Articles on Inflammation & Sleep Disorder

Gozal D. Serpero LD. Sans Capdevila O. Kheirandish-Gozal L. Systemic inflammation in non-obese children with obstructive sleep apnea. Sleep Medicine. 9(3):254-9, 2008. BACKGROUND: Obstructive sleep apnea (OSA) has been associated with increased systemic inflammatory responses that may contribute to an increased risk for end-organ morbidity. The changes in levels of pro-inflammatory cytokine IL-6 , and the anti-inflammatory cytokine IL-10, both of which play a major role in atherogenesis, a major consequence of OSA, have not specifically been assessed in pediatric patients. METHODS: Consecutive non-obese children (aged 4-9years) who were polysomnographically diagnosed with OSA, and age-, gender-, ethnicity-, and BMI-matched control children underwent a blood draw the next morning after a sleep study and plasma samples were assayed for interleukins 6 (IL-6) and 10 (IL-10). These tests were repeated 4-6months after tonsillectomy and adenoidectomy (T&A) in children with OSA. RESULTS: IL-6 levels were higher and IL-10 plasma levels were lower in children with OSA and returned to control levels after T&A. CONCLUSIONS: Systemic inflammation is a constitutive component and consequence of OSA in many children, even in the absence of obesity, and is reversible upon treatment in most patients.

Lavie L. Lavie P. Smoking interacts with sleep apnea to increase cardiovascular risk. Sleep Medicine. 9(3):247-53, 2008. BACKGROUND: Sleep apnea syndrome is an important risk factor for atherosclerosis and cardiovascular morbidity and so is cigarette smoking. In both atherosclerosis and cardiovascular disease, oxidative stress and inflammation have been implicated as underlying pathophysiologic mechanisms. We investigated oxidative stress and inflammatory markers in 70 non-smoking and smoking patients with sleep apnea. METHODS: Thirty-five sleep apnea patients aged 20-60 years who smoke 20 or more cigarettes/day and for at least 5 years were individually matched by gender, age (+/-5 years), body mass index (BMI; categorized as, 'normal weight', 'overweight', and 'obese'), sleep apnea severity (categorized as 'mild', 'moderate', and 'severe'), and presence of cardiovascular diseases, with 35 patients who never smoked. Blood samples were drawn after an overnight fasting for determination of lipids profile, oxidative stress markers thiobarbituric acid reactive substances, peroxides and paraoxonase-1 and inflammatory markers C-reactive protein, ceruloplasmin, and haptoglobin. RESULTS: Smokers showed significantly higher levels of C-reactive protein, ceruloplasmin, and haptoglobin and triglycerides and lower levels of high-density lipoprotein (HDL) cholesterol than non-smokers. There was a significant interaction effect between smoking and apnea severity on ceruloplasmin and HDL levels. Smokers with severe sleep apnea had the highest level of ceruloplasmin and the lowest level of HDL. CONCLUSION: There is a synergistic effect between cigarette smoking and sleep apnea on some of the biochemical cardiovascular risk markers. Patients with severe sleep apnea who smoke are at a greater cardiovascular risk than smokers with mild-moderate sleep apnea and patients who do not smoke.

Suarez EC. Self-reported symptoms of sleep disturbance and inflammation, coagulation, insulin resistance and psychosocial distress: evidence for gender disparity. Brain, Behavior, & Immunity. 22(6):960-8, 2008. Self-reported ratings of sleep quality and symptoms of poor sleep have been linked to increased risk of coronary heart disease (CHD), Type 2 diabetes and hypertension with recent evidence suggesting stronger associations in women. At this time, the mechanisms of action that underlie these gender-specific associations are incompletely defined. The current study examined whether gender moderates the relation of subjective sleep and sleep-related symptoms to indices of inflammation, coagulation, insulin resistance (IR) and psychosocial distress, factors associated with increased risk of cardiovascular and metabolic disorders. Subjects were 210 healthy men and women without a history of sleep disorders. The Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality and frequency of sleep symptoms. In multivariate-adjusted models, overall poor sleep quality, more frequent problems falling asleep (>2 night/week) and longer periods to fall asleep (>30 min) were associated with greater psychosocial distress, higher fasting insulin, fibrinogen and inflammatory biomarkers, but only for women. The data suggest that subjective ratings of poor sleep, greater frequency of sleep-related symptoms, and longer period of time to fall asleep are associated with a mosaic of biobehavioral mechanisms in women and that these gender-specific associations have direct implications to recent observations suggesting gender differences in the association between symptoms of poor sleep and cardiovascular disease.

Ishikawa J. Hoshide S. Eguchi K. Ishikawa S. Pickering TG. Shimada K. Kario K. Increased low-grade inflammation and plasminogen-activator inhibitor-1 level in nondippers with sleep apnea syndrome. Journal of Hypertension. 26(6):1181-7, 2008. OBJECTIVE: Patients with sleep apnea syndrome have an increased risk of cardiovascular events and frequently show a nondipper pattern (blunted nocturnal decline <10%) of systolic blood pressure. We investigated neurohumoral activation and risk factors in relation to nocturnal blood pressure dipping pattern and sleep apnea syndrome. METHODS: We conducted sleep polysomnography and ambulatory blood pressure monitoring and measured high-sensitivity C-reactive protein, tissue-type plasminogen activator inhibitor-1, and neurohumoral factors in 121 outpatients with suspected sleep apnea syndrome who were classified into four groups on the basis of the presence or the absence of dipping/nondipping and sleep apnea syndrome. RESULTS: Nondippers with sleep apnea syndrome had higher high-sensitivity C-reactive protein (overall P < 0.001), plasminogen activator inhibitor-1 (overall P = 0.004), and aldosterone levels (overall P = 0.010) than any of the other three groups. After adjustment for significant covariates such as age, sex, body mass index, waist circumference, smoking, alcohol drinking, aspirin use, presence of diabetes, and insulin, nondippers with sleep apnea syndrome still had a higher high-sensitivity C-reactive protein level than nondippers without sleep apnea syndrome (geometric mean: 1.47 vs. 0.37 mg/l, P = 0.001). In multiple linear regression analysis controlling for confounding factors related with sleep apnea syndrome, high-sensitivity C-reactive protein was significantly correlated with 3% oxygen desaturation index (P = 0.047). Plasminogen activator inhibitor-1 level was also highest in the nondippers with sleep apnea syndrome but not independent of obesity. Plasminogen activator inhibitor-1 level correlated with insulin (r = 0.32, P = 0.002) and high-sensitivity C-reactive protein levels (r = 0.26, P = 0.005). CONCLUSION: Nondipper status was associated with an increased high-sensitivity C-reactive protein level in patients who also had sleep apnea syndrome but not in those who did not. High-sensitivity C-reactive protein level was closely affected by the desaturation level. Plasminogen activator inhibitor-1 level is also increased in nondippers with sleep apnea syndrome and is related to insulin and high-sensitivity C-reactive protein levels.

Yamauchi M. Kimura H. Oxidative stress in obstructive sleep apnea: putative pathways to the cardiovascular complications. [Review] [145 refs] Antioxidants & Redox Signaling. 10(4):755-68, 2008. Obstructive sleep apnea (OSA) is a major public health problem because of its high prevalence in morbidity and mortality. A growing body of evidence suggests that OSA is an important risk factor for cardiovascular diseases. Although the mechanism for the initiation and aggravation of cardiovascular disease has not been fully elucidated, one theorized mechanism is intermittent hypoxia, which is produced by each sleep-disordered breathing event. This repeated hypoxia and reoxygenation cycle is similar to hypoxia-reperfusion injury, which initiates oxidative stress. Recent studies have suggested that OSA is associated with increased levels of oxidative stress or antioxidant deficiencies or both. Oxidative stress is involved in the activation of redox-sensitive transcription factors, which regulate downstream products such as inflammatory cytokines, chemokines, and adhesion molecules. This pathway may be able to explain the pathogenesis of atherosclerosis, a common pathologic factor underlying all types of cardiovascular disease. In addition, endothelial dysfunction derived from oxidative stress can contribute to cardiovascular diseases. This review summarizes current available evidence for and against the occurrence of oxidative stress in OSA and discusses the putative pathways initiating cardiovascular consequences associated with OSA.

Mehra R. Redline S. Sleep apnea: a proinflammatory disorder that coaggregates with obesity. [Review] [72 refs] Journal of Allergy & Clinical Immunology. 121(5):1096-102, 2008. Both obesity and sleep apnea are prevalent health conditions that frequently coaggregate. Obesity-associated inflammation may influence asthma control; the relation of sleep apnea to asthma or allergic rhinitis may be bidirectional. Both obesity and sleep apnea are associated with augmented levels of inflammation and oxidative stress, and it is biologically plausible that the proinflammatory effects of one disorder influence the expression of the other disorder. This article elucidates mechanistic associations among obesity, sleep apnea, and systemic inflammation; highlights interrelationships between these factors with cardiopulmonary disease; and identifies specific areas for future research directions.

Gozal D. Capdevila OS. Kheirandish-Gozal L. Metabolic alterations and systemic inflammation in obstructive sleep apnea among nonobese and obese prepubertal children. American Journal of Respiratory & Critical Care Medicine. 177(10):1142-9, 2008. RATIONALE: Obstructive sleep apnea (OSA) has been associated with a higher prevalence and severity of the metabolic syndrome in adult patients, even after controlling for obesity. In contrast, OSA in prepubertal children does not appear to correlate with the magnitude of such metabolic derangements. OBJECTIVES: To further establish the potential mechanistic role of OSA in metabolic regulation in prepubertal children. METHODS: Fasting glucose, insulin, C-reactive protein, apolipoprotein B, and serum lipid concentrations were determined during the initial polysomnographic diagnosis of OSA and 6-12 months after adenotonsillectomy in both obese and nonobese children. MEASUREMENTS AND MAIN RESULTS: Sixty-two children with OSA (37 obese and 25 nonobese), age 7.40 +/- 2.6 years (mean +/- SD) completed the study. After adenotonsillectomy, significant improvements in apnea-hypopnea index and sleep fragmentation occurred, particularly among nonobese children. In nonobese children, adenotonsillectomy was associated with mild increases in body mass index z scores, no changes in either fasting glucose or insulin, significant increases in high-density lipoprotein and reciprocal decreases in low-density lipoprotein, and reductions in plasma C-reactive protein and apolipoprotein B levels. In obese children, adenotonsillectomy did not result in body mass index or glucose changes, but was associated with marked improvements in all other measures. CONCLUSIONS: OSA does not appear to induce insulin resistance in nonobese pediatric patients but seems to play a significant role in obese patients. The significant improvements in lipid profiles, C-reactive protein, and apolipoprotein B after adenotonsillectomy in the two groups suggest a pathogenic role for OSA in lipid homeostasis and systemic inflammation independent of the degree of adiposity.

Tasali E. Ip MS. Obstructive sleep apnea and metabolic syndrome: alterations in glucose metabolism and inflammation. [Review] [145 refs] Proceedings of the American Thoracic Society. 5(2):207-17, 2008. Metabolic syndrome (MS), the commonly used term for the clustering of obesity, insulin resistance, hypertension, and dyslipidemia, affects millions of people worldwide, and is associated with an increased risk of cardiovascular disease and type 2 diabetes. Recently, it has been suggested that obstructive sleep apnea (OSA), an increasingly prevalent condition, may contribute to the development of MS and diabetes. Despite substantial evidence from both clinical and population studies to suggest an independent link between OSA and metabolic abnormalities, the issue still remains controversial. Obesity, particularly visceral obesity, is an important factor in the assessment of adverse metabolic outcome in OSA. Further prospective and interventional studies, with adequate sample sizes and longer follow-up, rigorous control for adiposity, and, ideally, randomization and control for any therapeutic intervention, are clearly needed to address the direction of causality. There are multiple mechanistic pathways involved in the interaction between OSA, obesity, and metabolic derangements. Chronic intermittent hypoxia and sleep fragmentation with sleep loss in OSA are likely key triggers that initiate or contribute to the sustenance of inflammation as a prominent phenomenon, but their complex interplay remains to be elucidated. In summary, OSA may represent a novel risk factor for MS and diabetes, and thus clinicians should be encouraged to systematically evaluate the presence of metabolic abnormalities in OSA and vice versa.

Gozal D. Kheirandish-Gozal L. Cardiovascular morbidity in obstructive sleep apnea: oxidative stress, inflammation, and much more. [see comment]. [Review] [116 refs] American Journal of Respiratory & Critical Care Medicine. 177(4):369-75, 2008. Sleep-disordered breathing and obstructive sleep apnea (OSA) are highly prevalent disorders throughout the lifespan, which may affect up to 2-10% of the population, and have now been firmly associated with an increased risk for cardiovascular and neurobehavioral complications. Nevertheless, the overall pathophysiologic mechanisms mediating end-organ injury in OSA remain undefined, particularly due to the very frequent coexistence of other disease states, such as obesity, that clearly complicate the potential cause-effect relationships. Two major, and to some extent overlapping, mechanisms have been proposed to explain the morbid consequences of OSA, namely increased generation and propagation of reactive oxygen species and initiation and amplification of inflammatory processes. The evidence supporting the validity of these concepts as well as that detracting from such mechanisms will be critically reviewed in the context of clinical and laboratory-based approaches. In addition, some of the contradictory issues raised by such evaluation of the literature will be interpreted in the context of putative modifications of the individual responses to OSA, as determined by genetic variants among susceptibility-related genes, and also by potential environmental modulators of the phenotypic expression of any particular end-organ morbidity associated with OSA.

Budhiraja R. Parthasarathy S. Quan SF. Endothelial dysfunction in obstructive sleep apnea. [Review] [101 refs] Journal of Clinical Sleep Medicine. 3(4):409-15, 2007. Obstructive sleep apnea (OSA) is a common disorder and is associated with adverse cardiovascular consequences, including hypertension and coronary artery disease. While the mechanisms responsible for increased risk of cardiovascular events in OSA have not yet been fully elucidated, hypoxia, inflammation, obesity, metabolic dysregulation, and sympathetic activation, may contribute to these consequences. Endothelial dysfunction may be another link between OSA and cardiovascular disease. Dysfunctional endothelium is characterized by an imbalance in production of vasoactive hormones, increased adherence of inflammatory mediators to endothelial cells and hypercoagulability, and is a known risk factor for cardiovascular events. Studies have directly measured vascular endothelial function in patients with OSA and found a muted response compared to controls. Other studies have evaluated biochemical markers of endothelial function including circulating levels of vasoactive and thrombosis mediators and provide further proof of endothelial dysfunction in this disorder. A better appreciation of the role of the dysfunctional endothelium in OSA will help shed light on the pathogenesis of cardiovascular disease in this disorder and may lead to development of novel therapies aimed at preventing untoward outcomes.

Williams A. Scharf SM. Obstructive sleep apnea, cardiovascular disease, and inflammation--is NF-kappaB the key?. [Review] [74 refs] Sleep & Breathing. 11(2):69-76, 2007. Obstructive sleep apnea (OSA) affects a large portion of the population and is associated with repeated airway collapse leading to chronic intermittent hypoxia, exaggerated swings in intrathoracic pressure and post apneic arousal. OSA is associated with heightened sympathoadrenal tone and is a risk factor for cardiovascular mortality and morbidity. In addition to well-known mechanical and autonomic effects, OSA appears to be associated with systemic inflammation. This could provide one mechanism leading to cardiovascular disease (CVD). A central factor in the inflammatory cascade is nuclear factor kappa B (NF-kappaB), which is involved in the transcription of numerous genes involved in the inflammatory cascade. The object of this article is to review recent literature on some of the aspects of OSA related to a proinflammatory state and the possible role of NF-kappaB as one mechanism providing a link between sleep apnea and CVD.

Ranjbaran Z. Keefer L. Stepanski E. Farhadi A. Keshavarzian A. The relevance of sleep abnormalities to chronic inflammatory conditions. [Review] [60 refs] Inflammation Research. 56(2):51-7, 2007. Sleep is vital to health and quality of life while sleep abnormalities are associated with adverse health consequences. Nevertheless, sleep problems are not generally considered by clinicians in the management of chronic inflammatory conditions (CIC) such as asthma, RA, SLE and IBD. To determine whether this practice is justified, we reviewed the literature on sleep and chronic inflammatory diseases, including effects of sleep on immune system and inflammation. We found that a change in the sleep-wake cycle is often one of the first responses to acute inflammation and infection and that the reciprocal effect of sleep on the immune system in acute states is often protective and restorative. For example, slow wave sleep can attenuate proinflammatory immune responses while sleep deprivation can aggravate those responses. The role of sleep in CIC is not well explored. We found a substantial body of published evidence that sleep disturbances can worsen the course of CIC, aggravate disease symptoms such as pain and fatigue, and increase disease activity and lower quality of life. The mechanism underlying these effects probably involves dysregulation of the immune system. All this suggests that managing sleep disturbances should be considered as an important factor in the overall management of CIC.

Miller MA. Cappuccio FP. Inflammation, sleep, obesity and cardiovascular disease. [Review] [94 refs] Current Vascular Pharmacology. 5(2):93-102, 2007. Evidence is emerging that disturbances in sleep and sleep disorders play a role in the morbidity of chronic conditions. However, the relationship between sleep processes, disease development, disease progression and disease management is often unclear or understudied. Numerous common medical conditions can have an affect on sleep. For example, diabetes or inflammatory conditions such as arthritis can lead to poor sleep quality and induce symptoms of excessive daytime sleepiness and fatigue. It has also been suggested that poor sleep may lead to the development of cardiovascular disease for which an underlying inflammatory component has been proposed. It is therefore important that the development and progression of such disease states are studied to determine whether the sleep effect merely reflects disease progression or whether it may be in some way causally related. Sleep loss can also have consequences on safety related behaviours both for the individuals and for the society, for example the increased risk of accidents when driving while drowsy. Sleep is a complex phenotype and as such it is possible that there are numerous genes which may each have a number of effects that control an individual's sleep pattern. This review examines the interaction between sleep (both quantity and quality) and parameters of cardiovascular risk. We also explore the hypothesis that inflammation plays an essential role in cardiovascular disease and that a lack of sleep may play a key role in this inflammatory process. AIM: To review current evidence regarding the endocrine, metabolic, cardiovascular and immune functions and their interactions with regard to sleep, given the current evidence that sleep disturbances may affect each of these areas.

Wolf J. Lewicka J. Narkiewicz K. Obstructive sleep apnea: an update on mechanisms and cardiovascular consequences. [Review] [91 refs] Nutrition Metabolism & Cardiovascular Diseases. 17(3):233-40, 2007. BACKGROUND AND AIM: There is growing recognition of the widespread incidence and health consequences of obstructive sleep apnea (OSA). This review examines the evidence linking sleep apnea with cardiovascular disease and discusses potential mechanisms underlying this link. DATA SYNTHESIS: The weight of evidence provides increasing support for a causal relationship between OSA and hypertension. Furthermore, OSA may contribute to the initiation and progression of cardiac ischemia, heart failure and stroke. Chronic sympathetic activation appears to be a key mechanism linking OSA to cardiovascular disease. Other potential mechanisms include inflammation, endothelial dysfunction, increased levels of endothelin, hypercoagulability and stimulation of the renin angiotensin system. OSA, hypertension and obesity often coexist and interact, sharing multiple pathophysiological mechanisms and cardiovascular consequences. Effective treatment of OSA may attenuate neural and humoral abnormalities in circulatory control, improve blood pressure control and conceivably reduce the risk of future cardiovascular events. CONCLUSION: Patients with OSA are at increased risk for cardiovascular disease. OSA should be considered in the differential diagnosis of hypertensive patients who are obese. In particular, OSA should be excluded in patients with hypertension resistant to conventional drug therapy.

Okun ML. Coussons-Read ME. Sleep disruption during pregnancy: how does it influence serum cytokines?. Journal of Reproductive Immunology. 73(2):158-65, 2007. Women report their sleep to be disrupted during pregnancy. Sleep deprivation has been linked to elevations in pro-inflammatory cytokine levels. No information currently addresses the sleep-immune relationship during pregnancy. This study explores the relationship between subjectively reported sleep variables and circulating serum cytokine levels. Pregnant women (n=35; mean age=31.0+/-3.7 years) seen once a trimester completed sleep questionnaires, gave blood and recorded their sleep on a sleep diary at home for 2 weeks. Nonpregnant women (n=43; mean age=28.2+/-5.2 years) underwent the same protocol once. Subjective sleep variables were compared to serum cytokine levels for IL-4, -6, -10 and TNF-alpha as well as C-reactive protein (CRP) determined by ELISA. Nonparametric analyses and linear regression were performed to explore relationships between the sleep and immune variables. Pregnant women subjectively reported their sleep to be worse than in the nonpregnant group. Serum cytokine levels differed between the two groups and varied by trimester. As anticipated, IL-10 was significantly higher in all trimesters; however CRP, an indicator of systemic inflammation, was higher in all trimesters compared to the nonpregnant sample. Subjectively reported sleep disruption was associated with increases in TNF-alpha in the pregnant sample and CRP in the nonpregnant sample. These data confirm that disrupted sleep experienced during pregnancy, as well as during the nonpregnant state, is related to increases in inflammatory markers. Future exploration of these relationships should include functional assessments of immunity as well as polysomnographically recorded sleep.

Devouassoux G. Levy P. Rossini E. Pin I. Fior-Gozlan M. Henry M. Seigneurin D. Pepin JL. Sleep apnea is associated with bronchial inflammation and continuous positive airway pressure-induced airway hyperresponsiveness. Journal of Allergy & Clinical Immunology. 119(3):597-603, 2007. BACKGROUND: Obstructive sleep apnea syndrome (OSA) is associated with systemic and upper airway inflammation. Pharyngeal inflammation has a potential role in upper airway collapse, whereas systemic inflammation relates to cardiovascular morbidity. However, the presence of an inflammatory involvement of lower airway has been poorly investigated. OBJECTIVE: The aim of the study was to demonstrate an inflammatory process at the bronchial level in patients with OSA and to analyze effects of continuous positive airway pressure (CPAP) application and humidification on bronchial mucosa. METHODS: The study was conducted by using sequential induced sputum for cell analysis and IL-8 production, nitric oxide exhalation measurement, and methacholine challenge before and after CPAP. RESULTS: Bronchial neutrophilia and a high IL-8 concentration were observed in untreated OSA compared with controls (75% +/- 20% vs 43% +/- 12%, P < .05; and 25.02 +/- 9.43 ng/mL vs 8.6 +/- 3.7 ng/mL, P < .001, respectively). IL-8 in sputum supernatant was correlated to apnea hypopnea index (P < .01; r = 0.81). After 1 month of CPAP, this inflammatory pattern remained unchanged, and an increase in airway hyperresponsiveness (AHR) was observed (P < .001). CONCLUSION: Obstructive sleep apnea syndrome is associated with bronchial inflammation. Our data demonstrate CPAP effect on the development of AHR, possibly facilitated by the pre-existing inflammation. Both issues should be evaluated during long-term CPAP use. CLINICAL IMPLICATIONS: Results showing a spontaneous bronchial inflammation in OSA and the development of a CPAP-related AHR require a long-term follow-up to evaluate consequences on chronic bronchial obstruction.

Alam I. Lewis K. Stephens JW. Baxter JN. Obesity, metabolic syndrome and sleep apnoea: all pro-inflammatory states. [Review] [107 refs] Obesity Reviews. 8(2):119-27, 2007. Obesity is associated with significant morbidity and mortality and is increasing in prevalence worldwide. Associated conditions include insulin resistance (IR), diabetes, hypertension and dyslipidaemia; a clustering of these has recently been termed as metabolic syndrome. Weight gain is a major predictor of the metabolic syndrome with waist circumference being a more sensitive indicator than body mass index as it reflects both abdominal subcutaneous adipose tissue and visceral adipose tissue (VAT). VAT has more metabolic activity and secretes a number of hormones and pro-inflammatory cytokines which are linked with the metabolic abnormalities listed above. Central obesity also increases the risk of obstructive sleep apnoea syndrome (OSAS), where the sleep disordered breathing may also independently lead to/or exacerbate IR, diabetes and cardiovascular risk. The contribution of OSAS to the metabolic syndrome has been under-recognized. The putative mechanisms by which OSAS causes or exacerbates these other abnormalities are discussed. We propose that activation of nuclear factor kappa B by stress hypoxia and/or by increased adipokines and free fatty acids released by excess adipose tissue is the final common inflammatory pathway linking obesity, OSAS and the metabolic syndrome both individually and, in many cases, synergistically.

Minoguchi K. Yokoe T. Tanaka A. Ohta S. Hirano T. Yoshino G. O'Donnell CP. Adachi M. Association between lipid peroxidation and inflammation in obstructive sleep apnoea. European Respiratory Journal. 28(2):378-85, 2006. In the present study, the authors examined the relationship between lipid peroxidation and inflammation in patients with obstructive sleep apnoea (OSA). A total of 40 obese patients with OSA were studied, along with 18 obese and 12 lean subjects without OSA. Overnight excretion of 8-isoprostane in urine and serum levels of high-sensitivity C-reactive protein (hsCRP) were measured. In addition, the effects of 3 months' treatment with nasal continuous positive airway pressure (nCPAP) were studied in 20 obese patients with moderate-to-severe OSA. Overnight urinary excretion of 8-isoprostane and serum levels of hsCRP were significantly higher in patients with moderate-to-severe OSA compared with patients with mild OSA and obese or lean subjects without OSA. Overnight urinary excretion of 8-isoprostane significantly correlated with apnoea-hypopnoea index, duration of hypoxia during sleep, body mass index, and serum levels of hsCRP in patients with OSA. The severity of OSA was an independent factor predicting the urinary excretion of 8-isoprostane. nCPAP significantly decreased urinary excretion of 8-isoprostane and serum levels of hsCRP. In conclusion, these results suggest that both obstructive sleep apnoea severity and obesity can independently contribute to elevations in urinary excretion of 8-isoprostane. Therefore, obstructive sleep apnoea may increase the risks of cardiovascular morbidity in obese patients.

Goldbart AD. Krishna J. Li RC. Serpero LD. Gozal D. Inflammatory mediators in exhaled breath condensate of children with obstructive sleep apnea syndrome. Chest. 130(1):143-8, 2006. BACKGROUND: Upper airway inflammation is now recognized in adults with obstructive sleep apnea (OSA) syndrome. However, the role played by eicosanoids such as leukotrienes and prostaglandins is unclear. OBJECTIVE: To investigate whether eicosanoids are measurable in exhaled breath condensate (EBC), and to determine whether differences in these inflammatory mediators emerge among children with and without sleep-disordered breathing (SDB). METHODS: EBC was collected from 50 consecutive snoring children undergoing overnight polysomnography for suspected SDB, and from 12 nonsnoring control subjects. Prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and cysteinyl leukotrienes (cys-LTs: leukotriene C4 [LTC4]/leukotriene D4 [LTD4]/leukotriene E4 [LTE4]) EBC levels were analyzed using enzyme-linked immunosorbent assay. RESULTS: LTB4 levels were elevated in children with an apnea-hypopnea index (AHI) > 5/h (SDB; 97.6 +/- 6.3 pg/mL) compared to children with an AHI < 5/h (mild SDB; 66.4 +/- 19.1 pg/mL; p < 0.01) and control subjects (27.8 +/- 3.7 pg/mL; p < 0.01). Similarly, cys-LT (LTC4/LTD4/LTE4) concentrations were also increased in SDB (45.1 +/- 10.6 pg/mL in SDB vs 27.6 +/- 8.3 pg/mL in mild SDB, and 15.7 +/- 7.6 pg/mL in control subjects; p < 0.01). In contrast, PGE2 concentrations were similar among the three groups. CONCLUSIONS: Inflammatory mediators such as leukotrienes and prostaglandins can be readily quantified in EBC collected from the upper airway of children. Disease severity-dependent increases in leukotriene concentrations (LTB4 and LTC4/LTD4/LTE4) emerge among children and may serve as a noninvasive tool in the clinical assessment of these children.

Tam CS. Wong M. McBain R. Bailey S. Waters KA. Inflammatory measures in children with obstructive sleep apnoea. Journal of Paediatrics & Child Health. 42(5):277-82, 2006. AIM: To evaluate a range of inflammatory measures in children with obstructive sleep apnoea (OSA). METHODS: In total, 44 children with polysomnographically defined OSA (30 boys; mean age: 7.3 +/- 3.7 years) and 69 control subjects (44 boys; mean age: 7.6 +/- 4 years) were recruited. Controls were screened for symptoms of OSA by questionnaire at the time of elective surgery that was unrelated to the upper airway. Blood samples were analysed for C-reactive protein, and cytokines IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, GM-CSF, IFN-gamma and TNF-alpha. RESULTS: The majority of the children had mild OSA (32/44). Children with OSA (respiratory disturbance index 5.3 +/- 6.5 events/h) had significantly higher IFN-gamma and IL-8 levels than controls (P < 0.001 and 0.003, respectively), although correction for age, sex and body mass index reduced these differences (IFN-gammaP = 0.002, and IL-8 P = 0.051). There were no significant correlations between inflammatory measures and body mass index, respiratory disturbance index, or other sleep, desaturation, or arousal parameters including respiratory or spontaneous arousal indices, desaturation index or severity, sleep efficiency, or apnoea/hypopnoea duration in the OSA group. CONCLUSION: Children with OSA, even of mild severity, have significantly elevated IFN-gamma levels and a trend towards elevated IL-8 levels compared with asymptomatic controls, consistent with a pro-inflammatory effect of OSA. These changes seen in mild OSA may precede changes in other pro-inflammatory cytokines found in studies of adults with more severe and long-standing disease, implying a potential benefit from early disease identification and intervention.

Htoo AK. Greenberg H. Tongia S. Chen G. Henderson T. Wilson D. Liu SF. Activation of nuclear factor kappaB in obstructive sleep apnea: a pathway leading to systemic inflammation. [see comment]. Sleep & Breathing. 10(1):43-50, 2006. Apnea-induced hypoxia and reoxygenation, which generates reactive oxygen species, may activate the oxidant-sensitive, proinflammatory transcription factor nuclear factor kappaB (NF-kappaB), increasing systemic inflammation in obstructive sleep apnea. We measured NF-kappaB activity in circulating neutrophils and plasma levels of NF-kappaB-controlled gene products, soluble E (sE)-selectin and soluble vascular cell adhesion molecule-1 (sVCAM-1) in control subjects and in obstructive sleep apnea (OSA) patients. To confirm a causal link with OSA, we reassessed these parameters after nasal continuous positive airway pressure (CPAP) therapy. Twenty-two subjects undergoing evaluation for symptoms of sleep-disordered breathing were grouped by apnea hypopnea index: control, less than 5/h; mild to moderate OSA, 11-40/h; severe OSA, more than 40/h. A morning venous blood sample was obtained. Neutrophils were isolated, and NF-kappaB activity was determined by electrophoretic mobility shift assay. Plasma sE-selectin and sVCAM-1 were assayed by enzyme-linked immunosorbent assay. Neutrophils in mild to moderate and severe OSA patients showed 4.8- and 7.9-fold greater NF-kappaB binding activity compared with control subjects (p<0.0001). The degree of NF-kappaB activation was positively correlated with indices of apnea severity. In five severe OSA patients, 1 month of CPAP therapy decreased neutrophil NF-kappaB activation to control levels. sE-selectin and sVCAM concentrations were reduced by CPAP in four of these five subjects. OSA leads to NF-kappaB activation, which may constitute an important pathway linking OSA with systemic inflammation and cardiovascular disease.

Kasasbeh E. Chi DS. Krishnaswamy G. Inflammatory aspects of sleep apnea and their cardiovascular consequences.[erratum appears in South Med J. 2006 Feb;99(2):163][summary for patients in South Med J. 2006 Jan;99(1):104; PMID: 16466139]. [Review] [114 refs] Southern Medical Journal. 99(1):58-67; quiz 68-9, 81, 2006. Obstructive sleep apnea (OSA) is a common medical condition that occurs in a considerable percentage of the population. Substantial evidence shows that patients with OSA have an increased incidence of hypertension compared with individuals without OSA, and that OSA is a risk factor for the development of hypertension. It is established that OSA may be implicated in stroke and transient ischemic attacks. OSA is associated with coronary heart disease, heart failure, and cardiac arrhythmias. Pulmonary hypertension may be associated with OSA, especially in patients with pre-existing pulmonary disease. Although the exact cause that links OSA with cardiovascular disease is unknown, there is evidence that OSA is associated with a group of proinflammatory and prothrombotic factors that have been identified as important in the development of atherosclerosis. OSA is associated with increased daytime and nocturnal sympathetic activity. Autonomic abnormalities seen in patients with OSA include increased resting heart rate, decreased R-R interval variability, and increased blood pressure variability. Both atherosclerosis and OSA are associated with endothelial dysfunction, increased C-reactive protein, interleukin 6, fibrinogen, plasminogen activator inhibitor, and reduced fibrinolytic activity. OSA has been associated with enhanced platelet activity and aggregation. Leukocyte adhesion and accumulation on endothelial cells are common in both OSA and atherosclerosis. Clinicians should be aware that OSA may be a risk factor for the development of cardiovascular disease.

Tan KC. Chow WS. Lam JC. Lam B. Wong WK. Tam S. Ip MS. HDL dysfunction in obstructive sleep apnea. Atherosclerosis. 184(2):377-82, 2006. OBJECTIVE: HDL is anti-atherogenic and has antioxidant property. HDL dysfunction has been reported in patients with coronary heart disease and we hypothesize that HDL may also be dysfunctional in obstructive sleep apnea (OSA), a condition associated with increased oxidative stress. METHODS: 128 OSA patients and 82 controls were recruited. HDL dysfunction was determined by evaluating the ability of HDL to inhibit LDL oxidation ex vivo. Plasma HDL was incubated with native LDL in the presence of dichlorofluorescein which fluoresced upon interaction with lipid oxidation products. Plasma levels of oxidized LDL and 8-isoprostane were measured by ELISA and a specific enzyme immunoassay, respectively. RESULTS: Plasma total 8-isoprostane levels were elevated in OSA subjects (p<0.01). Despite having similar concentrations of plasma lipids and apolipoproteins as controls, OSA subjects had greater degree of HDL dysfunction (p<0.01) and increased oxidized LDL levels (p<0.05). The apnea-hypopnea index was the main determinant of HDL dysfunction in OSA, accounting for 30% of its variance, with oxidized LDL and apolipoprotein AI contributing to 8% and 5% of its variance respectively (p<0.001). CONCLUSION: HDL is dysfunctional in preventing the formation and inactivation of oxidized lipids in OSA subjects and may partly contribute to their increased cardiovascular risk.

Shadan FF. Jalowayski AA. Fahrenholz J. Kline LE. Dawson A. Nasal cytology: a marker of clinically silent inflammation in patients with obstructive sleep apnea and a predictor of noncompliance with nasal CPAP therapy. Journal of Clinical Sleep Medicine. 1(3):266-70, 2005. STUDY OBJECTIVES: Patients with obstructive sleep apnea treated with nasal continuous positive airway pressure (CPAP) often complain of nasal side effects. We studied patients before and after initiation of nasal CPAP to see how treatment affected nasal function and markers of nasal inflammation. We searched for pretreatment findings that might help to predict noncompliance. METHODS: Nasal symptom scores, nasal flow by anterior rhinomanometry, mediator levels (intercellular adhesion molecule-1, interleukin-6, interleukin-8 and interleukin-13), and nasal scrapes for cytology were obtained at baseline and monthly for up to 3 months of nasal CPAP therapy. Compliance was assessed from the patient's report and by recording hours of usage for up to 19 months of follow-up. RESULTS: Thirty-eight patients with newly diagnosed obstructive sleep apnea were classified as having no rhinitis (42%), allergic rhinitis (37%), or nonallergic rhinitis (21%). There was no significant difference in compliance in patients with and without rhinitis. Compliant and noncompliant patients showed no significant differences in their baseline nasal symptom scores, nasal flow, and mediator levels. Nasal neutrophil counts before treatment were greater in noncompliant than in compliant patients (p = .004) and greater in those discontinuing because of nasal symptoms than in patients who quit for other reasons (p = .05). There was a positive correlation between neutrophil counts and nasal bacterial scores, both before and after treatment with nasal CPAP. CONCLUSIONS: Patients with increased neutrophil counts in the nasal scrape before beginning nasal CPAP are at increased risk of discontinuing therapy. They appear to have subclinical nasal inflammation that cannot be identified from clinical assessment, nasal symptom scores or rhinomanometry.

Kokturk O. Ciftci TU. Mollarecep E. Ciftci B. Elevated C-reactive protein levels and increased cardiovascular risk in patients with obstructive sleep apnea syndrome. International Heart Journal. 46(5):801-9, 2005. Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular morbidity and mortality. Inflammatory processes associated with OSAS may contribute to cardiovascular morbidity in these patients. C-reactive protein (CRP) is an important serum marker of inflammation. We tested the hypothesis that patients with OSAS have increased plasma CRP. After 173 male subjects underwent polysomnography, 94 were considered to have OSAS (apnea-hypopnea index (AHI) > 5), 38 cardiovascular disease (CVD), and 56 without CVD. Seventy-nine subjects were considered not to have OSAS (AHI < 5) and from among these 57 patients without CVD were enrolled as control subjects. Serum CRP levels were significantly elevated in the OSAS + CVD group compared to the two other groups (P < 0.05). When we evaluated the association between the serum CRP level and severity of OSAS, CRP levels were positively correlated with AHI in OSAS patients (r = 0.61, P < 0.001) OSAS, as a marker of inflammation and cardiovascular risk, is associated with elevated levels of CRP. According to these results, the link between cardiovascular morbidity and OSAS may be explained by the coexistence of other cardiovascular risk factors such as circulating CRP levels.

Ryan S. Taylor CT. McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation. 112(17):2660-7, 2005. BACKGROUND: Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/reoxygenation (IHR), is an independent risk factor for cardiovascular disease. We investigated the underlying molecular mechanisms of this association in a translational study. METHODS AND RESULTS: In a novel in vitro model of IHR, we used HeLa cells transfected with reporter constructs and DNA binding assays for the master transcriptional regulators of the inflammatory and adaptive pathways (NFkappaB and HIF-1, respectively) to investigate underlying transcriptional events initiated by repeated cell exposure to IHR. Furthermore, we prospectively studied 19 male OSAS patients (median apnea-hypopnea frequency, 48.5 episodes per hour; interquartile range [IQR], 28.5 to 72.9) and 17 matched normal control subjects. Circulating levels of the proinflammatory cytokine tumor necrosis factor-alpha and the adaptive factor erythropoietin were assayed in all subjects at baseline and again after 6 weeks of continuous positive airway pressure therapy in patients. Full blood count was measured as part of a detailed baseline evaluation. HeLa cells exposed to IHR demonstrated selective activation of the proinflammatory transcription factor NFkappaB (P<0.001 by ANOVA), whereas the adaptive regulator HIF-1 was not activated, as demonstrated by luciferase reporter assays and DNA binding studies. Circulating tumor necrosis factor-alpha levels were higher in OSAS patients (2.56 pg/mL; IQR, 2.01 to 3.42 pg/mL) than in control subjects (1.25 pg/mL; IQR, 0.94 to 1.87; P<0.001) but normalized with continuous positive airway pressure therapy (1.24 pg/mL; IQR, 0.78 to 2.35 pg/mL; P=0.002). In contrast, erythropoietin levels were similar throughout. Furthermore, circulating neutrophil levels were higher in OSAS patients than in control subjects, whereas the hematocrit was unaltered. CONCLUSIONS: These data demonstrate selective activation of inflammatory over adaptive pathways in IHR and OSAS, which may be an important molecular mechanism of cardiovascular disease.

Lavie L. Sleep-disordered breathing and cerebrovascular disease: a mechanistic approach. [Review] [87 refs] Neurologic Clinics. 23(4):1059-75, 2005. The observations described in this article point to the existence of increased oxidative stress and systemic inflammation in sleep apnea and have paved the way for establishing sleep apnea as an independent risk factor for cardio- and cerebrovascular morbidities. The proposed course of events is summarized in Fig. 1. It is suggested that hypoxia/reoxygenation,characteristic of sleep apnea, promotes the formation of ROS, particularly during the reoxygenation period, and can be deleterious to cells and tissues. ROS, however, regulate the activation of critical transcription factors that are redox sensitive, resulting in increased expression of sets of genes that encode proteins essential to adaptation to hypoxia (via hypoxia inducible factor I [hypoxia inducible factor-la]). Yet, redox-sensitive transcription factors (NFKB and AP-1) that elicit inflammatory pathways also are activated, thereby affecting inflammatory and immune responses by promoting activation of endothelial cells, leukocytes, and platelets. These activated cells express adhesion molecules and proinflammatory cytokines that may lead to endothelial injury and dysfunction and consequently to the development of cardio- and cerebrovascular morbidities. These may be exaggerated in patients who have sleep apnea in response to the intermittent hypoxia.

Motivala SJ. Sarfatti A. Olmos L. Irwin MR. Inflammatory markers and sleep disturbance in major depression. Psychosomatic Medicine. 67(2):187-94, 2005. OBJECTIVE: This study was conducted to determine whether immune activation occurs in major depression, and to evaluate the associations between disordered sleep and markers of inflammation in patients with major depressive disorder. METHODS: All-night polysomnography was obtained in patients with acute Diagnostic and Statistical Manual of Mental Disorders, 4th edition major depressive disorder (n = 22) and age-, gender-, and body weight-matched comparison controls (n = 18). After the onset of sleep, nocturnal serum levels of interleukin-6 (IL-6), soluble intercellular adhesion molecule (sICAM), monocyte chemotactic protein (MCP-1), and IL-6 soluble receptor (IL-6sR) were sampled. RESULTS: As compared with matched controls, depressed patients showed significant (p <.05) nocturnal elevations of circulating levels of IL-6 and sICAM. Both sleep latency and rapid eye movement (REM) density had moderate correlations with IL-6 and sICAM (r's > or = 0.30). Backward regression analyses indicated that sleep latency (beta = 0.34, p <.05) and REM density (beta = 0.27, p = .09) were better predictors of IL-6 than depressive status. Similarly, sleep latency (beta = 0.27, p = .06) and REM density (beta = 0.32, p = .02) were also better predictors of sICAM. CONCLUSION: These findings support the hypothesis that sleep disturbance is associated with elevated levels of the inflammatory markers IL-6 and sICAM. This relationship was not accounted for by other confounding factors such as age and body weight. These findings suggest that the elevations in inflammatory markers found in depressive subjects may be partially the result of disturbances of sleep initiation found in this population.

Boyd JH. Petrof BJ. Hamid Q. Fraser R. Kimoff RJ. Upper airway muscle inflammation and denervation changes in obstructive sleep apnea. American Journal of Respiratory & Critical Care Medicine. 170(5):541-6, 2004. Inflammatory cell infiltration and afferent neuropathy have been shown in the upper airway (UA) mucosa of subjects with obstructive sleep apnea (OSA). We hypothesized that inflammatory and denervation changes also involve the muscular layer of the pharynx in OSA. Morphometric analysis was performed on UA tissue from nonsnoring control subjects (n = 7) and patients with OSA (n = 11) following palatal surgery. As compared with control subjects, inflammatory cells were increased in the muscular layer of patients with OSA, with CD4+ and activated CD25+ T cells (both increased approximately threefold) predominating. Inflammation was also present in UA mucosa, but with a different pattern consisting of CD8+ (2.8-fold increase) and activated CD25+ (3.2-fold increase) T cell predominance. As ascertained by immunoreactivity for the panneuronal marker PGP9.5, there was a dramatic (5.7-fold) increase in intramuscular nerve fibers in OSA patients compared with control subjects, as well as direct evidence of denervation based on positive immunostaining of the muscle fiber sarcolemmal membrane for the neural cell adhesion molecule in patients with OSA. These data suggest that inflammatory cell infiltration and denervation changes affect not only the mucosa, but also the UA muscle of patients with OSA. This may have important implications for the ability to generate adequate muscular dilating forces during sleep.