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1 Thi study confirm and reinforce the hypothesis that OSA may be considered a systemic inflammatory disease, and that an imbalance of non-neuronal cholinergic and pro/anti-inflammatory cytokines may contribute to development and progression of comorbidities + 924 word(s) 924 2020-05-08 11:44:15 |
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Reale, M.; Velluto, L.; Di Nicola, M.; D’Angelo, C.; Costantini, E.; Marchioni, M.; Cerroni, G.; Guarnieri, B. Obstructive Sleep Apnea (OSA). Encyclopedia. Available online: (accessed on 06 December 2023).
Reale M, Velluto L, Di Nicola M, D’Angelo C, Costantini E, Marchioni M, et al. Obstructive Sleep Apnea (OSA). Encyclopedia. Available at: Accessed December 06, 2023.
Reale, Marcella, Lucia Velluto, Marta Di Nicola, Chiara D’Angelo, Erica Costantini, Michele Marchioni, Gianluigi Cerroni, Biancamaria Guarnieri. "Obstructive Sleep Apnea (OSA)" Encyclopedia, (accessed December 06, 2023).
Reale, M., Velluto, L., Di Nicola, M., D’Angelo, C., Costantini, E., Marchioni, M., Cerroni, G., & Guarnieri, B.(2020, May 08). Obstructive Sleep Apnea (OSA). In Encyclopedia.
Reale, Marcella, et al. "Obstructive Sleep Apnea (OSA)." Encyclopedia. Web. 08 May, 2020.
Obstructive Sleep Apnea (OSA)

OSA is a major primary sleep disorder characterized by repetitive nocturnal complete (apnea) or partial (hypopnea), collapses of the upper airway during sleep accompanied by oxyhemoglobin desaturation and/or electroencephalography (EEG) and vegetative arousals. Nocturnal OSA symptoms include sleep fragmentation, diminished amounts of slow wave and rapid eye movement (REM) sleep, nocturia and insomnia. 

cholinergic system cytokines inflammation

1. Introduction

Daytime symptoms include headache, depressive symptoms, cognitive alterations, fatigue and, in particular excessive daytime sleepiness (EDS), with different patterns between men and women [1][2][3]. EDS is not always present in OSA patients, and it does not invariably correlate with the severity of the disease, showing inter-individual differences with different responses to ventilatory treatments, albeit these aspects need to be better elucidated [4].

The hypothesis that systemic inflammation contributes to OSA risk and to OSA syndrome (OSAS)-associated morbidities is particularly interesting and has been under investigation as far back 1990, though in a small number of patients and with an under-representation of the female population [5][6]. Clinical studies of OSA and inflammation have yielded conflicting results and suggested that there are patient-specific or OSA-specific factors that predict inflammation, but which have not yet been fully identified.

Dyugovskaya et al. showed that in patients with OSA, various subpopulations of T cells acquire an activated phenotype with the downstream consequence of increased cytotoxicity against endothelial cells [7]. Furthermore, this activation process is associated with an increased intracellular content of the pro-inflammatory mediators Tumor necrosis factor (TNF) α and interleukin (IL)-8 and, a decrease of the anti- inflammatory cytokine IL-10 [8], in accord with the observation that in OSA patients repetitive airway obstructions causing intermittent hypoxia induces activation of nuclear factor-κB (NF-kB) and upregulation of pro-inflammatory genes [9].

2. History and Development

Over the years many studies have clarified and well documented the bidirectional relationship between the nervous system and the immune system [10] and the expression of most cholinergic system components in immune cells. IL-6 can go through the blood–brain barrier inducing neuroinflammation or neurodegeneration and also causing impairment of neurocognitive functions. The cross talk between the vagus nerve and the immune system was mainly ascribed to inhibiting the immune system [11]. Vagus nerve regulates the production of acetylcholine (ACh) in immune cells, that control inflammation through negative feedback by the binding to α7nAChR expressed by immune cells [11]. Sukys-Claudino et al. have speculated that a deficient cholinergic transmission plays a role in the pathogenesis of OSA in non-Alzheimer’s disease (AD) patients [12] and, a significant role of ACh in wakefulness and breathing was evidenced by Otuyama et al. in individuals with sleep-disordered breathing [13]. The study by Nardone et al. linked, in OSA patients, the impaired cognitive performance with a dysfunction of the cholinergic system [14]. Based on this, our aim is to investigate, in OSA patients, the non-neuronal cholinergic system and the Th17- and Treg-related cytokines and if nicotinic receptor α7 subunit is involved in Th17/Treg polarization and the synthesis of proinflammatory cytokines.

This preliminary study has some limitations. First of all, it may be biased, since the small differences in subject characteristics and the sample size, does not allow to significantly categorize male and female group and establish a clear relationship between sex and cholinergic and immune system in OSA patients. Since only 24% of patients have 15 AHI < 30, evaluation of cholinergic and immunological parameters did not give significantly differences respect to patients with AHI > 30.

Although underpowered, this study may provide interesting results for further investigation to better asses the mechanistic and functional relationship between sleep disordered breathing, inflammatory cytokines and non-neuronal cholinergic systems in males and females.

Here we hypothesize that in OSA patients the impairment of α7nAChR expression contributes to exacerbate inflammatory conditions making these patients more susceptible to comorbidity development. To the best of our knowledge, this is the first study to show the outcome of cholinergic and inflammatory system modulation in OSA patients. The complete mechanism through which OSA may be linked to impaired cholinergic pathway and if it could influence immune functions and metabolic or cardiovascular disease risk is not completely clarified. Thus, the results of this study can pave the way for new studies on the role of both inflammatory and cholinergic markers in OSA prognosis, comorbidities and related treatments in men and women.


  1. Ozen K. Basoglu; Mehmet Sezai Tasbakan; Gender differences in clinical and polysomnographic features of obstructive sleep apnea: a clinical study of 2827 patients. Sleep and Breathing 2017, 22, 241-249, 10.1007/s11325-017-1482-9.
  2. Christine Hj Won; Michelle Reid; Tamar Sofer; Ali Azarbarzin; Shaun Purcell; David White; Andrew Wellman; Scott Sands; Susan Redline; Sex Differences in Obstructive Sleep Apnea Phenotypes, the Multi-Ethnic Study of Atherosclerosis.. Sleep 2019, null, , 10.1093/sleep/zsz274.
  3. Maria R Bonsignore; Tarja Saaresranta; Renata L Riha; Sex differences in obstructive sleep apnoea.. null 2019, 28, , null.
  4. Hye-Jin Moon; Bongsu Kang; Hyunwoo Nam; Polysomnographic Parameters Related to Daytime Sleepiness in Obstructive Sleep Apnea Syndrome: A Preliminary Study. Sleep Medicine Research 2011, 2, 96-101, 10.17241/smr.2011.2.3.96.
  5. Lena Lavie; Obstructive sleep apnoea syndrome – an oxidative stress disorder. Sleep Medicine Reviews 2003, 7, 35-51, 10.1053/smrv.2002.0261.
  6. Hsiu-Ling Chen; Hsin-Ching Lin; Cheng-Hsien Lu; Pei-Chin Chen; Chih-Cheng Huang; Kun-Hsien Chou; Mao-Chang Su; Michael Friedman; Yi-Wen Chen; Wei-Che Lin; Systemic inflammation and alterations to cerebral blood flow in obstructive sleep apnea. Journal of Sleep Research 2017, 26, 789-798, 10.1111/jsr.12553.
  7. Larissa Dyugovskaya; Peretz Lavie; Lena Lavie; Lymphocyte Activation as a Possible Measure of Atherosclerotic Risk in Patients with Sleep Apnea. Annals of the New York Academy of Sciences 2005, 1051, 340-350, 10.1196/annals.1361.076.
  8. Larissa Dyugovskaya; Peretz Lavie; Lena Lavie; Phenotypic and Functional Characterization of Blood ?? T Cells in Sleep Apnea. American Journal of Respiratory and Critical Care Medicine 2003, 168, 242-249, 10.1164/rccm.200210-1226oc.
  9. Silke Ryan; Cormac T. Taylor; Walter T. McNicholas; Predictors of Elevated Nuclear Factor-κB–dependent Genes in Obstructive Sleep Apnea Syndrome. American Journal of Respiratory and Critical Care Medicine 2006, 174, 824-830, 10.1164/rccm.200601-066oc.
  10. The inflammatory reflex. Journal of Internal Medicine 2005, 257, 121-121, 10.1111/j.1365-2796.2004.01439.x.
  11. Takeshi Fujii; Masato Mashimo; Yasuhiro Moriwaki; Hidemi Misawa; Shiro Ono; Kazuhide Horiguchi; Koichiro Kawashima; Physiological functions of the cholinergic system in immune cells. Journal of Pharmacological Sciences 2017, 134, 1-21, 10.1016/j.jphs.2017.05.002.
  12. Lucia Sukys Claudino; Walter Moraes; Christian Guilleminault; Sergio Tufik; Dalva Poyares; Beneficial effect of donepezil on obstructive sleep apnea: A double-blind, placebo-controlled clinical trial. Sleep Medicine 2012, 13, 290-296, 10.1016/j.sleep.2011.09.014.
  13. Leonardo J. Otuyama; Camila F. Rizzi; Ronaldo Piovezan; Ksdy S. Werli; Evelyn L. Brasil; Lucia Sukys Claudino; Sergio Tufik; Dalva Poyares; The cholinergic system may play a role in the pathophysiology of residual excessive sleepiness in patients with obstructive sleep apnea. Medical Hypotheses 2013, 81, 509-511, 10.1016/j.mehy.2013.06.024.
  14. Raffaele Nardone; Jürgen Bergmann; Francesco Brigo; Yvonne Höller; Kerstin Schwenker; Cristina Florea; Alexander B. Kunz; Stefan Golaszewski; Eugen Trinka; Cortical afferent inhibition reflects cognitive impairment in obstructive sleep apnea syndrome: a TMS study. Sleep Medicine 2016, 24, 51-56, 10.1016/j.sleep.2016.08.003.
Subjects: Pathology
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Update Date: 29 Oct 2020