[Significance of immunological markers in patients with obstructive sleep apnea and comorbid pathology]. / Znachimost' immunologicheskikh markerov u patsientov s obstruktivnym apnoe sna i komorbidnoi patologiei.

OBJECTIVE: To determine the significance of immunological markers in patients with obstructive sleep apnea (OSA) and comorbid pathology. MATERIAL AND METHODS: Sixty-five patients were examined. Two groups of patients were distinguished: the main group with moderate and severe OSA and the control group without OSA. The subjects underwent anthropometry, polysomnography, assessment of cognitive and emotional disorders. Glial fibrillar acidic protein (GFAP), antibodies against NR1-NR2 subunits of NMDA receptors (AT to GRIN2A) and the acetylcholine receptor (AT to AChR), and brain-derived neurotrophic factor (BDNF) were studied by enzyme immunoassay. RESULTS: In patients with OSA, indicators of markers: GFAP (p=0.017), BDNF (p=0.006), antibodies to AChR (p=0.002), as well as chronic cerebral ischemia (p=0.000), depression on the HADS (p=0.004) and the Beck scale (p=0.000), drowsiness on the Epworth scale (p=0.001), asthenia on the visual analogue scale (p=0.000) and the MFI 20 (p=0.013) were higher than in the control group. A relationship was established in the main group between the identified subjective disorders on the Mini-Mental State Examination scale (MMSE) and BDNF (r=0.302, p=0.014) and the average score on the MMSE and BDNF (r=-0.266, p=0.032). CONCLUSION: The results demonstrate the relationship of neurospecific proteins with cognitive impairment in patients with OSA. The neuromarker GFAP in patients with sleep apnea has shown itself to be a predictor of decreased neurogenesis, and BDNF as a representative marker of neuroplasticity. Large values of AT to AChR in patients with OSA may indicate possible neuromuscular transmission disorders. Along with drowsiness and asthenia, patients with OSA have changes in the emotional background, mainly due to depression. The severity of depression and the severity of asthenia increase with increasing severity of apnea and are probably associated with low levels of saturation, which in turn leads to dysregulation of the prefrontal cortex, hippocampus and amygdala.

The impact of surgical intervention on peripheral blood T lymphocyte subsets and natural killer cell activity in pediatric obstructive sleep apnea hypopnea syndrome (OSAHS).

OBJECTIVE: This study aimed to investigate the impact of surgical intervention on peripheral blood T lymphocyte subsets and natural killer (NK) cell activity in pediatric patients with obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: A total of 36 OSAHS children, 32 children with tonsillar hypertrophy, and 30 healthy children were enrolled. Clinical data and polysomnography (PSG) results were collected. Peripheral blood samples were analyzed for T lymphocyte subsets, NK cells, and cytokine levels including Th1 (IFN-γ, IL-2, TNF-α), Th2 (IL-4, IL-10), and Th17 (IL-17). RESULTS: At baseline, OSAHS children exhibited lower LSaO2 levels and higher AHI values compared to healthy children. They also showed decreased percentages of CD3 + T cells, CD4 + T cells, NK cells, and elevated CD8 + T cells and CD4+/CD8 + ratio. Levels of IFN-γ, IL-2, TNF-α, IL-4, and IL-17 were significantly lower in OSAHS children. Post-surgery improvements were observed in LSaO2, AHI, and immune markers at 3 months and 6 months. Pearson's correlation analysis revealed significant associations between LSaO2, AHI, and peripheral blood immune parameters at baseline and 6 months post-surgery. CONCLUSION: Surgical intervention in pediatric OSAHS influences peripheral blood T lymphocyte subsets and NK cell activity. Early intervention and monitoring of immune function are crucial for the recovery and healthy development of affected children.

Intermittent hypoxia induces Th17/Treg imbalance in a murine model of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by cyclic normoxic and hypoxic conditions (intermittent hypoxia, IH) induced by the repeated closure of the upper-airway respiratory tract. As a pathomechanism of OSA, IH results in various comorbidities via chronic inflammation and related pathways. However, the role of other inflammatory cells, such as lymphocytes, has not been well-explored. This study aimed to examine the effects of IH on the distribution and balance of T cell subsets and other related cytokines, and mechanisms in the immune system. We modified OSA mouse model (male C57BL/6N male) using our customized chamber that controls specific sleep and oxygenic cycles. To induce hypoxia, the IH group was repeatedly exposed to 5% O2 and 21% O2 lasting for 120 s each for 7 h daily for 4 weeks. Mice were then subjected to a recovery period of 4 weeks, in which IH stimulation was ceased. T cells and related cytokines were analyzed using flow cytometry and immunohistochemistry. Compared with the control group, the IH group had significantly lower levels of CD4+CD25+Foxp3+ regulatory T cells but higher levels of Th 17, IL-4, HIF-1, and inflammatory cytokines. After the recovery period, these altered changes in the immune cells were recovered, and we found no significant difference in their levels between the control and recovery groups. This study revealed that the Th17/Treg ratio is increased by intermittent hypoxia, and this imbalance can explain immune-related diseases, including recently reported allergies, autoimmune, and even cancer diseases, arising from OSA.

Is there a relationship between the severity of obstructive sleep apnea syndrome and the systemic immune inflammation index?

AIM: Vascular dysfunction, oxidative stress and systemic inflammation are considered responsible for the pathophysiology of Obstructive sleep apnea syndrome (OSAS). It is thought that desaturation due to apnea-hypopnea attacks in OSAS patients activates inflammatory pathways. In this study, we aimed to reveal the relationship between inflammation parameters Systemic immune inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratios (PLR) severity of OSAS in patients who underwent polysomnography in our hospital's sleep laboratory. METHODS: We grouped our 171 patients who were followed up in our sleep laboratory with the diagnosis of OSAS according to their AHI values. We evaluated the correlation of SII, NLR, and PLR values obtained from the complete blood tests of our patients with OSAS diagnosis and OSAS severity. RESULTS: The mean NLR, PLR and SII values of patients with OSAS were statistically significantly higher than those without OSAS (p < 0.05). A positive correlation of 18% was found between the presence of OSAS and the SII value (p = 0.016). No statistically significant difference was found when comparing OSAS severity and NLR, PLR and SII values (p > 0.05). CONCLUSION: We observed that SII, NLR and PLR parameters, which are rapidly assessable systemic inflammation markers of this process, were independently associated in patients diagnosed with OSAS and that there was no change in SII, NLR, and PLR parameters with OSAS severity.

Upper airway manifestations of anti-IgLON5 disease: Otorhinolaryngological point of view.

INTRODUCTION: Anti-IgLON5 disease is a recently described neurological disorder with multisystemic features. The disease is characterized by the presence of IgLON5 antibodies in serum and cerebrospinal fluid. Our objective is to describe in detail the otorhinolaryngological manifestations of this disease, which are frequent and may include dysphagia, dysarthria, vocal cord paralysis and laryngospasm. METHODS: In this study, we present a series of 9 patients with anti-IgLON5 disease and otolaryngological manifestations. Patients were evaluated between July 2012 and March 2022 by video-polysomnography, fiber-optic laryngoscopy, and functional endoscopic evaluation of swallowing. RESULTS: The median age was 71 years, and 5 (56%) were female. Video-polysomnography showed a NREM/REM parasomnia in 6 patients (67%), obstructive sleep apnea in 8 (88%), stridor during sleep in 7 (78%) and central apneas in 1 (11%). Six out of the 9 patients (67%) presented episodes of acute respiratory failure that required mechanical ventilation, 6 had vocal fold palsy with 4 of them requiring tracheostomy (3 had to be performed on an emergency basis). Dysphagia occurred in 8 patients (89%). Prominent upper airway secretion and sialorrhea was also present in 3 cases. CONCLUSION: The anti-IgLON5 disease exhibits extensive otolaryngological symptoms, mainly affecting the upper airway. These symptoms affect the quality of life and can be life-threatening. Prompt acute management is essential for stridor, dyspnea, and dysphagia. Given the potential severity of the symptoms and rarity of the disease, it is important for otolaryngologists to be familiar with anti-IgLON5 disease. LEVEL OF EVIDENCE: Level 4.

Effect of continuous positive airway pressure treatment on Th17/Treg imbalance in patients with obstructive sleep apnea and a preliminary study on its mechanism.

BACKGROUND: Obstructive sleep apnea (OSA) can be considered a chronic inflammatory disease that impacts all bodily systems, including the immune system. This study aims to assess the Th17/Treg pattern in patients with OSA and the effect of continuous positive airway pressure (CPAP) treatment. METHODS: OSA patients and healthy controls were recruited. OSA patients recommended for CPAP treatment were followed up for three months. Flow cytometry was employed to determine the proportion of Th17 and Treg cells. Real-time quantitative polymerase chain reaction (PCR) and western blotting were utilized to detect the mRNA and protein levels of receptor-related orphan receptor γt (RORγt) and forkhead/winged helix transcription factor (Foxp3), respectively, in peripheral blood mononuclear cells (PBMCs). Enzyme-linked immunosorbent assay (ELISA) was performed to measure the serum levels of interleukin-17 (IL-17), IL-6, transforming growth factor-ß1 (TGF-ß1), and hypoxia-induced factor-1α (HIF-1α). RESULTS: A total of 56 OSA patients and 40 healthy controls were recruited. The proportion of Th17 cells, Th17/Treg ratio, mRNA and protein levels of RORγt, and serum IL-17, IL-6, and HIF-1α levels were higher in OSA patients. Conversely, the proportion of Treg cells, mRNA and protein levels of Foxp3, and serum TGF-ß1 levels were decreased in OSA patients. The proportion of Th17 and Treg cells in OSA can be predicted by the apnea hypopnea index (AHI), IL-6, TGF-ß1 and, HIF-1α. 30 moderate-to-severe OSA patients were adherent to three-month CPAP treatment, with improved Th17/Treg imbalance, IL-17, IL-6, TGF-ß1, and HIF-1α levels compared to pre-treatment values. CONCLUSION: There was a Th17/Treg imbalance in OSA patients. The prediction of Th17 and Treg cell proportions in OSA can be facilitated by AHI, as well as serum IL-6, TGF-ß1, and HIF-1α levels. Furthermore, CPAP treatment can potentially improve the Th17/Treg imbalance and reduce proinflammatory cytokines in OSA patients.

PSGL-1: a novel immune checkpoint driving T-cell dysfunction in obstructive sleep apnea.

Introduction: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy. Methods: The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using in vitro models. In addition, PSGL-1 impact on T-cells function was evaluated by ex vivo models. Results: Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia. Discussion: In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.

The Tonsil Lymphocyte Landscape in Pediatric Tonsil Hyperplasia and Obstructive Sleep Apnea.

Tonsil hyperplasia is the most common cause of pediatric obstructive sleep apnea (OSA). Despite the growing knowledge in tissue immunology of tonsils, the immunopathology driving tonsil hyperplasia and OSA remains unknown. Here we used multi-parametric flow cytometry to analyze the composition and phenotype of tonsillar innate lymphoid cells (ILCs), T cells, and B cells from pediatric patients with OSA, who had previous polysomnography. Unbiased clustering analysis was used to delineate and compare lymphocyte heterogeneity between two patient groups: children with small tonsils and moderate OSA (n = 6) or large tonsils and very severe OSA (n = 13). We detected disturbed ILC and B cell proportions in patients with large tonsils, characterized by an increase in the frequency of naïve CD27-CD21hi B cells and a relative reduction of ILCs. The enrichment of naïve B cells was not commensurate with elevated Ki67 expression, suggesting defective differentiation and/or migration rather than cellular proliferation to be the causative mechanism. Finally, yet importantly, we provide the flow cytometry data to be used as a resource for additional translational studies aimed at investigating the immunological mechanisms of pediatric tonsil hyperplasia and OSA.

The role of PD-L1 in the immune dysfunction that mediates hypoxia-induced multiple organ injury.

Hypoxia is a pathological condition common to many diseases, although multiple organ injuries induced by hypoxia are often overlooked. There is increasing evidence to suggest that the hypoxic environment may activate innate immune cells and suppress adaptive immunity, further stimulating inflammation and inhibiting immunosurveillance. We found that dysfunctional immune regulation may aggravate hypoxia-induced tissue damage and contribute to secondary injury. Among the diverse mechanisms of hypoxia-induced immune dysfunction identified to date, the role of programmed death-ligand 1 (PD-L1) has recently attracted much attention. Besides leading to tumour immune evasion, PD-L1 has also been found to participate in the progression of the immune dysfunction which mediates hypoxia-induced multiple organ injury. In this review, we aimed to summarise the role of immune dysfunction in hypoxia-induced multiple organ injury, the effects of hypoxia on the cellular expression of PD-L1, and the effects of upregulated PD-L1 expression on immune regulation. Furthermore, we summarise the latest information pertaining to the involvement, diagnostic value, and therapeutic potential of immunosuppression induced by PD-L1 in various types of hypoxia-related diseases, including cancers, ischemic stroke, acute kidney injury, and obstructive sleep apnoea. Video Abstract.

Effect of Sleep Surgery on C-Reactive Protein Levels in Adults With Obstructive Sleep Apnea: A Meta-Analysis.

OBJECTIVES/HYPOTHESIS: To evaluate associations between sleep surgery and CRP (C-reactive protein) levels in adults with obstructive sleep apnea (OSA). STUDY DESIGN: Meta-analysis. METHODS: Two authors independently searched PubMed, Medline, EMBASE, and Cochrane review databases until July 2019. The keywords used were sleep apnea, OSA, sleep apnea syndromes, surgery, C-reactive protein (CRP), and inflammatory markers. The effects of sleep surgery on CRP levels were examined using a random-effects model. RESULTS: Nine studies with 277 patients were analyzed (mean age: 46.5 years; 92% men; mean sample size: 30.8 patients). The mean change in the apnea-hypopnea index (AHI) after surgery was significantly reduced by -21.1 (95% confidence interval [CI], -28.4 to -13.7) events/hr. Overall, sleep surgery resulted in a significant reduction of CRP levels in patients with OSA (standardized mean difference [SMD] = -0.39, 95% CI, -0.67 to -0.11). Patients with postoperative AHI reduction >20 events/hr achieved a greater reduction in CRP than those with AHI reduction <20 events/hr (SMD: -0.72 vs. -0.14, P for heterogeneity = .007). According to subgroup analysis, differences in the CRP levels after surgery were nonsignificant in the different countries (i.e., United States vs. other countries), CRP types (i.e., CRP vs. high-sensitivity CRP), surgical procedures (i.e., pharyngeal surgery vs. other surgical procedures), and follow-up period (i.e., <6 vs. >6 months). CONCLUSIONS: Sleep surgery for OSA resulted in a significant reduction of CRP levels in adults. The beneficial effect of surgery on CRP levels is greater in patients with large improvement in OSA (i.e., AHI reduction >20 events/hr) after sleep surgery. Laryngoscope, 131:1180-1187, 2021.

Redistribution of Monocyte Subsets in Obstructive Sleep Apnea Syndrome Patients Leads to an Imbalanced PD-1/PD-L1 Cross-Talk with CD4/CD8 T Cells.

Obstructive sleep apnea syndrome (OSAS) represents a substantial disease of recurrent sleep fragmentation, leading to intermittent hypoxia and subsequent diseases such as cardiovascular, metabolic, or cognitive dysfunctions. In addition, OSAS is considered as low-grade systemic inflammation, which is associated with a higher incidence of cancer, severity of infections, and an overall immune dysregulation. This research project aims to comprehensively investigate the interplay of wholesome sleep and the immune functions of circulating monocytes and T cells in OSAS patients, which are known to be affected by oxidative stress. We studied the distribution of the CD14/CD16 characterized monocyte subsets in peripheral blood as well as their PD-L1 expression and complex formation with T cells. Furthermore, a detailed analysis of T cell subsets with regard to their PD-1 and PD-L1 expression was performed. Data revealed a decrease of classical monocytes accompanied by an increase of both CD16+ monocyte subsets in OSAS patients that was positively correlated with the body mass index. OSAS patients revealed an increased PD-1 and PD-L1 expression in T cells and monocytes, respectively, which was linked to the severity of monocyte subset alterations. The complex formation of monocytes and T cells was also elevated in OSAS patients, which indicates a deregulated PD-1/PD-L1 cross-talk between these cells. Our data show for the first time, to our knowledge, massive alterations of peripheral monocyte subsets in response to OSAS and its accompanying phenomena.

Toll-Like Receptor-4-Mediated Inflammation is Involved in Intermittent Hypoxia-Induced Lung Injury.

PURPOSE: Intermittent hypoxia (IH) is a recognized risk factor for multiple organs damage, resulting in lung injury. Its pathophysiology is still poorly understood. Toll-like receptor 4 (TLR4) signaling plays a critical role in host immune response to invading pathogen and non-infectious tissue injury. The role of TLR4-mediated inflammation in IH-induced lung injury was investigated in this study. METHODS: Lean adult male TLR4-deficient (TLR4-/-) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 6-8% for 25 s, 150 s/cycle, 8 h/day) or air (normoxic mice) for 6 weeks. Animals were sacrificed after 6-week exposure, and the lung tissues were harvested for morphological and inflammatory analyses. The expression of TLR4 and nuclear factor kappa-B (NF-κB) P65 were examined by real-time quantitative polymerase chain reaction and immunohistochemical method. Serum cytokine levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were analyzed by enzyme-linked immunosorbent assay. RESULTS: IH induced morphological and inflammation changes in the lung. IH for 6 weeks induced higher expression of TLR4 (C57BL/6-N vs C57BL/6-IH, P < 0.05) and resulted in higher release of TNF-α, IL-6 (P < 0.05), and NF-κB P65 (P < 0.05). These alterations were remitted by TLR4 deletion. CONCLUSIONS: TLR4-mediated inflammation plays an important role in the development of IH-induced lung injury in mice, possibly through mechanisms involving nuclear factor-κB. Targeting TLR4/NF-κB pathway could represent a further therapeutic option for sleep apnea patients.

Ghrelin suppresses migration of macrophages via inhibition of ROCK2 under chronic intermittent hypoxia.

OBJECTIVES: Migration of macrophages and atherosclerosis result in various diseases, including coronary heart disease. This study aimed to clarify the roles that ghrelin and Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) play in migration of macrophages under chronic intermittent hypoxia (CIH). METHODS: A rat model of CIH was constructed and changes in ghrelin and ROCK2 protein expression were measured by western blot assay. The migratory ability of macrophages was determined by the transwell assay. Hematoxylin and eosin staining was applied to detect the changes in intima-media thickness. RESULTS: We found that CIH enhanced migration of macrophages, and this effect was attenuated by exogenous ghrelin. Additionally, the facilitative effect of CIH on migration of macrophages was strengthened or decreased by upregulation or downregulation of ROCK2, respectively. This phenomenon indicated that ROCK2 was involved in CIH-induced migration in macrophages. Furthermore, western blot and transwell assays showed that ghrelin inhibited CIH-induced migration via ROCK2 suppression in macrophages. CONCLUSIONS: In summary, the present study shows that ghrelin inhibits CIH-induced migration via ROCK2 suppression in macrophages. Our research may help lead to identifying a new molecular mechanism for targeted therapy of atherosclerosis and its associated coronary artery diseases under intermittent hypoxia.

Alterations in Serum Adropin, Adiponectin, and Proinflammatory Cytokine Levels in OSAS.

Objective: The present study was planned to examine the relationships between obstructive sleep apnea syndrome (OSAS) and the newly revealed adipokines adropin and adiponectin concentrations that display significant metabolic and cardiovascular functions and the levels of proinflammatory cytokine levels. Method: A total of 166 overweight and obese male patients with a body mass index (BMI) >27 kg/m2 were included in the study. Among study participants, 84 were recently diagnosed with OSAS by polysomnography with an apnea-hypopnea index (AHI) ≥5, and 82 were nonapneic with normal polysomnography (AHI<5) findings. The serum adropin and adiponectin levels of all cases were analyzed via the enzyme-linked immunosorbent assay method. Serum interleukin-1 (IL-1) beta and tumor necrotizing factor-alpha (TNF-alpha) levels were determined using Luminex cytokine multiplex analyses. Results: The mean age of the OSAS patients was 50.9 ± 5.7 years and BMI was 32.4 ± 6.0 kg/m2, and there was no statistically significant difference determined with the control group (49.3 ± 5.8 years and 30.6 ± 5, 6 kg/m2) (p > 0.05). There were no statistically significant differences between the OSAS and control groups concerning total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and glucose levels. Adiponectin was lower in the OSAS group at a statistically significant level in comparison with the control group and was related at a statistically significant level to OSAS intensity. Adropin concentration was determined to be higher in the OSAS group at a statistically significant level in comparison with the control group. Conclusion: The results of our study suggest that increased adropin concentration may be an indicator of endothelium dysfunction in OSAS patients. Serum adropin and adiponectin levels may be new bioindicators used for diagnosis and risk assessment in OSAS patients.

Inflammatory markers in palatine tonsils of children with obstructive sleep apnea syndrome / Marcadores inflamatórios em tonsilas palatinas de crianças com síndrome da apneia obstrutiva do sono

Abstract Introduction Obstrutive sleep apnea syndrome is characterized by repeated episodes of upper airway obstruction, associated with intermittent hypoxia and hypercapnia, and the main risk factor in childhood is adenotonsillar hypertrophy. The lymphocytes in these structures are responsible for local and systemic immune responses. Objective Verify the levels of the inflammatory markers, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, CRP and α1-GP, in the tonsils of children with and without obstructive sleep apnea syndrome. Methods This cross-sectional prospective study included 34 children with complains of snoring, difficulty breathing during sleep or recurrent tonsillitis. Patients underwent to a complete otorhinolaryngological examination, nasal endoscopy and polysomnography and were divided into two groups with 17 children each: obstructive sleep apnea syndrome group and control group. All underwent an adenotonsillectomy. Cytokines were measured in the collected tonsils (ELISA and Multiplex methods). Results Statistically significant increasing were observed between IL-8 and IL-10 cytokines of patients with obstructive sleep apnea when compared to the control group; also between c-reactive protein and α1-GP of the tonsils cortical region in children with obstructive sleep apnea syndrome when compared with the medullary region. There were no statistically significant differences for the remaining inflammatory mediators. Conclusion After the analysis of the levels of pro and anti-inflammatory markers (IL-1β, IL-4, IL-6, IL-8, IL-10, Il-15, TNF-α, CRP, α1-GP) in the tonsils, we observed higher levels of markers IL-8 and IL-10 in pediatric patients with obstructive sleep apnea syndrome.

Resumo Introdução A síndrome da apneia obstrutiva do sono é caracterizada por episódios repetidos de obstrução das vias aéreas superiores, associados a hipóxia intermitente e hipercapnia, e o principal fator de risco na infância é a hipertrofia adenotonsilar. Os linfócitos nessas estruturas são responsáveis por respostas imunes locais e sistêmicas. Objetivo Dosar os marcadores inflamatórios, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, PCR e α1-GP, nas tonsilas de crianças com e sem síndrome da apneia obstrutiva do sono. Método Estudamos prospectivamente 34 crianças que se queixavam de ronco, dificuldade para respirar durante o sono ou tonsilites recorrentes. Os pacientes foram submetidos a exame otorrinolaringológico completo, endoscopia nasal e polissonografia e foram divididos em dois grupos com 17 crianças cada: síndrome de apneia obstrutiva do sono e controle. Todos foram submetidos à adenotonsilectomia. As citocinas foram medidas nas tonsilas coletadas (métodos ELISA e Multiplex). Resultados Com diferenças estatisticamente significantes, observou-se aumento das citocinas IL-8 e IL-10 em pacientes com apneia obstrutiva do sono em comparação ao grupo controle, assim como aumento dos níveis de proteína C reativa e de α1-GP na região cortical das tonsilas de crianças portadoras de síndrome da apneia obstrutiva do sono em comparação com a região medular. Não houve diferenças estatisticamente significantes para o restante dos mediadores inflamatórios. Conclusão Após a análise dos níveis de marcadores pró e anti-inflamatórios (IL-1β, IL-4, IL-6, IL-8, IL-10, Il-15, TNF-α, PCR, α1-GP) nas tonsilas, observamos níveis mais altos de marcadores IL-8 e IL-10 em pacientes pediátricos com síndrome da apneia obstrutiva do sono.

Inflammatory markers in palatine tonsils of children with obstructive sleep apnea syndrome.

INTRODUCTION: Obstrutive sleep apnea syndrome is characterized by repeated episodes of upper airway obstruction, associated with intermittent hypoxia and hypercapnia, and the main risk factor in childhood is adenotonsillar hypertrophy. The lymphocytes in these structures are responsible for local and systemic immune responses. OBJECTIVE: Verify the levels of the inflammatory markers, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, CRP and α1-GP, in the tonsils of children with and without obstructive sleep apnea syndrome. METHODS: This cross-sectional prospective study included 34 children with complains of snoring, difficulty breathing during sleep or recurrent tonsillitis. Patients underwent to a complete otorhinolaryngological examination, nasal endoscopy and polysomnography and were divided into two groups with 17 children each: obstructive sleep apnea syndrome group and control group. All underwent an adenotonsillectomy. Cytokines were measured in the collected tonsils (ELISA and Multiplex methods). RESULTS: Statistically significant increasing were observed between IL-8 and IL-10 cytokines of patients with obstructive sleep apnea when compared to the control group; also between c-reactive protein and α1-GP of the tonsils cortical region in children with obstructive sleep apnea syndrome when compared with the medullary region. There were no statistically significant differences for the remaining inflammatory mediators. CONCLUSION: After the analysis of the levels of pro and anti-inflammatory markers (IL-1ß, IL-4, IL-6, IL-8, IL-10, Il-15, TNF-α, CRP, α1-GP) in the tonsils, we observed higher levels of markers IL-8 and IL-10 in pediatric patients with obstructive sleep apnea syndrome.

AMPK activation increases postoperative cognitive impairment in intermittent hypoxia rats via direct activating PAK2.

The pathogenesis of postoperative cognitive impairment of obstructive sleep apnea-hypopnea syndrome (OSAHS) individuals remains unclear. AMP activated protein kinase (AMPK) is a ubiquitous sensor/effector of cell stresses. Thus we detected the role and underlying mechanisms of AMPK in postoperative cognitive impairment of OSAHS individuals in intermittent hypoxia rats. Cognitive function was evaluated by novel object recognition test and Barnes maze during the first 4 days after laparotomy. We found that laparotomy induced postoperative cognitive impairment and AMPK activation in intermittent hypoxia rats, but not in adult rats. Inhibiting AMPK activation via Compound C during laparotomy improved postoperative cognitive impairment and alleviated surgery-induced upregulation of p-PAK2, AMPK-PAK2 complex, and neuroinflammation (marked by microglial activation and IL-1ß level) in intermittent hypoxia rats. These data suggested that AMPK played an important role in postoperative cognitive impairment of OSAHS individuals via directly activating PAK2.

[Effect of resection of adenoids and/or tonsil on the immune indexes in children with obstructive sleep apnea hypopnea syndrome].

Objective: To study the effect on immune indexes in children with obstructive sleep apnea hypopnea syndrome (OSAHS) before and after resection of adenoid and/or tonsil. Methods: A total of 100 children with OSAHS due to adenoid hypertrophy were enrolled in Department of Otorhinolaryngology Head and Neck Surgery, the Second Hospital of Dalian Medical University from December 2016 to December 2018. Some cases were complicated with tonsil hypertrophy or chronic tonsillitis. 6 ml of fasting peripheral venous blood were collected from all subjects at the 1st day before surgery, 4th day, 1 month, 3 months and 6 months after surgery to detect lymphoid subsets percentage (CD3(+), CD4(+),CD8(+), CD4/CD8, CD19, NK) and level of immunoglobulin (IgG, IgA, IgM). Grouping: group A was a total of 51 cases with adenoid hypertrophy after Adenoid plasma ablation; group B was a total of 27 cases with adenoid hypertrophy and chronic tonsillitis after plasma ablation of adenoid and tonsil; and group C was a total of 22 cases hypertrophy of adenoid and tonsil after plasma ablation of adenoid and tonsil.In the baseline data, age, gender and other variables were analyzed by anova and chi-square test, repeated measurement anova was used for intra-group and inter-group comparison of observation indicators at different time points after operation, and independent sample t-test was used for comparison between the two groups at observation points 3 months after operation. Results: (1) In group A, the percentage of CD19 lymphocytes before surgery was higher than that at 4th day after surgery, and the difference was statistically significant (21.85±6.20 vs.19.18±5.91, P<0.05). The other immune indexes were not statistically different before and after surgery (P>0.05). (2) In group B, the percentage of CD19 lymphocytes, CD3(+)T lymphocytes, CD8(+)T lymphocytes and the level of IgG at 4th day after surgery were significantly different between those before surgery (all P<0.05). At the 1st month after surgery, the percentage of CD3(+)T lymphocytes, CD8(+)T lymphocytes, CD19 lymphocytes and the level of IgG were significantly different between those before surgery (all P<0.05). The other immune indexes were not statistically different before and after operation (P>0.05). (3) In group C, the percentage of CD19 lymphocytes and the CD3(+)T lymphocytes at 4th day after surgery were significantly different between those before surgery (all P<0.05).In the 1st month after surgery, the percentage of CD8(+)T lymphocytes and CD19 lymphocytes were significantly different between those before surgery (all P<0.05). The other immune indexes were not statistically different before and after operation (P>0.05). (4) Among three groups, the percentage of CD4(+)T lymphocytes, the levels of IgG and IgA before surgery between group A and Group B were statistically significant (all P<0.05). At 4th day after surgery, the percentage of CD4(+)T lymphocytes in group B and C were lower than those in group A, and the differences were statistically significant (32.22±6.14, 32.36±6.87 vs. 36.36±5.19, all P<0.05); the other immune indexes were not statistically different among each group before and after surgery (P>0.05). Conclusions: Resection of adenoid has no significant effect on the immune indexes in children with OSAHS. The children with OSAHS complicated with tonsil problems have immune index disorder before surgery. Surgery has a certain effect on the immune indexes of children with OSAHS in a short period of time, and tends to normal level after one month.

IL-33 Mediated Inflammation in Chronic Respiratory Diseases-Understanding the Role of the Member of IL-1 Superfamily.

Interleukin 33 (IL-33) is an alarmin cytokine from the IL-1 family. IL-33 is localized in the nucleus and acts there as a gene regulator. Following injury, stress or cell death, it is released from the nucleus, and exerts its pro-inflammatory biological functions via the transmembrane form of the ST2 receptor, which is present mainly as attached to immune cells. In recent years, IL-33 became a focus of many studies due to its possible role in inflammatory disorders. Among respiratory disorders, the contribution of IL-33 to the development of asthma, in particular, has been most identified. Increased level of IL-33 in lung epithelial cells and blood serum has been observed in asthma patients. The IL-33/ST2 interaction activated the Th2 mediated immune response and further production of many pro-inflammatory cytokines. Single nucleotide polymorphisms in the IL-33 gene cause a predisposition to the development of asthma. Similarly, in chronic pulmonary obstructive disease (COPD), both increased expression of IL-33 and the ST2 receptor has been observed. Interestingly, cigarette smoke, a key inducer of COPD, not only activates IL-33 production by epithelial and endothelial cells, but also induces the expression of IL-33 in peripheral blood mononuclear cells. Knowledge regarding its contribution in other respiratory disorders, such as obstructive sleep apnea, remains greatly limited. Recently it was shown that IL-33 is one of the inflammatory mediators by which levels in blood serum are increased in OSA patients, compared to healthy control patients. This mini review summarizes current knowledge on IL-33 involvement in chosen chronic respiratory disorders and proposes this interleukin as a possible link in the pathogenesis of these diseases.