Cytokines in OSA

Akin to neurotransmitters of the nervous system (such as NE), cytokines are key mediators of vast immune and neuroimmune interactions. There are many features of OSA that argue for the importance of studying cytokines, including neuroimmune interactions, mood changes (such as fatigue and depression), and behaviors that directly affect the course of the disorder (such as caffeine consumption, smoking, diet, and difficulties with adherence to treatment). Before reviewing studies of OSA and cytokines, we first briefly discuss cytokines in normal sleep in order to put into context effects seen as a result of the disrupted sleep of OSA.

15.4.1 Cytokines and Normal Sleep

The contributions of cytokines to sleep are far from straightforward. They are both sleep inducing (e.g., IL-1P, TNF-a) and sleep inhibiting (e.g., IL-10 and IL-4), depending on the cytokine, the dose, and the circadian phase (Opp 2002).

Sleep inhibiting cytokines may exert their effects through antagonizing somnogenic cytokines. IL-10 and IL-4, for example, may inhibit sleep by inhibiting the production of IL-1P and TNF-a (Kelley et al. 2003; Krueger, Obal, Fang, Kubota and Taishi 2001). Administration of TNF-a, IL-1P, or IL-18 increases the amount of nonrapid eye movement (NREM) sleep time and decreases the duration of REM sleep. TNF-a or IL-1P also increase the amplitude of slow wave EEG, while administration of IL-10 and IL-4 on the other hand inhibit NREM. While circulating IL-2 levels increase during sleep, there is little evidence that there is a direct sleep promoting effect of IL-2. Although the precise mechanisms of the somnogenic or antisomnogenic effects of cytokines have yet to be fully elucidated, growth hormone releasing hormone, corticotrophin releasing hormone, prostaglandins, and molecular intermediates (e.g., activation of the DNA transcription binding protein NF-kB) have been implicated.

Like TNF-a, IL-6 is a somnogenic proinflammatory cytokine associated with disturbed sleep and with fatigue. IL-6 negatively correlates with the amount of sleep as well as the depth of sleep. Better sleep is associated with decreased daytime secretion of IL-6, while nocturnal sleep disturbances are associated with increased daytime levels of IL-6 and TNF-a. In older adults, elevated IL-6 levels are associated with poor sleep and sleep disturbances, particularly when accompanied by elevations in cortisol levels (Vgontzas et al. 2003). It has been postulated that whether somnogenic and fatigue-inducing proinflammatory cytokines lead to sleepiness and deep sleep or to fatigue and poor sleep depends upon whether there is simultaneous hypothalamic pituitary adrenal (HPA) axis activation (Vgontzas et al. 2003; Opp 1995).

15.4.2 Cytokines and OSA

Inflammation is common in OSA, including elevated levels of proinflammatory cytokines. We compared plasma IL-6 levels obtained in the early morning from 53 patients with OSA with levels obtained from 97 nonapneic individuals of similar age and weight. Apneics had significantly higher IL-6 levels (p < 0.001) (Fig. 15.4).

Other studies show that in addition to IL-6, TNF-a levels are elevated in OSA independent of obesity (Vgontzas et al. 2000; Vgontzas, Papanicolaou, Bixler, Kales, Tyson, and Chrousos 1997) and the circadian rhythm of TNF-a is disrupted (Entzian, Linnemann, Schlaak, and Zabel 1996).

Apnea

Control

Figure 15.4. Plasma IL-6 levels in OSA and nonapnea. Patients with OSA have higher circulating IL-6 levels (p < 0.001).

In addition to proinflammatory cytokines, OSA leads to elevations of other mediators of inflammation, including intercellular adhesion molecule-1 (ICAM-1) and C-reactive protein (CRP) (Yokoe et al. 2003). CRP, a member of the pentraxin family of proteins, is an acute phase reactant marker of inflammation synthesized primarily in hepatocytes in response to IL-6. It is intimately involved in atherogenesis, and stimulates the release of proinflammatory cytokines, thereby inducing the expression of adhesion molecules such as ICAM-1. The elevated levels of TNF-a and IL-6 in OSA have been shown to be correlated with elevated CRP levels. Elevated levels of the soluble form of ICAM-1 (sICAM-1) and IL-6 are independently associated with increased morbidity and mortality independent of other established risk factors (Ridker, Hennekens, Roitman-Johnson, Stampfer, and Allen 1998). Thus, the disruption of sleep seen in OSA activates several different inflammatory pathways that may lead to increased susceptibility to cardiovascular diseases.

15.4.3 What Features of OSA Might Lead to Elevations of Inflammatory Cytokines?

As reviewed earlier in this chapter, studies repeatedly demonstrate that OSA is associated with sympathetic activation during both day and nighttime. Given the well-established link between sympathetic activation and elevated proinflammatory cytokines and systemic inflammation, perhaps the elevated proinflammatory cytokines levels observed in OSA are a byproduct of the increased sympathetic activity. As will be discussed later in the chapter, continuous positive airway pressure (CPAP) is a common treatment for OSA and reverses many of the clinical complaints and physiological features of OSA, including elevated NE, CRP, and IL-6 (Yokoe 2003).

Elevated cytokine levels in OSA might also be the result of hypoxia. OSA is associated with repetitive transient episodes of partial or complete obstruction of the upper airway during sleep and with transient drops in oxyhemoglobin saturation. High altitude studies show that exposure to chronic hypoxia leads to the release of inflammatory cytokines; including a several fold elevation of IL-6 levels (Hartmann et al. 2000).

The inflammatory reactions occurring in hypoxia, perhaps related to a recurring cycle of hypoxia/reoxygenation stress reminiscent of ischemia/reperfusion injury, might initiate a vicious cycle whereby the response is further amplified.

OSA is commonly associated with obesity, and abdominal fat is a major reservoir of cytokines. OSA is commonly seen in middle-aged obese men. Vgontzas and colleagues (1997) showed that OSA patients have a greater amount of visceral fat compared to obese non-OSA controls and higher levels of the adipose tissue-derived hormone leptin. The authors concluded that there is a strong independent association among OSA, visceral obesity, and elevated IL-6, TNF-a levels. Other findings from these investigators support the view that sleep apnea in obese patients may be a manifestation of the Metabolic Syndrome, in that cytokines and insulin resistance are mediators of excessive daytime sleepiness and sleep apnea in humans. They propose a model of a "bi-directional, feed forward, pernicious association between sleep apnea, sleepiness, inflammation, and insulin resistance, all promoting atherosclerosis and cardiovascular disease" (Vgontzas, Bixler, and Chrousos 2005).

Finally, in addition to sympathetic activation, studies suggest that the other branch of the autonomic nervous system, the parasympathetic nervous system, is related to inflammatory processes and elevated proinflammatory cytokines, but in the opposite fashion; i.e., parasympathetic activation supports anti-inflammatory pathways. Studies show that direct in vivo stimulation of the vagus nerve significantly attenuates the release of IL-6, TNF-a, and IL-ip (Borovikova et al. 2000). Our prior studies show that patients with sleep apnea have attenuated vagal activity (Nelesen, Yu, Ziegler, Mills, Clausen, and Dimsdale 2001). Thus, apneics may be susceptible to increased cytokine levels from both sides of the autonomic nervous system—increased sympathetic activity as well as decreased paras-ympathetic activity.

15.4.4 Cytokines in the Context of Mood and Quality of Life in OSA

We conclude this section of the chapter with a discussion of possible consequences of elevated cytokine levels and inflammation on the poor mood and low quality of life often observed in OSA.

OSA patients typically consult their doctor not because of "an elevated oxygen desaturation index" but because they are very sleepy, depressed or worried about their snoring. These complaints are subjective and thus aspects of personality may greatly influence patients' referral for treatment as well as compliance with treatment. Here we summarize some of our findings on the complexities of subjective report and mood in patients with this sleep disorder.

There is a growing literature linking cytokines and depressive symptoms. Perhaps some of the psychological symptoms experienced by OSA patients may be related to the elevated levels of proinflammatory cytokines. Apneics are noted for their increased incidence of depressive complaints, which may reflect elevations in cytokines.

Irwin (2001) has shown that the degree of sleep disturbance in depression is related to the degree of immune dysfunction. We have found that avoidant coping style, age, body mass index (BMI), and hypertension status all contribute to the depressive self-reports in OSA (Bardwell, Ancoli-Israel, and Dimsdale 2001).

OSA patients complain of fatigue. We find that OSA patients with high levels of depressive symptoms on the Center for Epidemiologic Studies Depression Scale (CESD > 16) report twice as much fatigue (Profile of Mood States) as OSA patients with fewer depressive symptoms.

We wondered if depressive symptoms in patients with OSA would account for some of the fatigue beyond that explained by OSA severity (Bardwell, Moore, Ancoli-Israel, and Dimsdale 2003). We found that higher levels of depressive symptoms in OSA are dramatically and independently associated with greater levels of fatigue: whereas the respiratory disturbance and the oxygen desaturation together accounted for 4.2% of the variance in fatigue scores in OSA patients, depressive symptoms accounted for 10 times the variance (i.e., an additional 42.3%) in fatigue scores. Thus, assessment and treatment of mood symptoms, not just treatment of the disordered breathing itself, might reduce the fatigue experienced by patients with OSA.

Another hallmark sign of OSA is debilitating sleepiness. Opp (2002) reviewed the literature on cytokines and sleep promotion, citing elevated IL-1, TNF and possibly IL-6 as mechanisms of excessive daytime sleepiness in OSA. Observations that the circadian rhythm of TNF-a is disrupted in OSA, with a loss of the nocturnal physiologic peaks and the presence of an additional daytime peak (Vgontzas et al. 1997; Entzian et al. 1996) support the notion that disrupted cytokines in OSA contribute to daytime sleepiness but not necessarily to nighttime sleep disruptions.

We have found that plasma sTNF-R1 levels are significantly correlated with sleepiness and impaired neuropsychological functioning in OSA. For instance, decreased performance on the Brief Visuospatial Memory Test and Trailmaking A Test is associated with increased levels of sTNF-R1 in OSA.

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