Intermittent hypoxia induces myofibroblast differentiation and extracellular matrix production of MRC5s via HIF-1α-TGF-ß/Smad pathway.

PURPOSE: To investigate whether or not intermittent hypoxia (IH), the main characteristic of obstructive sleep apnea (OSA) may affect the myofibroblast differentiation and extracellular matrix (ECM) production of lung fibroblast through the HIF-1α-TGF-ß/Smad pathway and assess the interventional role of a HIF-1α inhibitor, 2-methoxyestradiol (2-ME2). METHOD: The human lung fibroblast MRC5 cells were exposed to normoxia or IH conditions, and the expression of myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and ECM protein collagen I were evaluated. To clarify the underlying mechanism, the expression level of HIF-1α, TGF-ß, and p-Smads/Smads were measured and the effects of inhibiting HIF-1α with 2-ME2 on the α-SMA expression level and ECM production through the TGF-ß/Smad pathway were assessed. Si HIF-1α was applied to genetically inhibit HIF-1α in MRC5 cells, and the related proteins were assessed. RESULTS: IH increased the protein and mRNA expression of Collagen I and α-SMA of MRC5 cells in a time-dependent manner. IH activated the protein and mRNA level of HIF-1α and TGF-ß and increased the phosphorylation of Smad2/Smad3 of MRC5 cells in a time-dependent manner. 2-ME2 inhibited the activation of HIF-1α induced by IH and decreased overexpression of TGF-ß, p-Smad2/Smad2, and p-Smad3/Smad3, which in turn partially reversed the upregulation of α-SMA and Collagen I induced by IH in MRC5 cells. When HIF-1α was successfully silenced by si-HIF-1α, upregulation of TGF-ß induced by intermittent hypoxia was partially decreased. CONCLUSIONS: This study showed that IH contributes to myofibroblast differentiation and excessive ECM production of MRC5 cells through activation of the HIF-1α-TGF-ß/Smad pathway. 2-ME2 partially attenuated myofibroblast differentiation induced by IH by inhibiting the HIF-1α-TGF-ß/Smad pathway.

Follistatin-like 1 mitigates intermittent hypoxia-induced melanoma lung metastasis in mice.

PURPOSE: Intermittent hypoxia (IH) mimicking obstructive sleep apnea (OSA) has been confirmed to induce tumor lung metastasis via oxidative stress and inflammation responses. Follistatin-like 1 (Fstl1), as a matricellular protein, plays critical roles in inflammatory diseases and cancer. This study aimed to investigate the effect and mechanism of Fstl1 on OSA-IH-induced tumor lung metastasis. METHODS: Fstl1+/+ or Fstl1+/- mice inoculated with B16F10 melanoma cells were exposed to OSA-IH. The number and area of mouse lung metastatic colonies were assessed. Markers for tumor metastasis, oxidative stress, and inflammation in lung melanoma tissue or B16F10 melanoma cells were quantified by western blotting, qRT-PCR, and immunohistochemistry. The migration of B16F10 cells was examined by wound healing assay. RESULTS: Fstl1 levels are decreased in lung tissues from OSA-IH injured mice inoculated with melanoma cells. Fstl1-deficient mice were highly susceptible to the OSA-IH model of melanoma lung metastasis, as assessed by increased number and area of lung metastatic colonies, and by the elevated levels of HIF-1α, Vegf, N-cadherin, and E-cadherin. Lung melanoma tissue in Fstl1+/- mice provided evidence of increased oxidative stress, as determined by increased levels of NRF2 and P22phox and decreased level of Sod2, as well as increased inflammatory response, as determined by elevated levels of NF-κB P65, Tnf-α and Il-6. Conversely, stable overexpression of Fstl1 in B16F10 cells under OSA-IH exposure attenuated the migration of B16F10 cells and levels of tumor-related markers, as well as decreased oxidative stress and inflammatory responses. CONCLUSION: These results suggest that Fstl1 may protect against OSA-IH-induced tumor lung metastasis through oxidative stress and inflammatory responses. Fstl1 may serve as a promising target for OSA-related cancer.

A predictive model for optimal continuous positive airway pressure in the treatment of pure moderate to severe obstructive sleep apnea in China.

BACKGROUND: Numerous predictive formulas based on different ethnics have been developed to determine continuous positive airway pressure (CPAP) for patients with obstructive sleep apnea (OSA) without laboratory-based manual titrations. However, few studies have focused on patients with OSA in China. Therefore, this study aimed to develop a predictive equation for determining the optimal value of CPAP for patients with OSA in China. METHODS: 526 pure moderate to severe OSA patients with attended CPAP titrations during overnight polysomnogram were spited into either formula derivation (419 patients) or validation (107 patients) group according to the treatment time. Predictive model was created in the derivation group, and the accuracy of the model was tested in the validation group. RESULTS: Apnea hypopnea index (AHI), body mass index (BMI), longest apnea time (LAT), and minimum percutaneous oxygen saturation (minSpO2) were considered as independent predictors of optimal CPAP through correlation analysis and multiple stepwise regression analysis. The best equation to predict the optimal value of CPAP was: CPAPpred = 7.581 + 0.020*AHI + 0.101*BMI + 0.015*LAT-0.028*minSpO2 (R2 = 27.2%, p < 0.05).The correlation between predictive CPAP and laboratory-determined manual optimal CPAP was significant in the validation group (r = 0.706, p = 0.000). And the pressure determined by the predictive formula did not significantly differ from the manually titrated pressure in the validation cohort (10 ± 1 cmH2O vs. 11 ± 3 cmH2O, p = 0.766). CONCLUSIONS: The predictive formula based on AHI, BMI, LAT, and minSpO2 is useful in calculating the effective CPAP for patients with pure moderate to severe OSA in China to some extent.

The level of carbon dioxide is the determinant of successful noninvasive ventilation pressure titration in patients with nonhypercapnic primary central sleep apnea: a case report.

Primary central sleep apnea is classified as nonhypercapnic central sleep apnea. High loop gain, lower CO2 reserves, and other reasons can lead to hypocapnia in patients who develop intermittent hyperventilation during sleep. Therefore, it is necessary to monitor nocturnal CO2 level for these patients. We report a female patient diagnosed with nonhypercapnic primary central sleep apnea who complained of snoring, apnea, and excessive daytime sleepiness. With the monitoring of transcutaneous partial pressure of CO2, manual noninvasive ventilation pressure titration was performed with continuous positive airway pressure, bilevel positive airway pressure in a spontaneous-timed mode, and adaptive servo-ventilation mode for 3 nights, respectively. Only adaptive servo-ventilation mode could stabilize the transcutaneous partial pressure of CO2 above the apneic threshold (approximately 40 mm Hg) with successfully eliminating central apnea events. It is concluded that the level of CO2 is the determinant of successful noninvasive ventilation pressure titration in patients with nonhypercapnic central sleep apnea. CITATION: Han X, Zhao D, Wang J, Wang Y, Dong L, Chen B-y. The level of carbon dioxide is the determinant of successful noninvasive ventilation pressure titration in patients with nonhypercapnic primary central sleep apnea: a case report. J Clin Sleep Med. 2022;18(1):319-324.

Polymorphonuclear neutrophils promote endothelial apoptosis by enhancing adhesion upon stimulation by intermittent hypoxia.

PURPOSE: This study explored the interactive effects between polymorphonuclear neutrophils (PMNs) and vascular endothelial cells under intermittent hypoxia (IH) and investigated the mechanisms underlying these effects. METHODS: Endothelial cells were co-cultured with PMNs isolated from rats exposed to normoxia or IH. The PMN apoptotic rate was determined using flow cytometry. Expression of apoptosis-related proteins in the endothelial cells were evaluated using Western blotting, and the levels of intercellular adhesion molecules in the co-culture supernatants were measured using enzyme-linked immunosorbent assay. RESULTS: The PMN apoptotic rate in the IH-exposed rat group was significantly lower than that of the normoxia control group. There was a positive relationship between the PMN apoptotic rate and IH exposure time. In endothelial cells co-cultured with PMNs isolated from IH-exposed rats, a significant increase in the protein expression levels of Bax, Bcl-2, and caspase-3 and a significant decrease in the Bcl-2/Bax ratio were observed. Furthermore, the intercellular cell adhesion molecule-1(ICAM-1) and E-select element (E-S) levels were elevated significantly in the co-cultured supernatants of endothelial cells and PMNs from IH-exposed rats compared to that from controls. The above IH-induced alterations were partially restored by tempol pretreatment. CONCLUSIONS: The apoptotic rate was low in PMNs from IH-exposed rats, which consequently increased the apoptotic signals in endothelial cells in vitro. This may be associated with the increased levels of intercellular adhesion molecules. Further, tempol partially attenuates the PMN-mediated pro-apoptotic effects on endothelial cells under IH.

Intermittent hypoxia-induced autophagy via AMPK/mTOR signaling pathway attenuates endothelial apoptosis and dysfunction in vitro.

PURPOSE: The aim of this study was to examine whether or not intermittent hypoxia (IH) upregulated autophagy and the contributions of autophagy to endothelial apoptosis and dysfunction in human umbilical vein endothelial cells (HUVECs). METHOD: HUVECs were incubated under normoxia and IH conditions. After 3-, 6-, 12-, and 24-h exposure, the autophagic vacuoles and autophagosomes were observed by transmission electron microscopy and monodansylcadaverine staining. The protein levels of autophagy-related biomarkers and AMPK/mTOR pathway were measured by Western blot. The apoptosis-related proteins and the percentage of apoptotic cells were evaluated by Western blot and flow cytometry, respectively, while the levels of endothelial function biomarkers were assessed by ELISA. RESULTS: IH induced autophagy, as determined by the increased numbers of the autophagic vacuoles, autophagosomes, and by the elevated levels of Beclin-1 protein, the LC3II/LC3I ratio, and p62 degradation. IH-induced autophagic flux peaked at 12-h duration and weakened at 24 h. IH increased the ratio of p-AMPK/AMPK and decreased the ratio of p-mTOR/mTOR, while compound C restored the alteration. A significant decrease in the Bcl-2 level and the Bcl-2/Bax ratio and a significant increase in the protein expression levels of Bax and cleaved caspase 3 and in the percentage of apoptosis were observed under IH exposure. Moreover, the NO level was reduced, while the ET-1 and VEGF levels were raised under IH condition. These alterations were suppressed by the pretreatment of 3-methyladenine. CONCLUSIONS: IH upregulates autophagy through AMPK/mTOR pathway in HUVECs in vitro, which might be protective against endothelial apoptosis and dysfunction caused by IH.

Obstructive sleep apnea and respiratory center regulation abnormality.

PURPOSE: Obstructive sleep apnea (OSA) is a complex disease in which phenotypic analysis and understanding pathological mechanisms facilitate personalized treatment and outcomes. However, the pathophysiology responsible for this robust observation is incompletely understood. The objective of the present work was to review how respiratory center regulation varies during sleep and wakeness in patients with OSA. DATA SOURCES: We searched for relevant articles up to December 31, 2019 in PubMed database. METHODS: This review examines the current literature on the characteristics of respiratory center regulation during wakefulness and sleep in OSA, detection method, and phenotypic treatment for respiratory center regulation. RESULTS: Mechanisms for ventilatory control system instability leading to OSA include different sleep stages in chemoresponsiveness to hypoxia and hypercapnia and different chemosensitivity at different time. One can potentially stabilize the breathing center in sleep-related breathing disorders by identifying one or more of these pathophysiological mechanisms. CONCLUSIONS: Advancing mechanism research in OSA will guide symptom research and provide alternate and novel opportunities for effective treatment for patients with OSA.

Treatment-emergent central sleep apnea: a unique sleep-disordered breathing.

Treatment-emergent central sleep apnea (TECSA) is a specific form of sleep-disordered breathing, characterized by the emergence or persistence of central apneas during treatment for obstructive sleep apnea. The purpose of this review was to summarize the definition, epidemiology, potential mechanisms, clinical characteristics, and treatment of TECSA. We searched for relevant articles up to January 31, 2020, in the PubMed database. The prevalence of TECSA varied widely in different studies. The potential mechanisms leading to TECSA included ventilatory control instability, low arousal threshold, activation of lung stretch receptors, and prolonged circulation time. TECSA may be a self-limited disorder in some patients and could be resolved spontaneously over time with ongoing treatment of continuous positive airway pressure (CPAP). However, central apneas persist even with the regular CPAP therapy in some patients, and new treatment approaches such as adaptive servo-ventilation may be necessary. We concluded that several questions regarding TECSA remain, despite the findings of many studies, and it is necessary to carry out large surveys with basic scientific design and clinical trials for TECSA to clarify these irregularities. Further, it will be vital to evaluate the baseline demographic and polysomnographic data of TECSA patients more carefully and comprehensively.

Slow-wave sleep is associated with incident hypertension in patients with obstructive sleep apnea: a cross-sectional study.

OBJECTIVE: This study aimed to examine the association between slow-wave sleep ([SWS] N3 stage) and the risk of hypertension in patients with obstructive sleep apnea (OSA) or primary snorers. METHODS: A retrospective cross-sectional study of 1145 participants who were evaluated for suspected OSA at our Sleep Medical Center were included. Among these participants, 1022 had OSA and 123 were primary snorers. Logistic regression modeling was performed to evaluate the association between the prevalence of hypertension and combined OSA and SWS based on polysomnographic measurements. RESULTS: Patients with OSA in the lowest SWS quartile (quartile 1, < 2.0%) showed a two-fold increased risk of hypertension after adjustment for confounding factors compared with primary snorers (odds ratio, 2.13 [95% confidence interval 1.54-2.06]). In logistic analysis stratified according to SWS quartiles, there was no significant difference in the risk of hypertension between patients with OSA and primary snorers in quartile 1. However, in the highest quartile (quartile 4), SWS was significantly associated with incident hypertension in patients with OSA rather than primary snorers. CONCLUSION: SWS is associated with prevalent hypertension in patients with OSA. Notably, a low proportion of SWS confers a stronger association with incident hypertension than OSA.

Association study of genetic variations of inflammatory biomarkers with susceptibility and severity of obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) increases health risks of cardiovascular disease and stroke. Both genetic factors and environmental exposures contribute to the occurrence of OSA. The purpose of this study was to determine the role of four functional inflammatory single nucleotide polymorphisms (SNPs) (VWF rs1063856, IL-6 rs1800796, TNF rs1800629, and CRP rs2794521) in the susceptibility and severity of OSA. METHODS: A case-control study of OSA among Chinese population was conducted. Genotyping was performed using ABI TaqMan SNP genotyping technique. RESULTS: We found VWF rs1063856 (OR = 1.50, 95% CIs = 1.10-2.04; p = 0.010), IL-6 rs1800796 (OR = 1.32, 95% CIs = 1.11-1.56; p = 0.002), TNF rs1800629 (OR = 1.44, 95% CIs = 1.13-1.83; p = 0.003), and CRP rs2794521 (OR = 1.27, 95% CIs = 1.04-1.55; p = 0.021) were all significantly associated with increased susceptibility of OSA, while VWF rs1063856 (OR = 1.75, 95% CIs = 1.18-2.62; p = 0.006), IL-6 rs1800796 (OR = 1.39, 95% CIs = 1.10-1.76; p = 0.006) were associated with the severity of OSA. CONCLUSIONS: Our study indicated that functional variants of inflammatory biomarkers could cause the occurrence of OSA and influence the severity of OSA. These findings further support that inflammatory cytokines were closely related to the occurrence and development of OSA.

Intermittent hypoxia promotes melanoma lung metastasis via oxidative stress and inflammation responses in a mouse model of obstructive sleep apnea.

BACKGROUND: Recently, increased tumor incidence and cancer-related mortality have been reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), the hallmark feature of OSA, contributes to the metastasis of tumors. However, the molecular mechanisms by which tumor metastasis is accelerated by OSA-like IH remain to be elucidated. METHODS: C57BL/6 J male mice were subjected to intravenous injection of B16F10 melanoma cells before receiving IH treatment. Then, the animals were randomly distributed into three groups (n = 8 each): normoxia (N) group, IH group, and antioxidant tempol group (IHT, exposed to IH after treatment with tempol). After the mice were sacrificed, the number and weight of lung metastatic colonies were assessed. The lung tissues with tumor metastasis were analyzed for markers of oxidative stress and inflammation and for HIF-1α using western blotting and real-time PCR (qRT-PCR). The level of reactive oxygen species (ROS) in B16F10 cell was also assessed after N, IH and IH with tempol treatments. RESULTS: Compared with normoxia, IH significantly increased the number and weight of mouse lung metastatic colonies. Treatment of B16F10 cells with IH significantly enhanced ROS generation. Lung tissues with tumor metastasis provided evidence of increased oxidative stress, as assessed by p22phox and SOD mRNA levels and the NRF2 protein level, as well as increased inflammation, as assessed by TNF-α and IL-6 mRNA levels and the NF-κB P65 protein level. HIF-1α protein levels were increased in response to IH treatment. Tempol, an important antioxidant, ameliorated IH-induced melanoma lung metastasis in mice and reduced oxidative stress and inflammation responses. CONCLUSIONS: These results support the hypothesis that oxidative stress and inflammation responses play an important role in the pathogenesis of OSA-like IH-induced melanoma lung metastasis in mice. Antioxidant intervention provides a novel strategy for the prevention and treatment of cancer in OSA populations.

A novel enzyme-assisted ultrasonic approach for highly efficient extraction of resveratrol from Polygonum cuspidatum.

Resveratrol is a promising multi-biofunctional phytochemical, which is abundant in Polygonum cuspidatum. Several methods for resveratrol extraction have been reported, while they often take a long extraction time accompanying with poor extraction yield. In this study, a novel enzyme-assisted ultrasonic approach for highly efficient extraction of resveratrol from P. cuspidatum was developed. According to results, the resveratrol yield significantly increased after glycosidases (Pectinex® or Viscozyme®) were applied in the process of extraction, and better extraction efficacy was found in the Pectinex®-assisted extraction compared to Viscozyme®-assisted extraction. Following, a 5-level-4-factor central composite rotatable design with response surface methodology (RSM) and artificial neural network (ANN) was selected to model and optimize the Pectinex®-assisted ultrasonic extraction. Based on the coefficient of determination (R(2)) calculated from the design data, ANN model displayed much more accurate in data fitting as compared to RSM model. The optimum conditions for the extraction determined by ANN model were substrate concentration of 5%, acoustic power of 150W, pH of 5.4, temperature of 55°C, the ratio of enzyme to substrate of 3950 polygalacturonase units (PGNU)/g of P. cuspidatum, and reaction time of 5h, which can lead to a significantly high resveratrol yield of 11.88mg/g.

The Prevalence and Clinical Features of Hypertension in Patients With Obstructive Sleep Apnea Hypopnea Syndrome and Related Nursing Strategies.

BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) is a common sleep-related breathing disorder. Hypertension is frequently a concomitant disorder in patients with OSAHS. PURPOSE: This study investigates the prevalence and clinical features of hypertension in patients with OSAHS and explores the related nursing strategies. METHODS: Three thousand six hundred seven patients were included in this study. Subjects were divided into four groups that were categorized according to apnea-hypopnea index (AHI) scores as follows: control group (control, n = 354) with AHI < 5, mild OSAHS (mild, n = 658) with 5 ≤ AHI < 15, moderate OSAHS (moderate, n = 753) with 15 ≤ AHI < 30, and severe OSAHS (severe, n = 1842) with AHI ≥ 30. Blood pressure (BP) values were measured at four time points (daytime, evening, nighttime, and morning). The prevalence of hypertension and BP values in the different groups were compared at four time points. Finally, the nighttime-to-daytime mean BP (MBP; RN/D) and morning-to-evening MBP (RM/E) ratios were calculated. RESULTS: The prevalence of hypertension in the control group, mild group, moderate group, and severe group were 22.32%, 34.65%, 39.04%, and 55.37%, respectively. AHI positively correlated with the prevalence of hypertension (r = .191, p < .001). The daytime, nighttime, evening, and morning MBP rose as AHI increased. The ratios of nighttime-to-daytime MBP (RN/D) and morning-to-evening MBP (RM/E) increase with the severity of the illness (F = 9.821 and 18.957; p < .001). The daytime BP correlates significantly with AHI and lowest oxygen saturation (LSaO2; systolic BP, r = .195 and -.206; diastolic BP, rs = .248 and -.251, p < .01). Daytime MBP increases gradually in small fluctuations concurrent with increases in AHI until 61-65. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: OSAHS is an independent risk factor for hypertension. Patients with OSAHS have a significant increase in nighttime and morning BP, which means they lose normal BP diurnal rhythm. Therefore, nurses should take necessary measures based on the clinical features of hypertension in patients with OSAHS to minimize the risk of cardiocerebral vascular incidents.

Formoterol as reliever medication in asthma: a post-hoc analysis of the subgroup of the RELIEF study in East Asia.

BACKGROUND: As-needed formoterol can effectively relieve asthma symptoms. Since budesonide/formoterol is available as maintenance and reliever therapy in Asia, formoterol is now being used as-needed, but always with concomitant inhaled corticosteroids. The objective of this analysis was to assess the safety and efficacy of formoterol therapy in patients in East Asia (China, Indonesia, Korea, the Philippines and Singapore) with asthma. METHODS: Post-hoc analyses of data from the East Asian population of the RELIEF (REal LIfe EFfectiveness of Oxis® Turbuhaler® as-needed in asthmatic patients; study identification code: SD-037-0699) study were performed. RESULTS: This sub-group comprised 2834 randomised patients (formoterol n = 1418; salbutamol n = 1416) with mean age 35 years; 50.7% were male. 2678 patients completed the study. There was no significant difference in the total number of adverse events (AEs) reported in the formoterol and salbutamol groups (21.3% vs 20.9% of patients; p = 0.813), nor in the total number of serious AEs and/or discontinuations due to AEs (4.6% vs 5.5%, respectively; p = 0.323). Compared with salbutamol, formoterol was associated with a significantly longer time to first exacerbation (hazard ratio 0.86; p = 0.023) and a 14% reduction in the risk of any exacerbation (p < 0.05). Relative to salbutamol, mean adjusted reliever medication use throughout the study was significantly lower in the formoterol group (p = 0.017) and the risk of increased asthma medication use was 20% lower with formoterol (p = 0.005). CONCLUSIONS: Among patients with asthma in East Asia, as-needed formoterol and salbutamol had similar safety profiles but, compared with salbutamol, formoterol reduced the risk of exacerbations, increased the time to first exacerbation and reduced the need for reliever medication.

Hippocampal mitogen-activated protein kinase activation is associated with intermittent hypoxia in a rat model of obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/re­oxygenation, may impair the cerebral system. Although mitogen­activated protein kinase (MAPK) signaling was observed to have a key role in hypoxia­induced brain injury, the intracellular events and their underlying mechanisms for intermittent hypoxia/re­oxygenation-associated damage to hippocamal MAPKs, including extracellular signal­regulated kinase (ERK)1/2, P38MAPK and c­Jun N­terminal kinase (JNK) remain to be elucidated and require further investigation. A total of five rats in each sub­group were exposed to intermittent hypoxia or continued hypoxia for 2, 4, 6 or 8 weeks. Histological, immunohistochemical and biological analyses were performed to assess nerve cell injury in the hippocampus. Surviving CA1 pyramidal cells were identified by hematoxylin and eosin staining. The levels of phosphorylated ERK1/2, P38MAPK and JNK were detected by western blotting. B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein (Bax) in neural cells were examined by immunohistochemistry. The malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities were measured by thiobarbituric acid and xanthine oxidation methods, respectively. Under continued hypoxia, the levels of phospho­ERK1/2 peaked at the fourth week and then declined, whereas phospho­P38MAPK and JNK were detected only in the late stages. By contrast, under intermittent hypoxia, ERK1/2, P38MAPK and JNK were activated at all time-points assessed (2, 4, 6 and 8 weeks). The levels of phospho­ERK1/2, P38MAPK and JNK were all higher in the intermittent hypoxia groups than those in the corresponding continued hypoxia groups. Bcl­2 was mainly increased and reached the highest level at six weeks in the continued hypoxia group. Of note, Bcl­2 rapidly increased to the peak level at four weeks, followed by a decrease to the lowest level at the eighth week in the intermittent hypoxia group. Bax was generally increased at the late stages under continued hypoxia, but increased at all time-points under the intermittent hypoxia conditions. The two types of hypoxia induced an increase in the MDA content, but a decrease in SOD activity. Marked changes in these two parameters coupled with markedly reduced surviving cells in the hippocampus in a time­dependent manner were observed in the intermittent hypoxia group in comparison with the continued hypoxia group. OSAS­induced intermittent hypoxia markedly activated the MAPK signaling pathways, which were triggered by oxidative stress, leading to abnormal expression of downstream Bcl­2 and Bax, and a severe loss of neural cells in the hippocampus.

Delayed neutrophil apoptosis mediates intermittent hypoxia-induced progressive heart failure in pressure-overloaded rats.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnea (OSA) and heart failure (HF) are common coexisting diseases. Intermittent hypoxia (IH), caused by repeated apnea/hypopnea events, accompanied by increased systemic inflammation, might contribute to the promotion of HF. METHODS: To assess the hypothesis, rats were exposed to IH or normal air condition 4 weeks on the basis of normal heart function or pre-existing HF, which was induced by pressure overload caused by abdominal aortic constriction surgery performed 12 weeks earlier. Echocardiography was performed before and after IH exposure to evaluate left ventricular (LV) function. Serum concentrations of pro-inflammatory cytokines TNF-α and IL-6 were detected by enzyme-linked immunosorbent assay. Flow cytometric analysis was used to determine the apoptotic rate of polymorphonuclear neutrophils (PMNs). RESULTS: The echocardiographic study showed a significant decrease in LV fractional shortening (FS) and ejection fraction (EF) as well as an increase in the LV relative wall thickness (RWT) index in HF rats, which was aggravated by further exposure to IH compared with single-handed HF-only and sham-IH and sham-control groups. A reduced PMN apoptotic rate was observed in HF-IH rats compared with HF-only, sham-IH, and sham-control rats. Serum concentrations of TNF-α and IL-6 were also increased in HF-IH rats, accompanied by delayed PMN apoptosis, indicating significant systemic inflammation induced by IH. CONCLUSION: The results of this study demonstrated that IH aggravates LV remodeling and heart dysfunction in rats with pre-existing HF. Delayed neutrophil apoptosis, which was revealed in HF rats following exposure to IH, contributed to the exacerbation of myocardial damage and progression of heart dysfunction.

Functional disconnection of the right anterior insula in obstructive sleep apnea.

BACKGROUND: The right anterior insula (AIns) is an important node of the salience network and serves to switch between two major cognitive-related functional brain networks, ie, the central executive network (CEN) and the default mode network (DMN), both of which show functional deficits in obstructive sleep apnea (OSA) patients. However, the effect of OSA on functional connectivity of the right AIns remains uncertain. OBJECTIVE: To determine whether the resting-state functional connectivity (rsFC) between the right AIns and the CEN and DMN is disrupted in OSA patients, which may be associated with cognitive deficits in this disorder. METHODS: Twenty-four male OSA patients and 21 matched healthy controls underwent functional MRI examinations and clinical and neuropsychologic assessments. The rsFCs between the right AIns and the CEN and DMN were compared between the two groups and were correlated with clinical and neuropsychologic assessments. RESULTS: Compared with healthy controls, OSA patients showed significantly weakened rsFC between the right AIns and the DMN. Moreover, the functional disconnection between the right AIns and the medial prefrontal cortex was correlated with the severity of the OSA; and the functional disconnection between the right AIns and the posterior cingulate cortex was correlated with depressive scores and working memory performance. However, there were no significant inter-group differences in the rsFC between the right AIns and the CEN. CONCLUSIONS: These findings suggest that OSA selectively impairs the rsFC between the right AIns and the DMN, which may be a candidate substrate for cognitive impairment in OSA patients.

Cheyne-Stokes respiration during sleep: mechanisms and potential interventions.

Cheyne-Stokes respiration is characterized by a typical waxing and waning pattern in breathing amplitude, interspersed with central apnoeas or hypopnoeas. This article reviews current knowledge regarding Cheyne-Stokes respiration with a particular emphasis on the mechanisms and latest methods of intervention.

Obstructive sleep apnea promotes cancer development and progression: a concise review.

BACKGROUND: Obstructive sleep apnoea-hypopnoea (OSA) is an increasingly common sleep disorder which is widely accepted to be associated with high rates of morbidity and mortality. OSA is an independent risk factor for cardiovascular diseases, cerebrovascular disease, and metabolic disease. Recently, several studies have demonstrated that patients with OSA have a higher prevalence of cancer and cancer-related mortality. The epidemiological surveys suggest that patients with OSA had a higher incidence of cancer and cancer-related mortality than patients without OSA. Animal studies indicate that the activation of HIF-1 and VEGF pathways in response to intermittent hypoxia may promote the blood supply which supports tumor growth. In addition, tumor-associated macrophages may be altered by intermittent hypoxia (or sleep fragmentation) to a tumor-promoting phenotype yielding more aggressive cancer behavior. CONCLUSIONS: The relationship between OSA and cancer has been confirmed, in which patients with OSA have a relative high prevalence of cancer and cancer-related mortality. The mechanism of OSA promoting cancer development and progression may be related with intermittent hypoxia and possibly sleep fragmentation. The activation of several cancer-related pathways may play an important role in tumor growth and metastasis. More clinical data and basic studies are needed to explain and confirm the relationship between OSA and cancer.