Mitochondrial replication, transcription, and function in obstructive sleep apnea.

We assessed mitochondrial replication, transcription, and function in the upper airways of obstructive sleep apnea (OSA) patients and the effects of uvulopalatopharyngoplasty. Twenty subjects with mild and 40 with moderate to severe OSA requiring uvulopalatopharyngoplasty were included. Mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in uvula specimens were assessed by immunohistochemical staining, and their mRNA and protein expression was examined using reverse-transcription polymerase chain reaction and western blotting, respectively. The mitochondrial to nuclear DNA (Mt/N) ratio in the blood, exhaled breath condensate (EBC), and uvula was measured using quantitative reverse-transcription polymerase chain reaction. TFAM and PGC-1α protein concentrations in the plasma and EBC were determined using enzyme-linked immunosorbent assay. All tested parameters were higher in the OSA group than in the control. Three months later, 21 uvulopalatopharyngoplasty-responsive patients with OSA showed decreased TFAM and PGC-1α concentrations and EBC Mt/N ratio while these remained high in 19 uvulopalatopharyngoplasty-unresponsive patients. The OSA group showed severe inflammation, increased mitochondrial replication and transcription-related signaling, and mitochondrial dysfunction in the uvula. Successful OSA treatment using uvulopalatopharyngoplasty restored the TFAM and PGC-1α levels and EBC Mt/N ratio.

Continuous positive airway pressure affects mitochondrial function and exhaled PGC1-α levels in obstructive sleep apnea.

Purpose: Subjects with obstructive sleep apnea (OSA) exhibit systemic and upper airway oxidative stress and inflammation, which cause mitochondrial dysfunction. The intend of this study is to estimate mitochondrial function (mitochondrial DNA/nuclear DNA [Mt/N] ratio) and protein levels of peroxisome proliferator-coactivated receptor gamma co-activator 1-alpha (PGC1-α) in the exhaled breath condensate (EBC) and plasma before and after continuous positive airway pressure (CPAP) treatment. Materials and methods: Twenty healthy individuals (control) and 40 subjects with severe or moderate OSA were recruited to undergo CPAP treatment and evaluation in a sleep study. The Mt/N ratio in the EBC and blood were assayed by quantitative real-time polymerase chain reaction. Enzyme-linked immunosorbent assay was used to measure the protein concentration of PGC1-α in the EBC and plasma. All experiments were performed after 3 months of CPAP treatment in subjects with OSA. Results: We observed no noteworthy differences between the control and treatment groups. Moreover, there were no differences in the Mt/N ratio in the blood and plasma levels of PGC1-α in subjects with OSA before and after treatment. However, the Mt/N ratio and protein levels of PGC1-α in the EBC of OSA subjects were higher than those in the control group and returned to normal levels after CPAP treatment. Conclusions: We successfully treated subjects with OSA by CPAP, which restored the Mt/N ratio and levels of PGC1-α in the EBC.

Effects of continuous positive airway pressure on resolvin and matrix metalloproteinase-9 in patients with obstructive sleep apnea.

PURPOSE: Resolvin is a checkpoint controller in inflammation. Matrix metalloproteinase-9 (MMP-9) is an airway remodeling regulator. We evaluated the levels of resolvin and MMP-9 protein in the serum and exhaled breath condensate (EBC) before and after continuous positive airway pressure (CPAP) treatment. METHOD: We enrolled 20 non-OSA snorers and 40 patients with moderate to severe OSA scheduled for CPAP treatment. ELISA was used to assess resolvin and MMP-9 levels in the serum and EBC. All patients underwent sleep assessment at baseline and 3 months after CPAP. RESULTS: There was no between-group difference; moreover, there were no differences in the pre- and post-treatment serum levels of resolvin and MMP-9 in patients with OSA. Compared with non-OSA snorers, patients with OSA had lower resolvin and higher MMP-9 levels in the EBC. After CPAP treatment, the EBC levels of resolvin and MMP-9 in patients with OSA returned to normal. CONCLUSIONS: Successful OSA treatment by CPAP can normalize EBC levels of resolvin and MMP-9.

Effects of continuous positive airway pressure on exhaled transforming growth factor-ß and vascular endothelial growth factor in patients with obstructive sleep apnea.

BACKGROUND: Both transforming growth factor ß (TGF-ß) and vascular endothelial growth factor (VEGF) are master regulators of airway remodeling; however, their pathological roles in obstructive sleep apnea (OSA) remain unclear. The aim of the present study was to evaluate the expression of TGF-ß and VEGF protein in the serum and exhaled breath condensate (EBC) before and after continuous positive airway pressure (CPAP) treatment in OSA patients. METHODS: Forty patients with moderate to severe OSA requiring CPAP and 20 healthy subjects were prospectively recruited. The concentrations of TGF-ß and VEGF protein in the serum and EBC were evaluated by enzyme-linked immunosorbent assay. All OSA patients underwent a sleep study that was repeated 3 months after receiving CPAP therapy. RESULTS: Protein concentrations of TGF-ß and VEGF in the serum did not differ between healthy controls and OSA patients before CPAP treatment. There was also no difference in the serum protein concentrations of TGF-ß and VEGF of the OSA patients before and after CPAP treatment. However, both the TGF-ß and VEGF protein concentrations in the EBC were higher in the OSA patients than those in control subjects, and recovered to normal levels after CPAP. CONCLUSIONS: Successful treatment of OSA by CPAP can restore the TGF-ß and VEGF protein concentrations in the EBC.

Application of classification criteria of Sjogren syndrome in patients with sicca symptoms: Real-world experience at a medical center.

BACKGROUND: Patients who have symptoms of sicca, such as dry eyes and mouth, may have Sjögren's syndrome (SS). However, the conservative culture makes patients hesitate to undergo an invasive biopsy, which contributes to the difficulty of confirming a diagnosis. We aimed to identify the characteristics of patients with sicca symptoms to develop a better predictive value for each item included in the three different diagnostic criteria for SS and clarify the best diagnostic tools for the local population. METHODS: This is a single-center retrospective case-control study from January 2016 to December 2017. Patients who underwent sialoscintigraphy because of clinical symptoms of xerostomia and xerophthalmia at one medical center were reviewed via the patients' electronic medical records. RESULTS: Of 515 patients enrolled, the severity of results for sialoscintigraphy and Schirmer's test was correlated with a diagnosis of SS and generated receiver operator characteristic curve. The area under curve (AUC) was 0.603 for positive Schirmer's test, 0.687 for positive anti-Ro/La results, 0.893 for a positive salivary gland biopsy. The AUC was 0.626 and 0.602 for Schirmer's test which is redefined as <10 mm/5 minutes in either eye and according to 2016 the American College of Rheumatology/ European League Against Rheumatism criteria, respectively. CONCLUSION: Our results indicate the cut-off point for defining a positive test result in the Schirmer's test is worth modified to <10 mm/5 minutes in either eye.

Effect of oral appliance on circulating leukocyte telomere length and SIRT1 in obstructive sleep apnea.

OBJECTIVES: The increased cardiovascular risk seen in patients with obstructive sleep apnea (OSA) may be due to combination of oxidative stress, systemic inflammation and damage to leukocyte telomere length (LTL) seen with aging. Another molecule, Sirtuin 1 (SIRT1), a histone/protein deacetylase, regulates endothelial nitric oxide synthase and is involved in different aspects of cardiovascular disease, aging and stress resistance. The aim of this study was to evaluate the effects of mandibular advancement device (MAD) on the circulating LTL and SIRT1 protein level in peripheral blood mononuclear cells (PBMCs) in patients with OSA. MATERIALS AND METHODS: Forty patients with moderately severe to severe OSA who desired MAD and 20 healthy controls were prospectively enrolled. The LTL was measured by quantitative polymerase chain reaction while SIRT1 protein levels in PBMC was assessed using a Sirtuin 1 ELISA Kit. All study subjects underwent baseline sleep study, with OSA patients having repeat testing at 3 months after MAD. RESULTS: Compared to healthy subjects, patients with OSA at baseline had lower LTL and SIRT1 protein levels in PBMC. After 3 months of MAD, 24 OSA patients, designated as MAD responders, median (range) LTL increased from (0.556 [0.393-0.748]) to (0.708 [0.533-0.893]) and SIRT1 protein levels in PBMC increased from 0.58 ± 0.23 pg/µg of total protein to 0.95 ± 0.26 pg/µg of total protein. For the 16 MAD unresponsive patients, LTL and SIRT1 protein levels remained low. CONCLUSIONS: Successful treatment of OSA with MAD can restore LTL and SIRT1 protein levels in PBMC. CLINICAL RELEVANCE: LTL and SIRT1 protein levels in PBMC can be improved following effective treatment of OSA using MAD.

Effects of nasal CPAP on exhaled SIRT1 and tumor necrosis factor-α in patients with obstructive sleep apnea.

Exhaled breath condensate (EBC) has been used to examine airway inflammation and oxidative stress. This study aimed to evaluate if there were abnormal Sirtuin 1 (SIRT1) protein and tumor necrosis factor (TNF)-α levels in EBC and to determine if these levels could be improved after nasal continuous positive airway pressure (CPAP) treatment. Thirty-five patients with moderately severe to severe obstructive sleep apnea syndrome (OSAS) who wanted nasal CPAP treatment and 20 healthy controls were prospectively enrolled. The EBC SIRT1 protein levels and EBC TNF-α protein levels were assessed by ELISA. All patients underwent sleep studies that were repeated 3 months after nasal CPAP treatment in patients with OSAS. Results showed that in OSAS before nasal CPAP treatment, the EBC SIRT1 protein levels were lower than that in normal subjects, whereas the EBC TNF-α protein levels were higher. After nasal CPAP treatment, the EBC SIRT1 levels increased and EBC TNF-α levels decreased. In conclusion, successful treatment of OSAS by nasal CPAP can normalize the levels of EBC SIRT1 and EBC TNF-α.

Effect of Nasal CPAP on SIRT1 and Endothelial Function in Obstructive Sleep Apnea Syndrome.

BACKGROUND: Sirtuin 1 (SIRT1), a histone/protein deacetylase, has been implicated in aging, metabolism, and stress resistance. SIRT1 regulates endothelial nitric oxide (NO) synthase, restores NO availability, and is involved in different aspects of cardiovascular disease. The aim of this study was to evaluate any abnormalities with regard to SIRT1 protein level in the blood, SIRT1 activity, and impaired endothelial function in patients with obstructive sleep apnea syndrome (OSAS). We also investigated whether or not OSAS patients who received nasal continuous positive airway pressure (CPAP) treatment showed improvements in the levels of SIRT1. METHODS: Thirty-five patients with moderately severe to severe OSAS who requested nasal CPAP treatment and 20 healthy controls were prospectively enrolled. The SIRT1 protein levels in blood and its activity, and the serum levels of nitric oxide derivative (NO x ) were assessed. All subjects participated in sleep studies, which were repeated 3 months after nasal CPAP treatment in the patients with OSAS. RESULTS: In the patients with OSAS, the level of SIRT1 in the blood, its activity, and that of NO x was lower than those of normal subjects before nasal CPAP treatment. After nasal CPAP treatment, the level of SIRT1 in the blood and its activity increased from 0.55 ± 0.32 pg/µg of total protein and 3085.53 ± 1071.57 arbitrary fluorescence units (AFUs)/µg of total protein to 1.13 ± 0.43 pg/µg of total protein and 5344.65 ± 1579.71 AFUs/µg of total protein. The serum levels of NO x in the patients with OSAS increased from 16.36 ± 5.78 to 25.94 ± 5.17 µM. CONCLUSIONS: Successful treatment for OSAS with nasal CPAP can restore blood levels of the SIRT1 protein and its activity and serum levels of NO x .

Effect of oral appliance on endothelial function in sleep apnea.

OBJECTIVES: This study evaluated the effects of mandibular advancement device (MAD) on serum levels of nitric oxide derivatives and endothelial function by endothelium-dependent flow-mediated dilation (FMD) in obstructive sleep apnea syndrome (OSAS). METHODS: Thirty patients with moderately severe-to-severe OSAS who desired MAD and 15 healthy controls were prospectively enrolled. FMD was measured by high-resolution B-mode ultrasonography, while serum NO x level from peripheral blood samples was measured by ELISA. All subjects participated in the sleep studies, which were repeated 2 months after MAD in OSAS patients. RESULTS: Serum NO x level and FMD were lower in patients with OSAS than in controls prior to MAD. Serum NO x levels in 19 of 30 patients with OSAS, the designated MAD responders, increased from 11.8 ± 5.8 µM pre-MAD to 22.7 ± 4.9 µM post-MAD. The FMD increased from 5.9 ± 4.6 pre-MAD to 10.5 ± 4.8 post-MAD. For the 11 unresponsive patients, serum NO x and FMD remained impaired after MAD. CONCLUSIONS: Successful treatment of OSAS with MAD can restore serum levels of NO x and FMD. CLINICAL RELEVANCE: Endothelial function can be improved following effective treatment of OSAS using MAD.

Effect of uvulopalatopharyngoplasty on leptin and endothelial function in sleep apnea.

OBJECTIVES: This study evaluated the effects of uvulopalatopharyngoplasty (UPPP) on serum leptin levels and endothelial function in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Fifteen healthy subjects and 35 patients with moderate to severe OSAS who desired UPPP were prospectively enrolled. The serum levels of leptin and nitric oxide derivative (NOx) from their peripheral blood samples were measured by enzyme-linked immunosorbent assay. All subjects participated in sleep studies, which were repeated 3 months after UPPP in the patients with OSAS. RESULTS: Before UPPP, the patients with OSAS had a higher serum level of leptin and a lower NOx level than did the control subjects. The serum leptin levels in the 17 of the 35 patients with OSAS who were surgical responders decreased from 24.2 ± 6.1 ng/mL before operation to 15.9 ± 6.0 ng/mL after operation. The serum NOx levels in these 17 patients increased from 18.5 ± 7.5 µmol/L before operation to 27.3 ± 8.2 µmol/L after operation. In the 18 patients who were unresponsive to surgery, the serum leptin and NOx levels remained impaired after the UPPP. CONCLUSIONS: Successful treatment of OSAS with UPPP leads to the normalization of serum leptin and NOx levels.

Effect of treatment by nasal continuous positive airway pressure on serum high mobility group box-1 protein in obstructive sleep apnea.

BACKGROUND: Serum levels of high mobility group box-1 protein (HMGB1) are increased in a variety of inflammatory disorders. Obstructive sleep apnea syndrome (OSAS) is associated with inflammation secondary to chronic intermittent hypoxia, but HMGB1 levels in treated and untreated OSAS have not been evaluated. METHODS: Twenty healthy subjects and 30 subjects with moderately severe or severe OSAS who desired nasal continuous positive airway pressure (CPAP) treatment were enrolled. Serum levels of HMGB1 and nitric oxide derivative (NO(x)) from peripheral blood samples were measured, and all subjects underwent a sleep study. These studies were repeated 2 months after nasal CPAP treatment in the patients with OSAS. RESULTS: In OSAS before nasal CPAP treatment, the serum level of HMGB1 was higher but that of NO(x) was lower than those levels of normal subjects. The HMGB1 levels correlated negatively with NO(x) levels in subjects with OSAS. After nasal CPAP treatment, the HMGB1 and NO(x) returned to normal levels. CONCLUSION: Elevated HMGB1 levels and reduced NO(x) levels in patients with OSAS normalized after nasal CPAP treatment.

Effect of uvulopalatopharyngoplasty on endothelial function in obstructive sleep apnea.

OBJECTIVES: This study evaluates the effects of uvulopalatopharyngoplasty (UPPP) on serum levels of nitric oxide derivatives (NO(x)) and endothelial function by endothelium dependent flow-mediated dilation (FMD) in obstructive sleep apnea syndrome (OSAS). STUDY DESIGN: Prospective study. SUBJECTS AND METHODS: Fifteen healthy subjects and 30 subjects with moderately severe to severe OSAS who desired UPPP were prospectively enrolled. FMD was measured by high-resolution B-mode ultrasonography; serum level of NO(x) from peripheral blood samples was also measured. All subjects participated in sleep studies. These studies were repeated 3 months after UPPP in OSAS patients. RESULTS: For healthy patients, there was no difference in serum level of NO(x) and FMD between baseline and 3 months later. The serum levels of NO(x) in 14 of 30 patients with OSAS - designated surgical responders - increased from 13.9 +/- 5.5 microM preoperation to 28.9 +/- 8.2 microM postoperatively. FMD increased from 5.2 +/- 5.0 preoperatively to 10.0 +/- 4.7 postoperatively. For the 16 unresponsive patients, serum NOx and FMD remained impaired after UPPP. CONCLUSION: Successful treatment of OSAS with UPPP leads to restoration of FMD and normal serum levels of NO(x).

Work of breathing in eucapnic and hypercapnic sleep apnea syndrome.

BACKGROUND: Upper airways in patients with obstructive sleep apnea syndrome (OSAS) are more likely narrower than those of normal subjects, a factor in increasing the work of breathing (WOB) in these individuals. OBJECTIVES: To evaluate WOB while sitting and while supine, both awake and during stage 2 sleep, in patients with hypercapnic or eucapnic OSAS. METHOD: Twenty normal control subjects without OSAS, 20 patients with eucapnic moderate or severe OSAS and another 8 patients with hypercapnic severe OSAS were studied. WOB was measured by esophageal manometry with the subjects seated and then with the subjects supine, both while awake and during stage 2 sleep. RESULTS: In both the control and the eucapnic group, WOB was normal in the sitting position. When the eucapnic subjects lay supine, their WOB increased, both while awake and asleep. In contrast, the hypercapnic subjects had an abnormally high WOB both sitting and supine, whether awake or asleep. CONCLUSION: WOB was increased in subjects with hypercapnic OSAS in both the sitting and supine positions. While eucapnic individuals with OSAS have increased WOB when supine, it is normal when they are sitting upright.

Effect of uvulopalatopharyngoplasty on work of breathing during wakefulness in obstructive sleep apnea syndrome.

OBJECTIVES: We evaluated the effects of uvulopalatopharyngoplasty (UPPP) on the work of breathing (WOB) in obstructive sleep apnea syndrome (OSAS). METHODS: Fifteen healthy subjects and 30 subjects with OSAS who desired UPPP were prospectively enrolled. All underwent measurement of WOB while awake as well as in a sleep study. These studies were repeated 3 months after UPPP in the patients with OSAS. RESULTS: In OSAS before UPPP, the WOB while supine was increased above that of normal subjects. After UPPP, the WOB while supine remained elevated in those whose OSAS did not respond to surgery, and it returned to normal levels in patients whose OSAS improved after UPPP. CONCLUSIONS: Abnormal WOB in patients with OSAS returns to normal if UPPP results in amelioration of OSAS.