechanisms or introduce completely new, potentially pathogenic mechanisms. For example, chronic intermittent asphyxia administered over 5 weeks in adult rats impairs muscle contractility in upper airway dilator muscles (Bradford et al. 2005) and shifts muscle fibre types towards more fatigable fast-twitch fibres (Pae et al. 2005). In contrast, exposures to more moderate protocols of intermittent hypoxia increase the expression of key molecules within the phrenic motor nucleus, suggesting an increase in the ability to elicit phrenic LTF (Satriotomo I, Dale E.A. and G. S. Mitchell, unpublished observations). These neurochemical changes suggest an enhanced capacity for phrenic LTF and a greater potential to compensate for the onset of OSA, but without deleterious side-effects, such as systemic hypertension.
Linking LTF, OSA and hypertension?
Since acute and chronic intermittent hypoxia elicit long-lasting facilitation and enhanced facilitation (respectively) of sympathetic nerve activity (Prabhakar et al. 2005), mechanisms similar to phrenic LTF may link OSA with the increased sympathetic tone (Somers et al. 1989a,b) and systemic hypertension (Hoffmann et al. 2004) characteristic of OSA patients. Further studies are warranted.
Pharmacological approaches to the treatment of OSA
Although CPAP is a frequent and often effective treatment for OSA, patient compliance with this cumbersome apparatus is low (40%; Loube, 1999). New therapies are desirable, possibly using a pharmacological approach. However, despite many efforts, no effective pharmacological approaches to OSA have yet been found (Smith & Quinnell, 2004). Based on our present understanding of the cellular and synaptic mechanisms that underlie LTF, we may be able to develop new strategies to harness respiratory plasticity, thereby regulating upper airway tone and preserving upper airway patency.
Several drug studies have focused on serotonergic function and/or sex hormone levels, factors known to influence the expression of respiratory plasticity (Behan et al. 2003; Behan & Thomas, 2005). Although OSA is sexually dimorphic and is reduced by hormone replacement therapy in postmenopausal women (Bixler et al. 2001), multiple attempts to use sex hormones in the treatment of OSA have produced marginal or even counter-productive results (Smith & Quinnell, 2004). Sex hormone therapy may yet prove useful in cases where inadequate sex hormone levels specifically contribute to OSA. Attempts to manipulate the serotonergic nervous system often focus on selective serotonin reuptake inhibitors (SSRIs; Smith & Quinnell, 2004), which decrease the number of apnoeas in NREM, but not REM, sleep (Kraiczi et al. 1999). Consonant with this observation, the SSRI paroxetine increases genioglossus EMG during sleep (Sunderram et al. 2000), suggesting improved upper airway patency. However, although it was helpful in relieving apnoeas, paroxetine did not resolve other symptoms associated with OSA, such as daytime sleepiness (Kraiczi et al. 1999). Selective serotonin reuptake inhibitors are not expected to be helpful in REM sleep because serotonergic raphe neurones are virtually inactive (Trulson & Jacobs, 1979).
Novel (but untested) therapeutic strategies
Chronic intermittent hypoxia. If OSA is associated with defects in the capacity to elicit upper airway LTF, then treatments that restore LTF may improve upper airway patency. Ironically, the most easily applied treatment to restore LTF in rats with age/sex hormone (Zabka et al. 2003) or genetically related deficiencies in XII nerve LTF (Wilkerson et al. 2005a) is daily exposure to intermittent hypoxia; seemingly the very factor leading to many OSA-related pathologies. However, judicious administration of daytime intermittent hypoxia may induce metaplasticity and strengthen upper airway LTF sufficiently to minimize nocturnal apnoeas. Minimizing nocturnal apnoeas may offset the daily treatments with modest intermittent hypoxia. For example, daily exposure to 10 hypoxic episodes establishes the capacity for XII nerve LTF in Brown Norway rats, a strain that does not normally express XII nerve LTF. In association, BDNF protein expression and ERK1/2 activation are increased near the phrenic motor nucleus (Wilkerson et al. 2005a). More impressively, 10 hypoxic episodes presented three times weekly increases BDNF and TrkB protein and ERK1/2 phosphorylation within phrenic motor neurones (Dale E.A., Satriotomo I & G. S. Mitchell, unpublished observations). Thus, regular hypoxic exposures may have a considerable impact on upper airway LTF and the occurrence of apnoeas in individuals in the early stages of OSA. Later in the progression of OSA, the ability of enhanced LTF may be exhausted by the spontaneous apnoeas and intermittent hypoxia, and other (possibly mechanical) factors may dominate the expression of OSA.
Regulation of gene expression in upper airway motor neurones. RNA interference offers promise to regulate gene expression via the exogenous administration of siRNA. We used this technique successfully to regulate BDNF protein expression in the rat phrenic motor nucleus of rat species, the first report of successful RNA interference in the adult mammalian nervous system in vivo (Baker-Herman et al. 2004). However, the application of RNA interference to sleep apnoea requires stable (or at least prolonged) transfection of upper airway motor neurones with siRNAs or microRNAs targeting key molecules regulating upper airway tone. The protein targeted for knock down by siRNAs must constrain LTF expression so that the net effect is a gain of function. For example, okadaic acid-sensitive protein phosphatases represent an interesting target, since their inhibition enables phrenic LTF (Wilkerson et al. 2006). Hurdles to overcome include the development of suitable delivery techniques, demonstration that the siRNA selectively degrades target mRNA and protein, and the ability to enhance LTF without severe side-effects, such as uncontrolled cell proliferation and tumour formation. We have refined our delivery techniques and have proof of concept that siRNAs can be effectively delivered to XII motor neurones by retrograde transport from tongue injections of fluorescently labelled siRNAs (Golder F. J., Baker-Herman T.L. & G. S. Mitchell, unpublished observations), and that these injections have functional consequences in modulating XII nerve or phrenic LTF (Baker-Herman T.L. & G. S. Mitchell, unpublished observations). Although substantial hurdles must be overcome before RNA interference can become a viable therapy for OSA, our understanding of RNA interference is in its infancy; based on its exceptional potential, further investigations are warranted.
Small molecules can simulate the actions of neurotrophins. Since BDNF and TrkB signalling are key elements in the mechanism of phrenic LTF, it may be possible to bypass difficulties with protein or siRNA delivery to the central nervous system. Endogenous ligands with Gs protein-coupled metabotropic receptors trans-activate receptor tyrosine kinases, such as TrkB receptors (Lee & Chao, 2001). For example, adenosine 2A receptors (Lee & Chao, 2001) and the pituitary adenylate cyclase-activating peptide (PACAP) receptor (Lee et al. 2002) trigger such an effect. By administering receptor agonists of limited molecular weight and that cross the blood–brain barrier, an upper airway facilitation may be induced, thereby representing an intriguing prospect to improve upper airway patency without complications attendant to protein trophic factor delivery (Golder et al. 2006).
Summary and conclusions
In closing, our understanding of the links (if any) between respiratory LTF following intermittent hypoxia and OSA remains incomplete. Although many similarities between LTF and OSA suggest that LTF stabilizes breathing and assures upper airway patency in subjects that do not yet meet the clinical criteria for OSA (i.e. AHI > 10), no direct evidence for such a causal relationship currently exists. A number of observations raise questions about this hypothesis, such as uncertainties regarding the existence of LTF in human subjects, and the ability of upper airway LTF, if present, to overcome potentially severe mechanical limitations in maintaining a patent upper airway. We can be sure that at least some portion of OSA is attributable to neural mechanisms, since OSA is present only during sleep (a neural mechanism). Regardless, a detailed understanding of the cellular mechanisms giving rise to LTF may provide insights necessary to develop new treatment strategies that are effective in the treatment of OSA. New pharmaceutical approaches may be developed that ‘harness’ the inherent capacity for plasticity in respiratory motor neurones. Among the new, possible therapeutic approaches, we suggest that routine exposure to diurnal acute intermittent hypoxia may augment respiratory plasticity (i.e. LTF) and minimize nocturnal OSA. RNA interference has potential to regulate motoneurone excitability and, thus, upper airway tone. The key is to design siRNA sequences that target inhibitory constraints of LTF, thereby inducing a ‘gain of function’. Small molecules have been identified that simulate the properties of key proteins (e.g. BDNF) in LTF. Such small molecules already exist, and may have superior access to upper airway motor neurones, thus allowing regulation of downstream signalling mechanisms without side-effects attendant to hypoxia, serotonin receptor activation or the administration of siRNAs. Each approach faces major hurdles, but their potential makes them worthy avenues for consideration and possible testing. Progress in the translation of these ideas (and others) into medically acceptable approaches would be advanced considerably by the development of a good animal model of OSA.
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