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Obstructive Sleep Apnea and Inflammation: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by David Gozal.

Obstructive sleep apnea syndrome (OSAS) is a markedly prevalent condition across the lifespan, particularly in overweight and obese individuals, which has been associated with an independent risk for neurocognitive, behavioral, and mood problems as well as cardiovascular and metabolic morbidities, ultimately fostering increases in overall mortality rates.

  • sleep apnea
  • inflammation
  • cytokines
  • interleukin 6
  • morbidity
  • tumor necrosis factor
  • end-organ injury

1. Obstructive Sleep Apnea Syndrome (OSAS) and Morbidity

Obstructive sleep apnea syndrome (OSAS) is characterized by recurring events of partial or complete upper airway collapse during sleep, resulting in altered alveolar ventilation, intermittent hypoxemia along with increased respiratory efforts and intra-thoracic negative pressure swings that frequently lead to arousal and therefore perturb sleep continuity and result in fragmented sleep architecture. Obesity is a major risk factor of OSAS [1,2,3,4[1][2][3][4][5][6][7],5,6,7], and both of these conditions impose adverse neurocognitive, mood, behavioral, cardiovascular, and metabolic consequences in both children and adults. In addition, as the awareness and consequently the frequency of diagnosing OSAS have increased, a large list of additional OSAS-associated morbidities has been reported, including chronic kidney disease, erectile dysfunction, ocular conditions, Alzheimer disease, nocturia, and even cancer in adults, while in children enuresis and bruxism are frequent adverse consequences [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Efforts are ongoing to develop new and more effective therapies for OSAS based on underlying mechanisms promoting upper airway collapsibility during sleep [32,33][32][33]. However, the current first line treatment for OSAS in children is surgical adenotonsillectomy (T&A) and in adults consists of the administration of nasal continuous positive airway pressure (CPAP) therapy, both of which can result in transformative outcomes [34].
Although OSAS is associated with a 2–3-fold increased risk of developing a large spectrum of end-organ morbidities, not all patients with OSAS manifest evidence of any given end-organ dysfunction. The variability of the clinical phenotype has prompted intense investigation, especially focused around the role of systemic inflammation in OSAS-associated morbidities, particularly those affecting neurocognitive, cardiovascular, or metabolic functions [35,36,37,38,39,40,41,42][35][36][37][38][39][40][41][42]. However, exploration of systemic inflammatory pathways as candidate biomarkers failed to identify distinctive panels of circulating inflammatory markers that accurately differentiated between at-risk OSAS pediatric patients from those who appear to be less susceptible [20,43,44,45,46,47,48,49,50,51,52][20][43][44][45][46][47][48][49][50][51][52]. These are problematic findings since many of the OSAS morbidities are usually silent, progressive, and potentially reversible during earlier stages but can slowly progress to become either irreversible or only partially reversible over time [53,54][53][54]. Moreover, because the interactions between OSAS and obesity are multifaceted, it is difficult to identify exclusive OSAS biomarkers, since obesity can usually alter the expression and circulating levels of such biomarkers, and vice versa [55,56,57,58,59,60,61,62][55][56][57][58][59][60][61][62]. In addition, treatment of OSAS has been associated with worsening obesity [63], which can potentially dampen the response of inflammatory biomarkers to treatment. 

2. Tumor Necrosis Factor-α

Tumor necrosis factor-α (TNF-α) is a classic pro-inflammatory cytokine that has been implicated in the regulation of sleep [72,73,74,75][64][65][66][67]. Systemic administration of TNF-α promotes the probability and depth of physiological sleep states, particularly enhancing the time spent in non-rapid eye movement (NREM) sleep phase. In addition, TNF-α levels exhibit circadian patterns, are enhanced following sleep deprivation, and the targeted disruption of TNF-α receptors or their inhibition in the CNS will result in the suppression of spontaneous NREM sleep [62]. Of note, TNF-α will traditionally lead to the activation of NF-κB pathways that in turn activate nitric oxide synthase, cyclooxygenase 2, and adenosine A1 receptors, all of which are implicated in sleep regulation [72,73,74,75][64][65][66][67]. Sleep fragmentation paradigms mimicking the sleep disruption that characterizes OSAS induces substantial up-regulation of TNF-α expression in the CNS and other tissues in mice, along with increased sleep propensity along with cognitive and mood disturbances, similar to those occurring in OSAS, even in the absence of restricted sleep duration [76,77][68][69]. Moreover, treatment with a TNF-α neutralizing antibody in wild-type mice subjected to fragmented sleep, or when the same sleep perturbation is applied to double TNF-α receptor null mice, results in marked attenuation of the increased sleep propensity as well as in attenuation of the cognitive and behavioral disturbances induced by sleep disruption [78,79][70][71]. In addition to the intrinsic causal link between sleep perturbations and TNF-α demonstrated in both murine and human experiments, similar studies in mice focused on the chronic intermittent hypoxia that characterizes OSAS further demonstrated the recruitment of TLR-4-NF-κB pathways along with increased cellular and extracellular levels of TNF-α, thereby lending further credence to the pathophysiological role of this cytokine in the context of OSAS [78,79,80,81,82,83,84,85,86,87,88,89,90,91,92][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84]. In addition to OSAS or its intrinsic components fostering a pro-inflammatory state and manifesting as increased circulating levels of TNF-α, it is also possible that the reciprocal relationships might favor the emergence of upper airway dysfunction or of other mechanisms that facilitate the onset of OSAS. For example, intermittent hypoxia can generate inflammatory processes in the carotid body, which then translate into altered immunoregulation as well as perturbations in control of breathing that may facilitate the propensity for respiratory instability during sleep [93,94,95,96,97,98,99][85][86][87][88][89][90][91]. Furthermore, although specific studies are lacking in relation to upper airway musculature, increases in TNF-α in the context of other conditions (e.g., obesity) may promote muscle dysfunction and therefore enhance the likelihood of upper airway dysfunction [100,101,102][92][93][94].

3. Interleukin 6

Interleukin 6 (IL-6) belongs to the so-called IL-6 family of cytokines. All of its members, which include cardiotrophin-1, oncostatin M, leukemia inhibitory factor, cardiotrophin-like cytokine, ciliary neurotrophic factor, and the interleukins 11, 27, 30, and 31, bind to the glycoprotein 130 (gp130) as a β-receptor to activate intracellular signaling cascades. These cascades generally consist of homo- or heterodimers of gp130 in combination with other cytokine receptors [161][95]. Plasma levels of the inflammatory biomarker hs-CRP, whose expression is IL-6 dependent in liver, predict the risk of vascular disease in addition to other disease conditions such as diabetes and cognitive function deterioration. In the context of OSAS, hs-CRP levels tend to be elevated in afflicted children, independent of the degree of obesity [38]. Adipose tissue inflammation is induced by intermittent hypoxia and by chronic sleep fragmentation, can result in elevated IL-6 release [162,163,164[96][97][98][99][100][101][102],165,166,167,168], and may cross-talk with endothelial cells via adipocyte-derived mediators such as IL-6 to promote NF-κB-dependent endothelial dysfunction [169][103]. Furthermore, IL-6 plasma levels correlate with endothelial dysfunction, arterial stiffness, and the magnitude of subclinical atherosclerosis and are also predictive of incident type 2 diabetes and obesity [170,171][104][105]. The marked overlap between the repertoire of conditions in which IL-6 is either a risk biomarker or an actual effector of morbidity and the OSAS morbid consequences suggest that IL-6 may serve as a reliable reporter of either the presence of OSAS or of the risk of OSAS-associated morbidities. This assumption is further buttressed by the fact that intermittent hypoxia, one of the hallmark characteristics of OSAS, induces polarization of macrophages along with increased production of IL-6 [172][106]. Biopsies of adipose tissue and blood samples in obese patients with and without OSAS, revealed substantial increases in tissue expression and circulating levels of a variety of pro-inflammatory cytokines, including IL-6, and such changes were markedly attenuated by six months of CPAP therapy [159][107]. Interestingly, adult patients with OSAS and objective EDS documented by reduced sleep latencies exhibited significantly elevated daytime and nighttime IL-6 plasma levels, that were absent when no EDS was present [154][108]. Pooling of eight published reports in adults with OSAS revealed that plasma levels of IL-6 ranged from 1.2 to 131.66 pg/mL before CPAP treatment and significantly decreased to between 0.45 to 66.04 pg/mL after CPAP treatment (p < 0.05), but they also indicated that there was significant inter-individual heterogeneity [155][109]. Similar heterogeneity was detected in IL-6 levels in children with OSAS [156,173,174,175,176][110][111][112][113][114] and may be related to genetic variance for both IL-6 and CRP genes [176][114].

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