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lu, MD
Chicago, IL
Dr. Hatipolu is Clinical Assistant Professor of Medicine, Section of Respiratory and Critical Care Medicine, Department of Medicine, University of Illinois at Chicago; Dr. Rubinstein is Professor of Medicine, Section of Respiratory and Critical Care Medicine, Department of Medicine, University of Illinois at Chicago and VA Chicago Health Care System.
Correspondence to: Israel Rubinstein, MD, FCCP, Department of Medicine (M/C 719), University of Illinois at Chicago, 840 South Wood St, Room 173, Chicago, IL 60616-7323; e-mail:IRubinst{at}uic.edu
Obstructive sleep apnea syndrome (OSAS) is characterized by repeated episodes of upper airway occlusion during sleep that are associated with excessive daytime sleepiness and abnormalities in cardiopulmonary and metabolic function. Anatomic narrowing of the airway, increased collapsibility of upper airway tissue, abnormal upper airway reflexes, and pharyngeal inspiratory muscle dysfunction contribute to the occurrence of airway occlusion.
Studies have implicated local and systemic inflammation in the pathophysiology of this seemingly all-mechanical problem. Histologic analysis of tissues obtained from patients undergoing uvulopalatopharyngoplasty for obstructive sleep apnea reveals marked subepithelial edema,1 excessive plasma cell infiltration,2 and reduction in surface area of connective tissue papillae that provide anchorage for epithelium.3 In the nasal lavage fluid of patients with obstructive sleep apnea, polymorphonuclear leukocytes and concentrations of bradykinin and vasoactive intestinal peptide are increased.45 These inflammatory changes are postulated to occur, in part, due to snoring that evokes vibration frequencies associated with soft-tissue damage.6 In addition to local inflammation, evidence of systemic inflammation is present in patients with OSAS.
Tumor necrosis factor (TNF)-
and interleukin-6 levels are elevated in patients with OSAS when compared with patients with hypersomnia7 and subjects with nonapneic obesity.8 Importantly, the circadian rhythm of TNF- secretion in patients with OSAS is markedly different compared with healthy volunteers.9 Application of nasal continuous positive airway pressure (CPAP) for 3 months does not change the abnormal circadian pattern, implying a role for inflammation independent of mechanical obstruction in pathogenesis of obstructive sleep apnea. Given that TNF- is thought to modulate somnolence and fatigue, this cytokine may play a role in mediating the constitutional symptoms of obstructive sleep apnea.
C-reactive protein, a sensitive marker for systemic inflammation, is increased in patients with obstructive sleep apnea when compared with control subjects matched for age and body mass index.10 After 1 month of nasal CPAP therapy, there is a marked reduction in serum levels of C-reactive protein and monocyte production of interleukin-6 without a change in body mass index.11 Reactive oxygen species such as superoxide anion and hydroxyl radical are injurious to cells, and are implicated in ischemia reperfusion injury that is operant in conditions such as myocardial infarction and stroke. There is increased production of reactive oxygen species from inflammatory cells in patients with OSAS.1213 Following treatment with nasal CPAP, oxidative metabolism returns to normal levels.13 Whether ongoing inflammation, including in the CNS, plays a role in residual cognitive and behavioral abnormalities observed after successful nasal CPAP therapy in patients with OSAS remains to be determined.
In this issue of CHEST (see page 13), Goldbart and his colleagues report on the presence of a differential upregulation of cysteinyl leukotriene receptor (LTR)-1 and LTR-2 in tonsils of children undergoing tonsillectomy for OSAS. Expressions of both receptors were predominantly in the epithelial layer and extra follicular area within the tonsillar parenchyma, which presumably reflects the area affected by vibration trauma. The expression of both receptors was detected, albeit to a significantly lesser extent, in the tonsils of children who underwent tonsillectomy for recurrent infections.
Cysteinyl leukotrienes are major mediators of inflammation, particularly in asthma and allergic rhinitis. They have potent contractile activity on human bronchi, and also increase microvasculature permeability, mucus secretion, and eosinophil recruitment. LTR-1 and LTR-2 have been localized in bronchial smooth-muscle cells, interstitial macrophages, eosinophils, peripheral monocytes and macrophages, and mast cells. LTR-2 is also present in the heart, brain, and adrenal gland.14 To our knowledge, this is the first report of their presence in human tonsillar tissue. Furthermore, the leukotriene pathway is implicated in association with the inflammatory state of OSAS in children, again for the first time. Given that the regulation of LTRs is poorly understood and that specific receptor antagonists for LTR-2 are not yet available, additional research is warranted to elucidate the significance of these findings. Irrespective, Goldbart et al have unraveled an intriguing putative venue in the pathophysiology of OSAS in children and perhaps also in adults. Whether their observations are confined to the tonsils or could represent a more widespread phenomenon, including CNS involvement, in patients with OSAS is uncertain.
References
This article has been cited by other articles:
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  R. S. Irwin, R. Ownbey, P. T. Cagle, S. Baker, and A. E. Fraire Interpreting the histopathology of chronic cough: a prospective, controlled, comparative study. Chest, August 1, 2006; 130(2): 362 - 370. [Abstract] [Full Text] [PDF]
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A. D. Goldbart, J. Krishna, R. C. Li, L. D. Serpero, and D. Gozal Inflammatory Mediators in Exhaled Breath Condensate of Children With Obstructive Sleep Apnea Syndrome. Chest, July 1, 2006; 130(1): 143 - 148. [Abstract] [Full Text] [PDF]
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M. H. Baumann and D. D. Gutterman American College of Chest Physicians Evidence-Based Guidelines-the Next Generation: Considering Resource Use and Evolution to a Single Grading System Chest, January 1, 2006; 129(1): 10 - 12. [Full Text] [PDF]
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S. Teramoto, H. Yamamoto, Y. Yamaguchi, R. Namba, and Y. Ouchi Obstructive Sleep Apnea Causes Systemic Inflammation and Metabolic Syndrome Chest, March 1, 2005; 127(3): 1074 - 1075. [Full Text] [PDF]
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