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(Chest. 2004;126:1473-1479.)
© 2004 American College of Chest Physicians

Elevated Production of Tumor Necrosis Factor-{alpha} by Monocytes in Patients With Obstructive Sleep Apnea Syndrome*

Kenji Minoguchi, MD, PhD; Toshiyuki Tazaki, MD; Takuya Yokoe, MD, PhD; Hideko Minoguchi, MD, PhD; Yoshio Watanabe, MD; Mayumi Yamamoto, MD and Mitsuru Adachi, MD, PhD

* From the First Department of Internal Medicine, Showa University, Tokyo, Japan.

Correspondence to: Kenji Minoguchi, MD, PhD, First Department of Internal Medicine, Showa University, School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan; e-mail: minochan{at}fn.catv.ne.jp


   Abstract
TOP
 Abstract
Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Tumor necrosis factor (TNF)-{alpha} is involved in the pathogenesis of atherosclerosis. In the present study, we examined TNF-{alpha} production by monocytes, serum levels of TNF-{alpha}, and the effects of nasal continuous positive airway pressure (nCPAP) in patients with obstructive sleep apnea syndrome (OSAS).

Design: Prospective observational study.

Setting: University hospital.

Subjects: Twenty-four patients with OSAS, 15 obese control subjects, and 12 healthy subjects.

Measurements and results: After polysomnography, venous blood was collected at 5 AM. Spontaneous production of TNF-{alpha} by monocytes for 24 h and serum levels of TNF-{alpha} were investigated. In addition, patients with moderate-to-severe OSAS were treated with nCPAP for 1 month, and spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} were also measured. Spontaneous production of TNF-{alpha} by monocytes was significantly higher in patients with moderate-to-severe OSAS than in patients with mild OSAS (p < 0.0001), obese control subjects (p < 0.0001), or healthy subjects (p < 0.0001). Serum levels of TNF-{alpha} were also significantly higher in patients with moderate-to-severe OSAS than in patients with mild OSAS (p < 0.03), obese control subjects (p < 0.0005), or healthy subjects (p < 0.0001). Duration of hypoxia during total sleep time was independently associated with spontaneous production of TNF-{alpha} by monocytes in patients with OSAS and healthy and obese control subjects. nCPAP significantly decreased spontaneous production of TNF-{alpha} by monocytes (p < 0.03) and serum levels of TNF-{alpha} (p < 0.05) in patients with moderate-to-severe OSAS.

Conclusions: Spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} are elevated in patients with moderate-to-severe OSAS but are decreased by nCPAP.

Key Words: atherosclerosis • cardiovascular diseases • hypoxia • monocyte • sleep apnea • tumor necrosis factor-{alpha}


   Introduction
TOP
 Abstract
 Introduction
Methods and Materials
 Results
 Discussion
 Conclusion
 References
 
Tumor necrosis factor (TNF)-{alpha} is a pleiotropic proinflammatory cytokine that exerts multiple biological effects. TNF-{alpha} is produced by numerous immune cells and is involved in the pathogenesis of many diseases, including infectious diseases, auto-immune diseases, cancers, metabolic diseases, and cardiovascular diseases. TNF-{alpha} is also involved in the development of atherosclerosis. Early atherosclerosis is characterized by monocytes infiltrating into the vascular wall and later transforming into foam cells.1 Several studies12345 have indicated that TNF-{alpha} is involved in each step of atherosclerosis by inducing such adhesion molecules as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, stimulating production of monocyte chemoattractant protein-1 by endothelial cells, promoting the proliferation and migration of smooth-muscle cells, and inducing the expression of lectin-like oxidized low-density lipoprotein receptor-1. In addition, several in vivo studies67 have shown that plasma levels of TNF-{alpha} are associated with atherosclerosis. TNF-{alpha} is up-regulated in the myocardium in response to both transient myocardial ischemia and reperfusion.891011 Moreover, levels of TNF-{alpha} are persistently elevated in patients at increased risk of additional coronary events after myocardial infarction.12

Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular morbidity and mortality.1314 Plasma levels of TNF-{alpha} and interleukin-6 are increased in patients with OSAS.1516 Although nasal continuous positive airway pressure (nCPAP) is useful for decreasing the risk of cardiovascular mortality in patients with severe OSAS, whether it affects spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} after exposure to repeated apnea-related hypoxia in patients with OSAS is not completely studied. The purpose of the present study in patients with OSAS was to evaluate whether spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} are elevated, to identify independent variables for the production of TNF-{alpha} and serum levels of TNF-{alpha}, and to determine whether treatment with nCPAP improves sleep quality and decreases production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha}.


   Methods and Materials
TOP
 Abstract
 Introduction
 Methods and Materials
Results
 Discussion
 Conclusion
 References
 
Subjects
Twenty-four men with newly diagnosed OSAS and 15 men without OSAS (control subjects) were enrolled in this study. Also studied were 12 nonobese, healthy subjects in whom polysomnography was performed and showed no OSAS (Table 1 ). Obese subjects with snoring were recruited from the outpatient clinic for the evaluation of possible sleep apnea. These subjects were examined with polysomnography and classified as obese control subjects according to the data of apnea-hypopnea index (AHI). The diagnosis of OSAS was also established with polysomnography. The patients were asked about their regular medications and medical history, including cardiovascular diseases and smoking habits. Patients who smoked or had systemic infections at the time of the study or within 2 weeks before the study were excluded. Four of the 24 patients with OSAS and 2 of 15 obese control subjects had hypertension, which had been treated with calcium-channel antagonists for at least 6 months; medications were not changed during the study. Two of the 24 patients with OSAS and 1 of the 15 obese control subjects had diabetes mellitus; none of these subjects had received pharmacologic treatment. One patient with OSAS had a history of angina pectoris, but none of the subjects had a history of cerebrovascular disease. The study was approved by the Ethics Committee of Showa University Hospital, and all patients gave written informed consent.


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  		Table 1. Baseline Characteristics in Patients With OSAS and Healthy and Obese Control Subjects*

 
Polysomnography
Full polysomnography monitoring was performed with the Compumedics P-series Sleep System (Compumedics Sleep; Abbotsford, Australia). EEG, electro-oculography, electromyography, and ECG were performed simultaneously. Surface electrodes were used to record two channels of EEG (C3A2, C4A1), right and left electro-oculography, and submental electromyography. Ventilatory flow at the nose and mouth was measured with thermistors. Ventilatory movements of the chest and abdomen were monitored by inductive plethysmography bands. The arterial oxygen saturation (SaO2) was measured transcutaneously with fingertip pulse oximetry. Apnea was defined as continuous cessation of airflow for > 10 s, and hypopnea was defined as a reduction in airflow for > 10 s with oxygen desaturation of ≥ 4% or an EEG arousal from sleep. Apneas were classified as obstructive, mixed, or central according to standard criteria by American Academy of Sleep Medicine. The AHI was calculated as the total number of episodes of apnea and hypopnea per hour of sleep. An AHI of ≥ 5 was considered diagnostic of OSAS. An AHI ≥ 5 to < 20 indicated mild OSAS, AHI ≥ 20 to < 30 indicated moderate OSAS, and AHI ≥ 30 indicated severe OSAS. Polysomnography was performed from 10 PM to 5 AM. Special staff technicians performed data processing. Of the 24 patients with OSAS, 12 patients were considered to have mild OSAS and 12 patients were considered to have moderate-to-severe OSAS. The Epworth sleepiness scale (ESS) was used to investigate changes in subjective daytime sleepiness.17

Purification of Monocytes and TNF-{alpha} Measurement
Samples of peripheral venous blood were collected at 5 AM just after awakening so that serum levels of TNF-{alpha} and production of TNF-{alpha} by monocytes could be measured before patients had begun to breath normally. Peripheral blood mononuclear cells were isolated with a Ficoll-Hypaque gradient (Pharmacia Diagnostics; Uppsala, Sweden). CD14+ monocytes were isolated by negative selection using magnetic beads (MACS MicroBeads; Miltenyi Biotec; Auburn, CA) according to the instructions of the manufacturer. Monocytes (1 x 105/mL) were cultured for 24 h in RPMI 1640 supplemented with 10% volume/volume human AB serum, 100 U/mL penicillin, and 100 U/mL streptomycin. These media were free of lipopolysaccharide. The total number of monocytes was counted, and cell viability was analyzed by staining with trypan blue before culture and after 24 h of culture. A preliminary study suggested that culture of monocytes from 12 patients with OSAS for 24 h did not affect cell number or cell viability compared with baseline levels (data not shown). The supernatants were collected, spun, and stored at – 80°C, and the concentration of TNF-{alpha} was measured with an enzyme-linked immunosorbent assay kit (Biosource International; Camarillo, CA), which could detect concentrations as low as 3.9 pg/mL. Serum levels of TNF-{alpha} were also measured with a high-sensitivity enzyme-linked immunosorbent assay kit (Biosource International), which could detect concentrations as low as 0.12 pg/mL.

nCPAP Treatment
Patients with moderate-to-severe OSAS slept while using the automatic titration device (AutoSet; ResMed; North Ryde, Australìa). The following night, these patients slept with a conventional continuous positive airway pressure machine using the S6 CPAP device (ResMed; North Ryde; Australia) set at a fixed pressure determined from the results of the AutoSet, after which the patients were sent home. The duration of nCPAP treatment was 1 month. Compliance was assessed with hour-meter readings, and the mean daily duration of nCPAP use was 5.6 ± 0.9 h (± SD) in patients with moderate-to-severe OSAS. Patients with moderate-to-severe OSAS were admitted, and polysomnography was performed again as the patient received nCPAP. Samples of venous blood were obtained at 5 AM, and spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} were measured.

Statistical Analysis
The significance of differences within groups was analyzed with a Student paired t test, and the significance of differences between groups was performed by analysis of variance first, followed by t tests with Bonferroni correction. The correlation was analyzed with a Spearman rank correlation. To assess the relative strength of association with possible contributing factors of serum levels of TNF-{alpha} and of production of TNF-{alpha} by monocytes, we performed a multiple regression analysis for patients with OSAS and healthy and obese control subjects as a single group. In this analysis, we used spontaneous production of TNF-{alpha} by monocytes or serum levels of TNF-{alpha} as dependent variables and evaluated the order of inclusion in the model of the following independent variables: age, metabolic variables, body mass index (BMI), AHI, percentage of time with SaO2 < 90%, lowest SaO2, and ESS. Data are expressed as mean ± SD; p < 0.05 was considered to indicate significance.


   Results
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
Discussion
 Conclusion
 References
 
Production of TNF-{alpha} by Monocytes and Serum Levels of TNF-{alpha}
Levels of spontaneously produced TNF-{alpha} by monocytes were significantly higher in patients with moderate-to-severe OSAS (501.3 ± 378.8 pg/mL) than in healthy subjects (61.7 ± 40.3 pg/mL, p < 0.0001), obese control subjects (82.2 ± 51.9 pg/mL, p < 0.0001), or patients with mild OSAS (104.2 ± 139.2 pg/mL, p < 0.0001; Fig 1 ). Serum levels of TNF-{alpha} were significantly higher in patients with moderate-to-severe OSAS (2.34 ± 0.54 pg/mL) than in healthy subjects (1.12 ± 0.39 pg/mL, p < 0.0001), obese control subjects (1.60 ± 0.31 pg/mL, p < 0.0005), or patients with mild OSAS (1.80 ± 0.43 pg/mL, p < 0.03; Fig 2 ). When patients with OSAS complicated by other conditions were excluded from the analysis, spontaneous production of TNF-{alpha} by monocytes (p < 0.05) and serum levels of TNF-{alpha} (p < 0.05) were still greater in patients with moderate-to-severe OSAS than in healthy subjects, obese control subjects, or patients with mild OSAS.



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  		Figure 1. Spontaneous production of TNF-{alpha} by monocytes. Spontaneous production of TNF-{alpha} by monocytes (1 x 105/mL) for 24 h was measured in healthy subjects (n = 12), obese control subjects (n = 15), patients with mild OSAS (n = 12), and patients with moderate-to-severe OSAS (n = 12). The boxes represent the interquartile range (25th to 75th centiles); the horizontal line insides the box represent medians; the error bars represent the 95% confidence intervals of the mean. NS = not significant.

 


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  		Figure 2. Serum levels of TNF-{alpha}. Serum levels of TNF-{alpha} were measured in healthy subjects (n = 12), obese control subjects (n = 15), patients with mild OSAS (n = 12), and patients with moderate-to-severe OSAS (n = 12). The boxes represent the interquartile range (25th to 75th centiles); the horizontal line insides the box represent medians; the error bars represent the 95% confidence intervals of the mean. See Figure 1 legend for expansion of abbreviation.

 
Correlation Between Production of TNF-{alpha} by Monocytes or Serum Levels of TNF-{alpha} and Polysomnography Variables, Metabolic Variables, and ESS in Patients With OSAS
Spearman rank correlation coefficients between spontaneous production of TNF-{alpha} or serum levels of TNF-{alpha} with age, metabolic variables, polysomnography variables, and ESS in patients with OSAS are shown in Table 2 . Spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} were positively correlated with AHI, the percentage of time with SaO2 < 90%, BMI, and ESS and were negatively correlated with lowest nocturnal SaO2. Spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} were also significantly correlated in patients with OSAS (r = 0.48, p = 0.017). Thus, in men with OSAS, production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} were most often elevated in those who were more obese, had severe OSAS with more-severe nocturnal hypoxia, and had greater daytime sleepiness.


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  		Table 2. Correlation Coefficients Between Spontaneous Production of TNF-{alpha} by Monocytes or Serum Levels of TNF-{alpha} and Metabolic Variables and Polysomnographic Variables in Patients With OSAS

 
Multiple Regression Analysis in Patients With OSAS and Control Subjects
To examine independent predictors of spontaneous production of TNF-{alpha} by monocytes or serum levels of TNF-{alpha} in patients with OSAS and healthy and obese control subjects, we performed multiple regression analysis. Among the clinical variables, the strongest predictor of spontaneous production of TNF-{alpha} by monocytes was percentage of time with SaO2 < 90% (p = 0.001). In addition, the independent predictors of serum levels of TNF-{alpha} were BMI (p = 0.003), followed by percentage of time with SaO2 < 90% (p = 0.005).

Effects of nCPAP on Production of TNF-{alpha} by Monocytes and Serum Levels of TNF-{alpha} in Patients With Moderate-to-Severe OSAS
In patients with moderate-to-severe OSAS, BMI did not change significantly and no new cardiovascular diseases or infectious diseases were detected during the 1 month of treatment with nCPAP. However, treatment with nCPAP significantly decreased AHI (59.2 ± 14.7 to 1.67 ± 1.9 events per hour, p < 0.001); increased the lowest nocturnal SaO2 (68.5 ± 9.4 to 90.8 ± 5.5%, p < 0.001) and total sleep time (339.7 ± 84.6 to 429.5 ± 50.9 min, p < 0.01); and decreased percentage of time with SaO2 < 90% (42.2 ± 20.0 to 0.10 ± 0.3%, p < 0 0.001), the arousal index (45.9 ± 13.3 to 17.1 ± 7.4 per hour, p < 0.01), and ESS (13.5 ± 3.2 to 6.17 ± 3.0, p < 0.01). Treatment with nCPAP also significantly decreased spontaneous production of TNF-{alpha} by monocytes (501.3 ± 361.3 to 234.9 ± 176.9 pg/mL, p < 0.03; Fig 3 , left, A). In addition, serum levels of TNF-{alpha} were significantly decreased by the treatment with nCPAP (2.34 ± 0.54 to 1.85 ± 0.72 pg/mL, p < 0.05; Fig 3, right, B).



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  		Figure 3. Effect of nCPAP on spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha}. Patients with moderate-to-severe OSAS were treated with nCPAP for 1 month. Changes in spontaneous production of TNF-{alpha} by monocytes (1 x 105/mL, left, A) and serum levels of TNF-{alpha} (right, B) were demonstrated (n = 12). The boxes represent the interquartile range (25th to 75th centiles); the horizontal line insides the box represent medians; the error bars represent the 95% confidence intervals of the mean.

 
Changes in AHI after treatment with nCPAP for 1 month were correlated with changes in spontaneous production of TNF-{alpha} by monocytes (r = 0.78, p = 0.003) and serum levels of TNF-{alpha} (r = 0.73, p = 0.007). Changes in the percentage of time with SaO2 < 90% after treatment with nCPAP for 1 month were correlated with changes in spontaneous production of TNF-{alpha} by monocytes (r = 0.65, p = 0.022) and serum levels of TNF-{alpha} (r = 0.57, p = 0.043).


   Discussion
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
Conclusion
 References
 
We found that both spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} were significantly higher in patients with moderate-to-severe OSAS than in healthy and obese control subjects and patients with mild OSAS. In patients with OSAS and healthy and obese control subjects, the primary factor influencing spontaneous production of TNF-{alpha} by monocytes was duration of hypoxia during total sleep time. Furthermore, in patients with moderate-to-severe OSAS, treatment with nCPAP for 1 month significantly improved sleep quality and decreased spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha}. Therefore, we conclude that deterioration of sleep quality with repeated apnea-related hypoxia is associated with increases in TNF-{alpha} production by monocytes in patients with moderate-to-severe OSAS.

Several studies1819 have found that production of superoxide by neutrophils and monocytes is elevated in patients with OSAS. Expression of adhesion molecules CD15 and CD11c on monocytes and adherence to endothelial cells were also increased.19 Furthermore, nCPAP significantly decreases basal production of reactive oxygen species, expression of CD15 and CD11c on monocytes, and adherence of monocytes to endothelial cells.19 In this study, we found that spontaneous production of TNF-{alpha} was significantly higher in patients with moderate-to-severe OSAS than in healthy or obese control subjects or patients with mild OSAS. Therefore, monocytes from patients with moderate-to-severe OSAS are activated in vivo.

The production of TNF-{alpha} by monocytes was significantly correlated with percentage of time with SaO2 < 90% (percentage of total sleep time), which multiple regression analysis showed was the strongest predictor of the production of TNF-{alpha} by monocytes. These results suggest that monocytes are activated by apnea-related hypoxia in patients with OSAS. In fact, hypoxia has been suggested to induce both nuclear factor-{kappa}B activation and TNF-{alpha} gene transcription dependent on mitochondrial reactive oxygen species.20 Therefore, although BMI did not differ significantly between obese controls and patients with moderate-to-severe OSAS, production of TNF-{alpha} by monocytes was significantly higher in patients with moderate-to-severe OSAS.

Multiple regression analysis also indicated that BMI and SaO2 < 90% (percentage of total sleep time) were predictors of serum levels of TNF-{alpha}. These results suggest that serum levels of TNF-{alpha} are determined mainly by the production from adipocytes and monocytes due to hypoxia. The production of TNF-{alpha} is increased in adipose tissue from obese rodents or human subjects, and has been implicated in obesity-associated insulin resistance and the development of type 2 diabetes.2122 Because all patients with moderate-to-severe OSAS in our study were obese, the increased serum levels of TNF-{alpha} might be attributed to increased production by adipocytes. However, serum levels of TNF-{alpha} and spontaneous production of TNF-{alpha} by monocytes were significantly higher in patients with moderate-to-severe OSAS than in obese control subjects. In addition, treatment with nCPAP for 1 month significantly decreased serum levels of TNF-{alpha} without changes in BMI. Therefore, serum levels of TNF-{alpha} were elevated in patients with moderate-to-severe OSAS than in obese control subjects because production of TNF-{alpha} by monocytes was higher in these patients.

In the present study, we also found that serum levels of TNF-{alpha} and spontaneous production of TNF-{alpha} by monocytes in patients with mild OSAS were not significantly different from those in obese control subjects. Possible reasons for this lack of difference are that apnea-related hypoxia was not sufficiently severe, and that our sample size was too small.

Sympathetic nervous activation leads to ß2-adrenergic receptor-mediated leukocytosis.2324 In fact, treatment with epinephrine changes the distribution of lymphocyte subsets in human peripheral blood.23 In addition, infusion of isopreterenol increases the number of peripheral blood monocytes.24 A study25 in specific pathogen-free Swiss mice has shown that the circulating pool accounts for 40% of the population of peripheral blood monocytes and that the marginal pool accounts for 60%. Because treatment with nCPAP decreased catecholamine levels and sympathetic nerve activation in patients with OSAS, the monocytes obtained before and after nCPAP treatment might represent different populations and thus might explain the decrease in TNF-{alpha} production.2627

We have recently reported that serum levels of C-reactive protein and interleukin-6, which are risk factors for atherosclerosis and coronary artery disease, are elevated in patients with OSAS.16 Furthermore, levels of circulating adhesion molecules and chemokines are elevated in patients with OSAS.28293031 In the present study, we found that serum levels of TNF-{alpha} and production of TNF-{alpha} by monocytes were also higher in patients with moderate-to-severe OSAS than in healthy and obese control subjects. Therefore, these results suggest that progression of atherosclerosis may be accelerated in patients with moderate-to-severe OSAS. However, the significant decreases in these variables with nCPAP suggest that this treatment would be useful for decreasing or preventing cardiovascular morbidity in patients with OSAS.

A limitation of the present study is that the effects of nCPAP on spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} were not examined with a randomized and placebo-controlled design due to the difficulties of subjecting patients to a placebo version of nCPAP. However, we found significant correlations between changes in AHI and changes in spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} in patients with moderate-to-severe OSAS after treatment with nCPAP. Therefore, nCPAP might decrease production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} in patients with moderate-to-severe OSAS. The effects of nCPAP on TNF-{alpha} production by monocytes and serum levels of TNF-{alpha} should be examined in a large-scale placebo-controlled study.


   Conclusion
TOP
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
References
 
We have demonstrated that deterioration of sleep quality with repeated apnea-related hypoxia increases spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} in patients with moderate-to-severe OSAS. In addition, we have found that nCPAP decreases spontaneous production of TNF-{alpha} by monocytes and serum levels of TNF-{alpha} in patients with moderate-to-severe OSAS.


   Footnotes
 
Abbreviations: AHI = apnea hypopnea index; BMI = body mass index; ESS = Epworth sleepiness scale; nCPAP = nasal continuous positive airway pressure; OSAS = obstructive sleep apnea syndrome; SaO2 = arterial oxygen saturation; TNF = tumor necrosis factor

Received for publication December 30, 2003. Accepted for publication June 21, 2004.


   References
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 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 Conclusion
 References
 

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