REVIEW - JOURNAL OF FUNCTIONAL VENTILATION AND PULMONOLOGY. VOLUME 10 - ISSUE 32. 2019

ABSTRACT

Obstructive sleep apnea (OSA) is an increasingly common sleep-related respiratory disorder and is considered a chronic disease. OSA is considered a risk factor for cardiovascular disease.
Nitric oxide (NO) is an unorthodox molecule with many different molecular effects. NO is an endogenous substance synthesized from one of three nitric oxide synthase isoforms (eNOs) that converts L-arginine into L-citrulline and NO in the presence of oxygen and several other factors. Concentration of alveolar nitric oxide (CANO) is one of the manifestations of minor airway inflammation. It has been shown to increase in bronchial asthma, idiopathic pulmonary fibrosis and pulmonary hypertension. In OSA patients, both respiratory tract inflammation and oxidative stress can affect NO production. Several studies have shown an increase in NO in OSA patients and improved after treatment. CANO indicates the amount of NO in the alveoli and its diffusion through the capillary - alveolar membrane, so a decrease in eNOs will reduce diffusion and in the alveoli.
The measurement of NO in exhaled air, including large airway NO and alveolar NO, promises to be an in-depth assessment method that will help to better diagnose and monitor OSA.

KEYWORDS:  Nitric oxide;  FENO; CANO; OSA.

 RÉSUMÉ

L'apnée obstructive du sommeil (AOS) est un trouble respiratoire lié au sommeil de plus en plus courant et considérée comme une maladie chronique. L’AOS est considéré comme un facteur de risque de maladie cardiovasculaire.
Le monoxide d’azote (NO) est une molécule non orthodoxe ayant de nombreux effets moléculaires. NO est une substance endogène synthétisée à partir de l'une des trois isoformes de l'oxyde nitrique synthase (eNO) qui convertit la L-arginine en L-citrulline et NO en présence d'oxygène et de plusieurs autres facteurs. La concentration d'oxyde nitrique alvéolaire (CANO) est l'une des manifestations d'une inflammation mineure des voies respiratoires. Il a été démontré qu’il augmentait l’asthme bronchique, la fibrose pulmonaire idiopathique et l’hypertension pulmonaire. Chez les patients OSA, une inflammation des voies respiratoires et un stress oxydatif peuvent affecter la production de NO. Plusieurs études ont montré une augmentation du NO chez les patients souffrant d’AOS et une amélioration après traitement. CANO indique la quantité de NO dans les alvéoles et sa diffusion à travers la membrane capillaire - alvéolaire. Ainsi, une diminution des eNO réduira la diffusion et les alvéoles.
La mesure du NO dans l'air exhalé, y compris du NO dans les grandes voies respiratoires et du NO alvéolaire, promet d'être une méthode d'évaluation approfondie qui aidera à mieux diagnostiquer et surveiller l'AOS.

MOTS CLÉS:  Monoxide d’azote; FENO; CANO; AOS.

INTRODUCTION

Obstructive sleep apnea (OSA) is an increasingly common sleep-related respiratory disorder and is considered a chronic disease. OSA is considered a risk factor for cardiovascular disease. The landmark study investigating the incidence of obstructive sleep apnea was the Wisconsin cohort study on sleep in 1993 (WSCS: Winconsin Sleep Cohort Study). This study reported that the prevalence of obstructive sleep apnea - determined when the index of apnea (AHI) ≥5 times/hour, accompanied by excessive daytime sleepiness was 4% in men and 2 % of middle-aged women (aged 30-60). However, this proportion has been higher recently in industrialized countries (10% for women and 20% for men), which is related to obesity and improvement of disease diagnostic techniques. In Vietnam, the recently reported a multicenter study of OSA with prevalence is at 8.5% [1].

Systemic inflammation and upper respiratory tract infection are considered as an important factor in the pathophysiology of OSA. In OSA patients, there was an increase in FE_NO (nitrogen oxide fraction in the exhalation) compared to healthy subjects. This increase is related to the severity of OSA. Airway inflammation in OSA is thought to be due to the release of inflammatory cytokines due to hypoxemia during apnea and subsequent re-oxidation or mechanical vibration from snoring [2]. Inflammation involves structures of the pharynx including the hard palate - soft palate, pharynx and tongue.

NO (nitric oxide) is a molecule produced by oxidation stress and is a manifestation of inflammation. On the other hand, the role of NO in airway inflammation has been proved and applied in the diagnosis or monitoring of asthma treatment. More and more research on the importance of effective OSA diagnosis and treatment is being investigated for its long-term effects. Nocturnal hypoxemia due to airway collapse, followed by re-oxidation, has been shown to be associated with increased sympathetic activation, reactive oxygen formation, increased inflammatory factors and endothelial dysfunction. Therefore, there is a similar increase in NO in OSA.

OSA AND HYPERTENSION

OSA is the most common cause of secondary hypertension. Multiple observational studies have demonstrated the association between OSA and hypertension. In the Wisconsin Sleep Cohort (709 patients), Prepard et al. found a linear, dose-dependent relationship between the severity of OSA at baseline and the relative risk of developing hypertension during follow-up [3]. OSA is considered as an important risk factor of resistant hypertension, commonly defined as inability to adequately control blood pressure despite use of 3 antihypertensive agents of different classes including a diuretic. One of the pathogenesis of OSA-related hypertension is endothelial dysfunction due to oxidative stress [4-6]. In resistant hypertension patient with OSA, a meta-analysis  showed that CPAP treatment decreased 24-hour systemic blood pressure (SBP) of 4.78 mm Hg and diastolic blood pressure (DBP) of 2.95 mm Hg. However, in  some studies CPAP (continuous positive airway pressure) could reduce only nocturnal DBP or SBP but not the one in daytime [7-11].   It is important to control nocturnal BP  because nocturnal BP levels are a better predictor of cardiovascular risk than daytime BP levels [12,13].

OSA AND EXHALED NITRIC OXIDE (NO)

Nitric oxide (NO) is an unorthodox molecule with many different molecular effects. NO is an endogenous substance synthesized from one of three nitric oxide synthases (NOs) that converts L-arginine into L-citrulline and NO in the presence of oxygen and several other factors.

All three NOSs (types I, II, III) can be produced in various types of tissue such as the lungs, heart, pulmonary circulation and systemic circulation [11]. eNO is produced in the respiratory tract and is determined by measurement in different air streams. NO increases in the case of inflammation and may decrease due to hypoxemia affecting the metabolism of NOS. FENO has been shown to be closely related to inflammation with increased eosinophils and has been used in diagnosis, treatment or prophylaxis of asthma. However, FENO has also been studied in other chronic inflammatory conditions of the respiratory tract. NO is one of the mediators of pathogenesis of pulmonary hypertension. Patients with pulmonary hypertension have low NO. NO has also been extensively studied in cardiovascular disease because of its involvement in vasoconstriction and platelet aggregation.

Concentration of alveolar nitric oxide (CANO) is one of the manifestations of minor airway inflammation. It has been shown to increase in bronchial asthma, idiopathic pulmonary fibrosis and pulmonary hypertension. FENO measures NO levels throughout the respiratory tract. When measuring kinematic FENO at different flow rates through the 2 compartment method (2CM), it is possible to determine NO in the central or peripheral lung.

In summary, 2CM includes the alveolar cavity, which contains the exhaled airways of the alveoli and the small bronchi and the larger bronchial air cavity. The gas in the alveolar cavity is used to    measure CANO.

During exhalation NO of the cystic cavity goes into the bronchial cavity more than NO enters the alveoli. Jaw’NO and CANO can be measured linearly if they measure at least 3 flows and at least 100mL/s. The CANO measurement is not a direct measurement but a mathematical equation that uses at least 2 NO fractions in the exhaled breath (FENO) in 2 different compartments and computes.

OSA AND CANO

OSA is characterized by repeated episodes of shortness of breath or shortness of breath during sleep. Patients are categorized as a mild, moderate, or severe OSA depending on the apnea/hypopnea index (AHI), which is defined as the total numbers of obstructive apnea/hypopnea episodes per hour of sleep. In normal individuals the index is usually 5 or lower, while it is 5–15 in mild, 15–30 in moderate, and 30 or more in severe OSA patients.

OSA is considered an independent risk factor for cardiovascular disease. Upper airways resistance increase during  inspiration results in more negative intrathoracic pressure, arousal, sleep interruption for reopening of the airways. It is thought that episodic hypoxia causes oxidative stress and an increase in oxygen is the pathogenesis of cardiovascular disease in OSA. Because the structure and function of the upper airway is one of the pathophysiology of OSA, inflammation of the upper airway can affect its tonality during sleep. Many studies also show that due to oxidative stress and snoring are causes of respiratory inflammation in OSA patients. In OSA patients, oxidative stress causes intravascular damage [14-15]. And it seems that airway inflammation can predict OSA.

In OSA patients, both respiratory tract inflammation and oxidative stress can affect NO production. Several studies have shown an increase in NO in OSA patients and improved after treatment. Intermittent hypoxia (IH) in OSA, is characterized by repeated episodes of hypoxia interspersed with episodes of normal blood oxygen linked with increased reactive oxygen species/reactive nitrogen species (ROS/RNS) and oxidative stress, is potentially similar to the ischemia/reperfusion (I/R). Due to hypoxia, there is an increase in ROS production as a result of excessive mitochondrial reduction. Another important source of ROS in OSA is NADPH oxidase, 

primarily expressed in leukocytes and activated   during inflammatory processes such as infections, where it produces superoxide anions to destroy pathogens. Recent study show that the increase ROS from stimulating neutrophils and monocytes in OSA patient. Endothelial dysfunction manifests as an imbalance between vasodilating and vasoconstricting substances produced by or acting on the endothelium.

However, other studies analyzed nitrite/nitrate levels as a measure of circulating NO levels and reported reductions in OSA subjects compared to healthy subjects [3]. Explaining the problem, the study suggests that eNO is highly dependent on endothelial injury and in OSA the inflammation  is more related to the larger airways than the small airways. eNO is a major factor related to endothelial dependent vasodilation and its synthesis depends on the production and degradation of free oxygen radicals and NO products.

In OSA patients, physiological antioxidants cause re-oxidation after hypoxemia, which increases the production of free oxygen radicals, facilitates the reduction of NO synthesis co-factors and increases in total more superoxide and superxynitrite radicals. The lack of oxygen also disturbs the synthesis of eNOs, which lower NO in circulation and have a damaging effect on capillary beds.

One way to assess non-invasive eNO is to measure CANO. CANO indicates the amount of NO in the alveoli  and its diffusion through the capillary - alveolar membrane, so a decrease in eNO will reduce diffusion and in the alveoli. In addition, the study also explains that OSA associated with pulmonary hypertension may reduce eNO compared with OSA patients without pulmonary hypertension and CANO and FENO improved after CPAP treatment.

CONCLUSION

OSA is not a rare disease with an incidence of 10-20% and tends to increase. The measurement of NO in exhaled air, including large airway NO and alveolar NO, promises to be an in-depth assessment method that will help to better diagnose and monitor OSA. An increase in FENO and a decrease in CANO are being investigated potentially related to disease and disease severity. However, the results are conflicting and more studies are needed to evaluate.

CONFLICT OF INTEREST

Non.

REFERENCES

1. Duong-Quy S, Dang Thi Mai K, et al.. Study about the prevalence of the obstructive sleep apnoea syndrome in Vietnam. Rev Mal Respir. 2018 Jan;35(1):14-24.
2. Dempsey, J.A., et al., Pathophysiology of sleep apnea. Physiological reviews, 2010. 90(1): p. 47-112.
3. Dolan, E.,et al., Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 2005. 46(1): p. 156-61.
4. Dyugovskaya, L., P. Lavie, and L. Lavie, Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med, 2002. 165(7): p. 934-9.
5. https://www.atsjournals.org/doi/full/10.1164/ajrccm.165.7.2104126
6. Lavie, L., Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain. Sleep Med Rev, 2015. 20: p. 27-45.
7. Marin, J.M., et al., Association between treated and untreated obstructive sleep apnea and risk of hypertension. Jama, 2012. 307(20): p. 2169-76.
8. McNicholas, W.T., Diagnostic criteria for obstructive sleep apnea: time for reappraisal. Journal of thoracic disease, 2018. 10(1): p. 531-533.
9. Nieto, F.J., et al., Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. Jama, 2000. 283(14):. 1829-36.
10. Pedrosa, R.P., et al., Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension, 2011. 58(5): 811-7.
11. Peppard, P.E., et al., Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med, 2000. 342(19): p. 1378-84.
12. Schulz, R., et al., Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med, 2000. 162(2 Pt 1): 566-70.
13. Sugamura, K. and J.F. Keaney, Jr., Reactive oxygen species in cardiovascular disease. Free Radic Biol Med, 2011. 51(5): 978-92.
14. Calhoun David, A., et al., Resistant Hypertension: Diagnosis, Evaluation, and Treatment. Circulation, 2008. 117(25): e510-e526.
15. Liu, L., et al., Continuous Positive Airway Pressure in Patients With Obstructive Sleep Apnea and Resistant Hypertension: A Meta-Analysis of Randomized Controlled Trials. The Journal of Clinical Hypertension, 2016. 18(2): 153-158.

REFERENCES

1. Duong-Quy S, Dang Thi Mai K, et al.. Study about the prevalence of the obstructive sleep apnoea syndrome in Vietnam. Rev Mal Respir. 2018 Jan;35(1):14-24.
2. Dempsey, J.A., et al., Pathophysiology of sleep apnea. Physiological reviews, 2010. 90(1): p. 47-112.
3. Dolan, E.,et al., Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension, 2005. 46(1): p. 156-61.
4. Dyugovskaya, L., P. Lavie, and L. Lavie, Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med, 2002. 165(7): p. 934-9.
5. https://www.atsjournals.org/doi/full/10.1164/ajrccm.165.7.2104126
6. Lavie, L., Oxidative stress in obstructive sleep apnea and intermittent hypoxia--revisited--the bad ugly and good: implications to the heart and brain. Sleep Med Rev, 2015. 20: p. 27-45.
7. Marin, J.M., et al., Association between treated and untreated obstructive sleep apnea and risk of hypertension. Jama, 2012. 307(20): p. 2169-76.
8. McNicholas, W.T., Diagnostic criteria for obstructive sleep apnea: time for reappraisal. Journal of thoracic disease, 2018. 10(1): p. 531-533.
9. Nieto, F.J., et al., Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. Jama, 2000. 283(14):. 1829-36.
10. Pedrosa, R.P., et al., Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension, 2011. 58(5): 811-7.
11. Peppard, P.E., et al., Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med, 2000. 342(19): p. 1378-84.
12. Schulz, R., et al., Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med, 2000. 162(2 Pt 1): 566-70.
13. Sugamura, K. and J.F. Keaney, Jr., Reactive oxygen species in cardiovascular disease. Free Radic Biol Med, 2011. 51(5): 978-92.
14. Calhoun David, A., et al., Resistant Hypertension: Diagnosis, Evaluation, and Treatment. Circulation, 2008. 117(25): e510-e526.
15. Liu, L., et al., Continuous Positive Airway Pressure in Patients With Obstructive Sleep Apnea and Resistant Hypertension: A Meta-Analysis of Randomized Controlled Trials. The Journal of Clinical Hypertension, 2016. 18(2): 153-158.

ARTICLE INFO

DOI: 10.12699/jfvpulm.10.32.2019.1

Conflict of Interest
Non

Date of manuscript receiving
25/07/2019

Date of publication after correction
15/10/2019

Article citation 
Dang-Thi-MaiK. The measurement of exhaled nitric oxide (NO) in obstructive sleep apnea syndrome - OSAS. J Func Vent Pulm 2019;32(10):1-4.