Skip to main content
SpringerLink
Log in

Activation of nuclear factor κB in obstructive sleep apnea: a pathway leading to systemic inflammation

  • Original Article
  • Published:
Sleep and Breathing Aims and scope Submit manuscript

Abstract

Apnea-induced hypoxia and reoxygenation, which generates reactive oxygen species, may activate the oxidant-sensitive, proinflammatory transcription factor nuclear factor κB (NF-κB), increasing systemic inflammation in obstructive sleep apnea. We measured NF-κB activity in circulating neutrophils and plasma levels of NF-κB-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-κB 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-κB binding activity compared with control subjects (p<0.0001). The degree of NF-κB activation was positively correlated with indices of apnea severity. In five severe OSA patients, 1 month of CPAP therapy decreased neutrophil NF-κB activation to control levels. sE-selectin and sVCAM concentrations were reduced by CPAP in four of these five subjects. OSA leads to NF-κB activation, which may constitute an important pathway linking OSA with systemic inflammation and cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Baeuerle PA, Baichwal VR (1997) NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol 65:111–137

    Article  PubMed  CAS  Google Scholar 

  2. Chin K, Nakamura T, Shimizu K, Mishima M, Nakamura T, Miyasaka M, Ohi M (2000) Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 109(7):562–567

    Article  PubMed  CAS  Google Scholar 

  3. Clemens JA (2000) Cerebral ischemia: gene activation, neuronal injury, and the protective role of antioxidants. Free Radic Biol Med 28(10):1526–1531

    Article  PubMed  CAS  Google Scholar 

  4. Collins T, Cybulsky MI (2001) NF-kappaB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 107(3):255–264

    Article  PubMed  CAS  Google Scholar 

  5. Dean RT, Wilcox I (1993) Possible atherogenic effects of hypoxia during obstructive sleep apnea (natural history of sleep apnea). Sleep 16(Suppl 2):S15–S22

    PubMed  CAS  Google Scholar 

  6. Dyugovskaya L, Lavie P, Lavie L (2002) Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 165(7):934–939

    PubMed  Google Scholar 

  7. Entzian P, Linnemann K, Schlaak M, Zabel P (1996) Obstructive sleep apnea syndrome and circadian rhythms of hormones and cytokines. Am J Respir Crit Care Med 153:1080–1086

    PubMed  CAS  Google Scholar 

  8. Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P (2004) Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation 110(12):1564–1571

    Article  PubMed  CAS  Google Scholar 

  9. Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260

    Article  PubMed  CAS  Google Scholar 

  10. Hla K, Young T, Bidwell M, Palta M, Skatrud J, Dempsey J (1994) Sleep apnea and hypertension. A population based study. Ann Intern Med 120:382–388

    PubMed  CAS  Google Scholar 

  11. Hung J, Whitford E, Parsons R, Hillmean D (1990) Association of sleep apnea with myocardial infarction in men. Lancet 336:261–264

    Article  PubMed  CAS  Google Scholar 

  12. Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-kB activity. Annu Rev Immunol 18:621–663

    Article  PubMed  CAS  Google Scholar 

  13. Kribbs NB, Pack AI, Kline LR, Smith PL, Schwartz AR, Schubert NM, Redline S, Henry JN, Getsy JE, Dinges DF (1993) Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 147(4):887–895

    PubMed  CAS  Google Scholar 

  14. Lamas O, Moreno-Aliaga MJ, Martinez JA, Marti A (2003) NF-kappa B-binding activity in an animal diet-induced overweightness model and the impact of subsequent energy restriction. Biochem Biophys Res Commun 311(2):533–539

    Article  PubMed  CAS  Google Scholar 

  15. Lavie L (2003) Obstructive sleep apnoea syndrome—an oxidative stress disorder. Sleep Med Rev 7:35–51

    Article  PubMed  Google Scholar 

  16. Liu SF, Ye X, Malik AB (1997) In vivo inhibition of nuclear factor-kappa B activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock. J Immunol 159:3976–3983

    PubMed  CAS  Google Scholar 

  17. Moreno PR, Fuster V (2004) New aspects in the pathogenesis of diabetic atherothrombosis. J Am Coll Cardiol 44(12):2293–2300

    Article  PubMed  CAS  Google Scholar 

  18. Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, Komatsu R, Ikura Y, Ogami M, Shimada Y, Ehara S, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE (2002) Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 106(23):2894–2900

    Article  PubMed  Google Scholar 

  19. Nieto FJ,Young TB, Lind BK et al (2000) Association of sleep disordered breathing, sleep apnea and hypertension in a large community-based study. JAMA 283:1829–1836

    Article  PubMed  CAS  Google Scholar 

  20. Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T, Katayama H, Ouchi Y (1999) Increased levels of circulating ICAM-1, VCAM-1, and l-selectin in obstructive sleep apnea syndrome. J Appl Physiol 87(1):10–14

    PubMed  CAS  Google Scholar 

  21. Palomaki H, Partinen M, Erkinjuntti T, Kaste M (1992) Snoring, sleep apnea syndrome and stroke. Neurology 42(Suppl 6):75–82

    PubMed  CAS  Google Scholar 

  22. Pankow W, Nabe B, Lies A, Becker H, Kohler U, Kohl F-V, Lohman FW (1997) Influence of sleep apnea on 24-hour blood pressure. Chest 112:1253–1258

    Article  PubMed  CAS  Google Scholar 

  23. Peppard P, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep disordered breathing and hypertension. N Engl J Med 342:1378–1384

    Article  PubMed  CAS  Google Scholar 

  24. Prabhakar NR, Fields RD, Baker T, Fletcher EC (2001) Intermittent hypoxia: cell to system. Am J Physiol Lung Cell Mol Physiol 281(3):L524–L528

    PubMed  CAS  Google Scholar 

  25. Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, Seeger W, Grimminger F (2000) Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 162(2 Pt 1):566–570

    PubMed  CAS  Google Scholar 

  26. Shahar E, Whitney CW, Redline S et al (2001) Sleep-disordered breathing and cardiovascular disease cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 163:19–25

    PubMed  CAS  Google Scholar 

  27. Tailor A, Granger DN (2000) Role of adhesion molecules in vascular regulation and damage. Curr Hypertens Rep 2:78–83

    Article  PubMed  CAS  Google Scholar 

  28. Vgontzas AN, Papanicolaou DA, Bixler EO et al (1997) Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbances and obesity. J Clin Endocrinol Metab 82:1313–1316

    Article  PubMed  CAS  Google Scholar 

  29. Vgontzas AN, Papanicolaou DA, Bixler EO et al (2000) Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance and hypercytokinemia. J Clin Endocrinol Metab 85:1151–1158

    Article  PubMed  CAS  Google Scholar 

  30. Worsnop CJ, Naughton MT, Barter CE, Morgan TO, Anderson AI, Pierce RJ (1998) The prevalence of obstructive sleep apnea in hypertensives. Am J Respir Crit Care Med 157:111–115

    PubMed  CAS  Google Scholar 

  31. Yang CR, Hsieh SL, Ho FM, Lin WW (2005) Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. J Immunol 174(3):1647–1656

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

Funding for this paper was provided by departmental funds.

Author information

Authors and Affiliations

  1. Division of Pulmonary, Critical Care and Sleep Medicine, Long Island Jewish Medical Center and North Shore University Hospital, New Hyde Park, New York, NY, USA

    Aung K. Htoo, Harly Greenberg, Shraddha Tongia, Guoqian Chen, Todd Henderson, David Wilson & Shu Fang Liu

Authors
  1. Aung K. Htoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Harly Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shraddha Tongia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guoqian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Todd Henderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shu Fang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Harly Greenberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Htoo, A.K., Greenberg, H., Tongia, S. et al. Activation of nuclear factor κB in obstructive sleep apnea: a pathway leading to systemic inflammation. Sleep Breath 10, 43–50 (2006). https://doi.org/10.1007/s11325-005-0046-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11325-005-0046-6

Keywords

Search

Navigation