Sleep and Breathing

, Volume 17, Issue 2, pp 597–604 | Cite as

Analysis of systemic and airway inflammation in obstructive sleep apnea

  • Kensaku Aihara
  • Toru Oga
  • Yuichi Chihara
  • Yuka Harada
  • Kiminobu Tanizawa
  • Tomohiro Handa
  • Takefumi Hitomi
  • Kazuko Uno
  • Michiaki Mishima
  • Kazuo Chin
Original Article



The presence of both systemic and airway inflammation has been suggested in obstructive sleep apnea (OSA) by increased levels of inflammatory biomarkers in the circulation and respiratory specimens. We aimed to investigate the relationship between systemic and airway inflammation in OSA.


This study was conducted by simultaneously measuring various biomarkers both in serum and induced sputum of 43 patients. We compared the relationships of these biomarker levels with polysomnographic data and obesity measurements and also investigated their interrelationships between systemic and local compartments. We also assessed the relation of inflammatory markers with proximal airway resistance measured by impulse oscillometry.


In multiple regression analyses, each measured serum biomarker [leptin, interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF)] significantly correlated with waist circumference or fat area determined by computed tomography. In contrast, regarding airway inflammation, sputum IL-6, IL-8, TNF-α, and VEGF significantly correlated with OSA severity as indicated by the respiratory disturbance index or oxygen desaturation indices. Sputum IL-6, IL-8, TNF-α, and VEGF were significantly related to sputum neutrophil number, and sputum IL-8 and TNF-α were related to proximal airway resistance independently of body mass index. There were no significant interrelationships between the same biomarkers in serum and induced sputum.


Systemic and airway inflammation in OSA might be differently regulated by OSA itself and comorbid obesity, depending on the type of cytokine. Although we did not find apparent interrelationships between systemic and local compartments, further studies are needed to clarify this concept.


Airway inflammation Airway resistance Induced sputum Obstructive sleep apnea Systemic inflammation 



This work was supported in part by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (nos. 22590860 and 22590862) and Respiratory Failure Research Group and Health Science Research Grants (Comprehensive Research on Life-Style Related Diseases including Cardiovascular Diseases and Diabetes Mellitus) from the Japanese Ministry of Health, Labor and Welfare.

Conflict of interest

The Department of Respiratory Care and Sleep Control Medicine is funded by endowments from Philips-Respironics, Teijin Pharma, and Fukuda Denshi to Kyoto University.

Supplementary material

11325_2012_726_MOESM1_ESM.doc (70 kb)
ESM 1(DOC 69.5 kb)


  1. 1.
    McNicholas WT (2009) Obstructive sleep apnea and inflammation. Prog Cardiovasc Dis 51:392–399PubMedCrossRefGoogle Scholar
  2. 2.
    Quercioli A, Mach F, Montecucco F (2010) Inflammation accelerates atherosclerotic processes in obstructive sleep apnea syndrome (OSAS). Sleep Breath 14:261–269PubMedCrossRefGoogle Scholar
  3. 3.
    Sabato R, Guido P, Salerno FG, Resta O, Spanevello A, Barbaro MP (2006) Airway inflammation in patients affected by obstructive sleep apnea. Monaldi Arch Chest Dis 65:102–105PubMedGoogle Scholar
  4. 4.
    Petrosyan M, Perraki E, Simoes D, Koutsourelakis I, Vagiakis E, Roussos C, Gratziou C (2008) Exhaled breath markers in patients with obstructive sleep apnoea. Sleep Breath 12:207–215PubMedCrossRefGoogle Scholar
  5. 5.
    Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK (2002) Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 105:2462–2464PubMedCrossRefGoogle Scholar
  6. 6.
    Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M (2003) Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 107:1129–1134PubMedCrossRefGoogle Scholar
  7. 7.
    Guven SF, Turkkani MH, Ciftci B, Ciftci TU, Erdogan Y (2012) The relationship between high-sensitivity C-reactive protein levels and the severity of obstructive sleep apnea. Sleep Breath 16:217–221PubMedCrossRefGoogle Scholar
  8. 8.
    Ip MS, Lam KS, Ho C, Tsang KW, Lam W (2000) Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 118:580–586PubMedCrossRefGoogle Scholar
  9. 9.
    Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Kales A, Chrousos GP (2000) Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 85:1151–1158PubMedCrossRefGoogle Scholar
  10. 10.
    Al Lawati N, Mulgrew A, Cheema R, vanEeden S, Butt A, Fleetham J, Ryan F, Ayas N (2009) Pro-atherogenic cytokine profile of patients with suspected obstructive sleep apnea. Sleep Breath 13:391–395PubMedCrossRefGoogle Scholar
  11. 11.
    Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y (2003) Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 94:179–184PubMedGoogle Scholar
  12. 12.
    Ryan S, Taylor CT, McNicholas WT (2006) Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 174:824–830PubMedCrossRefGoogle Scholar
  13. 13.
    Gozal D, Lipton AJ, Jones KL (2002) Circulating vascular endothelial growth factor levels in patients with obstructive sleep apnea. Sleep 25:59–65PubMedGoogle Scholar
  14. 14.
    Schulz R, Hummel C, Heinemann S, Seeger W, Grimminger F (2002) Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. Am J Respir Crit Care Med 165:67–70PubMedCrossRefGoogle Scholar
  15. 15.
    Sharma SK, Kumpawat S, Goel A, Banga A, Ramakrishnan L, Chaturvedi P (2007) Obesity, and not obstructive sleep apnea, is responsible for metabolic abnormalities in a cohort with sleep-disordered breathing. Sleep Med 8:12–17PubMedCrossRefGoogle Scholar
  16. 16.
    Ryan S, Nolan GM, Hannigan E, Cunningham S, Taylor C, McNicholas WT (2007) Cardiovascular risk markers in obstructive sleep apnoea syndrome and correlation with obesity. Thorax 62:509–514PubMedCrossRefGoogle Scholar
  17. 17.
    Chin K, Shimizu K, Nakamura T, Narai N, Masuzaki H, Ogawa Y, Mishima M, Nakamura T, Nakao K, Ohi M (1999) Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 100:706–712PubMedCrossRefGoogle Scholar
  18. 18.
    Despres JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444:881–887PubMedCrossRefGoogle Scholar
  19. 19.
    Sundar KM, Daly SE, Pearce MJ, Alward WT (2010) Chronic cough and obstructive sleep apnea in a community-based pulmonary practice. Cough 6:2PubMedCrossRefGoogle Scholar
  20. 20.
    Aihara K, Oga T, Harada Y, Chihara Y, Handa T, Tanizawa K, Watanabe K, Hitomi T, Tsuboi T, Mishima M, Chin K (2012) Analysis of anatomical and functional determinants of obstructive sleep apnea. Sleep Breath 16:473–481PubMedCrossRefGoogle Scholar
  21. 21.
    Sariman N, Levent E, Cubuk R, Yurtlu S, Benli Aksungar F (2011) Bronchial hyperreactivity and airway wall thickening in obstructive sleep apnea patients. Sleep Breath 15:341–350PubMedCrossRefGoogle Scholar
  22. 22.
    Julien JY, Martin JG, Ernst P, Olivenstein R, Hamid Q, Lemiere C, Pepe C, Naor N, Olha A, Kimoff RJ (2009) Prevalence of obstructive sleep apnea–hypopnea in severe versus moderate asthma. J Allergy Clin Immunol 124:371–376PubMedCrossRefGoogle Scholar
  23. 23.
    Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR (2010) Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 182:325–331PubMedCrossRefGoogle Scholar
  24. 24.
    Tschumperlin DJ, Drazen JM (2006) Chronic effects of mechanical force on airways. Annu Rev Physiol 68:563–583PubMedCrossRefGoogle Scholar
  25. 25.
    Puig F, Rico F, Almendros I, Montserrat JM, Navajas D, Farre R (2005) Vibration enhances interleukin-8 release in a cell model of snoring-induced airway inflammation. Sleep 28:1312–1316PubMedGoogle Scholar
  26. 26.
    Almendros I, Acerbi I, Puig F, Montserrat JM, Navajas D, Farre R (2007) Upper-airway inflammation triggered by vibration in a rat model of snoring. Sleep 30:225–227PubMedGoogle Scholar
  27. 27.
    Kiefmann R, Rifkind JM, Nagababu E, Bhattacharya J (2008) Red blood cells induce hypoxic lung inflammation. Blood 111:5205–5214PubMedCrossRefGoogle Scholar
  28. 28.
    Aihara K, Oga T, Harada Y, Chihara Y, Handa T, Tanizawa K, Watanabe K, Tsuboi T, Hitomi T, Mishima M, Chin K (2011) Comparison of biomarkers of subclinical lung injury in obstructive sleep apnea. Respir Med 105:939–945PubMedCrossRefGoogle Scholar
  29. 29.
    Iber C, Ancoli-Israel S, Chesson A, Quan S (2007) The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. American Academy of Sleep Medicine, WestchesterGoogle Scholar
  30. 30.
    Takemura M, Matsumoto H, Niimi A, Ueda T, Matsuoka H, Yamaguchi M, Jinnai M, Muro S, Hirai T, Ito Y, Nakamura T, Mio T, Chin K, Mishima M (2006) High sensitivity C-reactive protein in asthma. Eur Respir J 27:908–912PubMedGoogle Scholar
  31. 31.
    Terada K, Muro S, Sato S, Ohara T, Haruna A, Marumo S, Kinose D, Ogawa E, Hoshino Y, Niimi A, Terada T, Mishima M (2008) Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation. Thorax 63:951–955PubMedCrossRefGoogle Scholar
  32. 32.
    Matsuoka H, Niimi A, Matsumoto H, Ueda T, Takemura M, Yamaguchi M, Jinnai M, Chang L, Otsuka K, Oguma T, Takeda T, Chin K, Mishima M (2008) Patients' characteristics associated with unsuccessful sputum induction in asthma. J Allergy Clin Immunol 121:774–776PubMedCrossRefGoogle Scholar
  33. 33.
    Kokkonen H, Soderstrom I, Rocklov J, Hallmans G, Lejon K, Rantapaa Dahlqvist S (2010) Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum 62:383–391PubMedGoogle Scholar
  34. 34.
    Kanazawa H, Asai K, Hirata K, Yoshikawa J (2002) Vascular involvement in exercise-induced airway narrowing in patients with bronchial asthma. Chest 122:166–170PubMedCrossRefGoogle Scholar
  35. 35.
    Kanazawa H, Nomura S, Yoshikawa J (2004) Role of microvascular permeability on physiologic differences in asthma and eosinophilic bronchitis. Am J Respir Crit Care Med 169:1125–1130PubMedCrossRefGoogle Scholar
  36. 36.
    Takeda T, Oga T, Niimi A, Matsumoto H, Ito I, Yamaguchi M, Matsuoka H, Jinnai M, Otsuka K, Oguma T, Nakaji H, Chin K, Mishima M (2010) Relationship between small airway function and health status, dyspnea and disease control in asthma. Respiration 80:120–126PubMedCrossRefGoogle Scholar
  37. 37.
    Haruna A, Oga T, Muro S, Ohara T, Sato S, Marumo S, Kinose D, Terada K, Nishioka M, Ogawa E, Hoshino Y, Hirai T, Chin K, Mishima M (2010) Relationship between peripheral airway function and patient-reported outcomes in COPD: a cross-sectional study. BMC Pulm Med 10:10PubMedCrossRefGoogle Scholar
  38. 38.
    Lin CC, Wu KM, Chou CS, Liaw SF (2004) Oral airway resistance during wakefulness in eucapnic and hypercapnic sleep apnea syndrome. Respir Physiol Neurobiol 139:215–224PubMedCrossRefGoogle Scholar
  39. 39.
    Cao J, Que C, Wang G, He B (2009) Effect of posture on airway resistance in obstructive sleep apnea–hypopnea syndrome by means of impulse oscillation. Respiration 77:38–43PubMedCrossRefGoogle Scholar
  40. 40.
    Ryan S, Taylor CT, McNicholas WT (2009) Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax 64:631–636PubMedGoogle Scholar
  41. 41.
    Mancuso P (2010) Obesity and lung inflammation. J Appl Physiol 108:722–728PubMedCrossRefGoogle Scholar
  42. 42.
    Vernooy JH, Drummen NE, van Suylen RJ, Cloots RH, Moller GM, Bracke KR, Zuyderduyn S, Dentener MA, Brusselle GG, Hiemstra PS, Wouters EF (2009) Enhanced pulmonary leptin expression in patients with severe COPD and asymptomatic smokers. Thorax 64:26–32PubMedCrossRefGoogle Scholar
  43. 43.
    Sinden NJ, Stockley RA (2010) Systemic inflammation and comorbidity in COPD: a result of ‘overspill’ of inflammatory mediators from the lungs? Review of the evidence. Thorax 65:930–936PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Kensaku Aihara
    • 1
  • Toru Oga
    • 2
  • Yuichi Chihara
    • 1
  • Yuka Harada
    • 1
  • Kiminobu Tanizawa
    • 1
  • Tomohiro Handa
    • 1
  • Takefumi Hitomi
    • 2
  • Kazuko Uno
    • 3
  • Michiaki Mishima
    • 1
  • Kazuo Chin
    • 2
  1. 1.Department of Respiratory MedicineKyoto University Graduate School of MedicineKyotoJapan
  2. 2.Department of Respiratory Care and Sleep Control MedicineKyoto University Graduate School of MedicineKyotoJapan
  3. 3.Louis Pasteur Center for Medical ResearchKyotoJapan

Personalised recommendations