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Increased 8-Isoprostane and Interleukin-6 in Breath Condensate of Obstructive Sleep Apnea Patients^*

^* From the Institute of Respiratory Diseases (Drs. Carpagnano, Resta, Foschino-Barbaro, and Gramiccioni), University of Bari, Bari, Italy; and the Department of Thoracic Medicine (Drs. Kharitonov and Barnes), National Heart and Lung Institute, Faculty of Medicine, Imperial College National Heart, Royal Brompton Hospital, London, UK.

Correspondence to: Peter J. Barnes, DM, DSc, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, United Kingdom; e-mail: p.j.barnes{at}ic.ac.uk

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Study objectives: Obstructive sleep apnea (OSA) is characterized by repeated episodes of upper airways obstruction during sleep that result in episodes of hypoxia. An increase of systemic biomarkers of inflammation and oxidative stress has been found in patients with OSA and obesity.

Design: The aim of this study was to measure the levels of markers of inflammation (interleukin [IL]-6) and oxidative stress (8-isoprostane) in the exhaled breath condensate of OSA and obese patients.

Patients and methods: Eighteen OSA patients (13 men; mean [± SEM] age, 44 ± 7 years), 10 obese subjects (4 men; mean age, 39 ± 8 years), and 15 healthy age-matched subjects (8 men; mean age, 42 ± 4 years) were recruited. IL-6 and 8-isoprostane were measured in exhaled breath condensate by a specific enzyme immunoassay kit.

Measurements and results: Higher concentrations of IL-6 were found in OSA patients (8.7 ± 0.3 pg/mL) than in healthy control subjects (1.6 ± 0.1 pg/mL; p < 0.0001). Obese subjects also had higher levels than healthy control subjects, but lower levels than OSA patients (2.1 ± 0.2 pg/mL, p < 0.05 and p < 0.0001 respectively). Furthermore, 8-isoprostane levels were found to be higher in OSA patients (7.4 ± 0.7 pg/mL) than in obese subjects (5 ± 0.3 pg/mL; p = 0.4) and healthy subjects (4.5 ± 0.5 pg/mL; p < 0.005). We found a positive correlation between these two markers and neck circumference and apnea/hypopnea index.

Conclusions: These findings suggest that inflammation and oxidative stress are characteristic in the airways of OSA patients but not in obese subjects, and that their levels depend on the severity of the OSA. The measurement of IL-6 and 8-isoprostane levels may prove to be useful in screening and monitoring obese patients who have a high risk of developing OSA.

Key Words: 8-isoprostane • interleukin-6 • obesity • obstructive sleep apnea

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
It is estimated that 2% of women and 4% of men experience obstructive sleep apnea (OSA), a condition that is characterized by repeated episodes of upper airways obstruction during sleep leading to significant hypoxemia.¹ Consequently, in many patients with OSA cyclical alterations of arterial oxygen saturation are observed with oxygen desaturation developing in response to apnea followed by the resumption of oxygen saturation during hyperventilation.² This phenomenon has been referred to as hypoxia/reoxygenation and might alter the oxidative balance through the induction of excess oxygen free radicals, quite like in the sequelae of ischemia/reperfusion injury. Some authors have reported an increase in the levels of systemic biomarkers of inflammation and oxidative stress in patients with OSA^{3 4} and obesity,^{5 6} suggesting a possible role in the pathogenesis and pathologic consequences of OSA (eg, cardiovascular complications and cerebrovascular accidents). Upper airway structure and function are altered in patients with OSA.² In addition, the accumulation of excess fat around the neck of obese subjects may reduce pharyngeal size, which is an important risk factor for sleep apnea.⁷ The presence of inflammation and oxidative stress in the cells of the upper airways mucosa has been described previously in patients with OSA by some authors,^{8 9} but not by others.⁴

There has been increased interest in the analysis of exhaled gases and condensates as a way of noninvasively monitoring inflammation and oxidative stress in the lungs.¹⁰ The collection of exhaled breath condensate is a completely noninvasive method, which can be repeated frequently because the maneuver does not affect the airway function or cause inflammation.

In this study, we analyzed the presence of 8- isoprostane, a marker of oxidative stress,¹¹ and interleukin (IL)-6, a marker of inflammation,¹² in the breath condensate of OSA patients and subjects matched for obesity in order to see whether these markers reflect the severity of OSA and whether they could be used to screen obese subjects with a high risk of developing OSA.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patients
The study population consisted of 18 OSA patients, 10 subjects matched for obesity who did not have OSA, and 15 age-matched normal control subjects (Table 1 ). All subjects were white and were recruited from the sleep laboratory of the Respiratory Disease Institute at University of Bari (Italy). Written informed consent was obtained from all subjects, and the institutional ethics committee approved the study. A complete physical examination was performed, including neurologic, cardiopulmonary, and ear, nose, and throat evaluations. Inclusion criteria for this study were an apnea-hypopnea index (AHI) > 20 and symptoms of excessive daytime sleepiness for OSA subjects, and an AHI < 5 for in control and obese subjects. The group of control subjects consisted of 15 subjects (eight men; mean [± SEM] age, 42 ± 4 years), of normal weight (body mass index, < 27 kg/m²), with no sleep disturbances, and with good health. OSA and obese subjects were weight-matched. Both OSA patients and obese subjects did not have any of the following conditions: endocrinologic disease; narcolepsy or idiopathic hypersomnia; neuromuscular disease; psychiatric disorders; overt cardiopulmonary disease; airway obstruction; anatomic maxillomandibular skeletal abnormalities; ear, nose, and throat pathology; or abuse of alcohol or any kind of drug. We excluded patients with rhinitis, sinusitis, and respiratory and systemic infections. All subjects had been ex-smokers for at least 3 months and had undergone no therapy with inhaled, oral, or nasal steroids or with anti-inflammatory drugs or ß-blockers for 4 weeks prior to the study. None of OSA patients used continuous positive airway pressure therapy.

Polysomnography
All subjects were evaluated in the sleep laboratory of the Respiratory Disease Institute, University of Bari for 1 night, and they were monitored continuously for 8 h using a 19-channel polysomnograph (CompuMedic; Abbotsford, Australia). Polysomnography was performed after the patients and subjects had spent a night of adaptation in the hospital. EEG, electrooculography, and chin electromyography recordings were obtained with surface electrodes according to standard methods.¹³ Airflow was monitored by a thermistor that was placed at the nose and at the mouth. Abdominal and ribcage movements were assessed by respiratory inductive plethysmography. All the night recordings of hemoglobin oxygen saturation were obtained by finger pulse oximetry. Snoring sounds (recorded with a microphone that was attached to the neck), electrocardiography, and sleep position also were recorded. Apnea was defined as a cessation of airflow lasting 10 s, and hypopnea was defined as a discrete reduction (two thirds) of airflow and/or abdominal ribcage movements lasting 10 s and associated with a decrease of > 3% in oxygen desaturation or arousals. Since > 85% of respiratory events were obstructive (ie, characterized by an increasing ventilator effort and paradoxical breathing), the specific pattern of apnea episodes was not taken into account in the statistical analysis. The number of events per hour was obtained by dividing the total number of events per total sleep time (TST) and was defined as the AHI. Oxyhemoglobin desaturation was evaluated in terms of the percentage of TST spent with an oxyhemoglobin saturation of < 90%. The sleep record was scored according to standardized criteria.¹³ Finally, the Epworth sleepiness scale (ESS) was used to measure sleep propensity. The ESS has been tested previously^{14 15} in both healthy subjects and patients with different kinds of sleep disorders.

Expired Breath Condensate
Expired breath condensate was collected at 8 AM by using a condenser, which allowed the noninvasive collection of nongaseous components of the expiratory air (EcoScreen; Jaeger; Wurzburg, Germany). Subjects breathed through a mouthpiece and a two-way nonrebreathing valve, which also served as a saliva trap. They were asked to breathe at a normal frequency and tidal volume, wearing a nose clip, for a period of 10 min. If subjects felt saliva in their mouths, they were instructed to swallow it. Condensate, at least 1 mL, was collected as ice at -20°C, was transferred to Eppendorf tubes, and was stored at 80°C immediately.

Measurement of 8-Isoprostane
A specific enzyme immunoassay kit (Cayman Chemical; Ann Arbor, MI) was used to measure 8-isoprostane concentrations in breath condensates. The assay was validated directly by gas chromatography/mass spectrometry. The antiserum used in this assay has 100% cross-reactivity with 8-isoprostane, 0.2% with prostaglandin (PG) F_2, PGF3, PGF1, and PGF₂, and 0.1% with 6-Keto PGF_1. The intra-assay and interassay variabilities were ± 5% and ± 6%, respectively. The detection limit of the assay was 4 pg/mL.

Measurement of 8-Isoprostane
A specific enzyme immunoassay kit (Cayman Chemical) was used to measure IL-6 concentrations in breath condensates. The assay was validated directly by gas chromatography/mass spectrometry. The intra-assay and interassay variabilities were 10%. The detection limit of the assay was 1.5 pg/mL.

Statistical Analysis
The data were expressed as the mean ± SEM. A Mann-Whitney test was used to compare groups, and correlations between variables were performed using the Spearman rank correlation test. Significance was defined as a p value of < 0.05.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
IL-6
IL-6 was measurable in the breath condensate of all subjects. Concentrations were significantly greater in obese patients (2.1 ± 0.2 pg/mL; p < 0.05) and in OSA patients (8.7 ± 0.3 pg/mL; p < 0.0001) than in healthy subjects (1.6 ± 0.1 pg/mL) [Fig 1 , left, A]. There was a significant difference between OSA and obese patients (p < 0.0001). A positive correlation was found between IL-6 and AHI levels (r = 0.6; p < 0.0005) [Fig 2 , left, A] and IL-6 and neck circumference (r = 0.5; p < 0.01) [Fig 2 , right, B].

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 1. IL-6 and 8-isoprostane concentrations in breath condensate of OSA (OSA), obese and control subjects.

View larger version (10K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Correlation between IL-6 concentrations and AHI and neck circumference.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Correlation between 8-isoprostane concentrations and AHI and neck circumference.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Correlation between IL-6 and 8-isoprostane.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

Our results are in agreement with a previous study by Vgontzas et al³ that found higher concentrations of systemic IL-6 in patients with OSA and obesity and may have some role in mediating sleepiness and fatigue in these subjects. Furthermore, Entzian et al¹⁶ showed significantly disturbed circadian rhythms of tumor necrosis factor- levels that persist after treatment, suggesting a possible role for cytokines in the pathogenesis of OSA. The local increase that we found in OSA and obese subjects confirm the involvement of this marker in the pathogenesis of these diseases.

Our results showed the presence of an upper airways inflammation after sleep in patients with moderate/severe OSA correlated with the severity of the disease and provided further support for the role of cytokines in the pathogenesis of and in clinical sequelae of obesity and OSA. Moreover, a state of chronic systemic inflammation in obese subjects was found by Visser et al⁶ who hypothesized that this was related to an increase in IL-6 production by an excess of adipose tissue. The relationship between IL-6 and neck circumference in our study may further suggest this hypothesis. Systemic oxidative stress has been demonstrated in OSA patients by an increased release of superoxides from polymorphonuclear neutrophils,⁴ an increased oxidative burst of neutrophils in OSA patients that could be reduced by sleep,¹⁷ and by continuous positive airway pressure therapy.⁴

In our study, we showed a high concentration of 8-isoprostane in the breath condensate of OSA patients, which was correlated with severity of AHI. We measured 8-isoprostane because this mediator may provide a quantitative index of oxidant stress in vivo. Due to its stability, specificity for lipid peroxidation, in vivo production, and relative abundance in biological fluids, 8-isoprostane is a reliable biomarker of lipid peroxidation and oxidative stress.¹⁸ Increased concentrations of markers of oxidative stress and IL-6 in exhaled breath condensate may reflect both systemic and local inflammation and oxidative stress in the respiratory tract

The noninvasive and simple technique that we used^{11 19} and the positive correlation between IL-6 and 8-isoprostane levels and AHI suggest that the two markers may be used to monitor the progression of OSA and the response of the patient to treatment. The inflammation and oxidative stress of the upper airways appears to be related to the degree of obesity and may be an early indication of OSA. Obese patients showed a lower level of IL-6 compared to OSA patients, but higher levels than those of control subjects.

The higher concentration of IL-6 in obese subjects compared to control subjects may be due to an increased production of this cytokine due to the greater deposition of adipose tissue in their neck, supported also by the positive correlation that we found between neck circumference and IL-6 or upper airways resistance. To confirm this last suggestion, we wish to measure, in a future study, the upper airway resistance in these patients using esophageal manometry and to observe whether the relationship between IL-6 and upper airways resistance exists.

It is possible that in obese subjects an increase in IL-6 in exhaled condensate may present an initial stage of OSA and that this marker may be utilized to screen subjects.

Despite the positive correlation between IL-6 and 8-isoprostane levels, which may be explained by a link between inflammation and oxidative stress, there was no significant difference in 8-isoprostane concentrations between obese patients and healthy subjects despite there being a difference in IL-6 levels. It is likely that the production of IL-6 is influenced by an excess of adipose tissue that is present locally in obese subjects, while the production of 8-isoprostane is directly related to repeated hypoxia as a result of the mechanical obstruction. In this regard, Vgontzas et al³ showed that sleep apnea represents an additional independent factor leading to increased inflammatory cytokines itself, independent of obesity, and may lead to elevated levels of 8-isoprostane.

Our results suggest that sleep-related upper airways inflammation and oxidative stress may play a role in the pathogenesis and natural history of OSA. Therefore, it would be interesting to explore whether these systemic and local events also could have a role in the development of cardiovascular complications and cerebrovascular accident that most commonly occur in OSA and in obese subjects. Shulz et al⁴ reported an enhanced release of superoxide from polymorphonuclear neutrophils in OSA patients, and this might induce the expression of vascular adhesion molecules, the proliferation of vascular smooth muscle cells, and the aggregation and activation of platelets. These events have been implicated in the pathogenesis of atherosclerosis, which is most common in OSA patients. The elevation of IL-6 levels in OSA patients has been reported⁴ in reactive oxygen species from polymorphonuclear neutrophils. Hyperoxia, hypoxia, and oxygen-derived free radicals act on endothelial and vascular smooth muscle cells to alter hormones, enzymes, and growth factors that effect vascular remodeling, reactivity, and tone in resistance vessels.²⁰ It has been suggested by Strohl²¹ that cytokine assays may be useful in the management of severe OSA as a marker for systemic complications such as cardiovascular disease.

In conclusion, we showed that inflammation and oxidative stress are not only systemic but are also present in the airways of patients with OSA. The increased concentrations of IL-6 and 8-isoprostane in breath condensate may be useful to distinguish OSA subjects from healthy obese subjects and could be used to assess the severity of OSA and its progression and response to treatment.

	Acknowledgements

 
We gratefully acknowledge the assistance of Dr. F. Carpagnano, without whose dedicated and expert technical assistance this study would not have been possible.

	Footnotes

 
Abbreviations: AHI = apnea/hypopnea index; ESS = Epworth sleepiness scale; IL = interleukin; OSA = obstructive sleep apnea; PG = prostaglandin; TST = total sleep time

Received for publication October 17, 2001. Accepted for publication May 8, 2002.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (65) Citing Articles via Google Scholar Google Scholar Articles by Carpagnano, G. E. Articles by Barnes, P. J. Search for Related Content PubMed PubMed Citation Articles by Carpagnano, G. E. Articles by Barnes, P. J.