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.

Differential expression of immune markers in the patients with obstructive sleep apnea/hypopnea syndrome.

PURPOSE: To evaluate phenotypic changes of various immune cells in the peripheral blood in the patients with sleep apnea/hypopnea syndrome (OSAHS). METHODS: This is a case-control study. The peripheral venous blood was collected. A subset of T cells, B cells, natural killer cells, and dendritic cells was analysed using various markers and flow cytometry. Regression curve analysis was made to examine the correlation between the change of immune cells and aponea hypoxia index (AHI) and oxygen desaturation. RESULTS: The percentage of CD3+/CD4+ T lymphocytes (P < 0.001) and CD19+ B cells (P < 0.001) and the CD4+/CD8+ ratio (P < 0.001) in the OSAHS patients were significantly increased compared with those in the control group without OSAHS, and CD4+/CD8+ ratio positively correlated with aponea hypoxia index (r = 0.37, P < 0.001) but negatively correlated with the lowest SaO2 (r = - 0.2, P < 0.001), whereas a greater reduction in the percentage of CD3+/CD8+ T cells (P < 0.001). Moreover, the ratios of CD3+/CD16+/CD56+ natural killer (NK)-like T cells (P < 0.05) and CD3-/CD16+/CD56+ NKT cells (P < 0.001) were significantly lower in the OSAHS group than those in the control group. However, no significant difference was observed in the percentage of CD3+ total T cells, CD8+/CD28+ T cells, CD8+/CD28- T cells, DC1, DC2, and DC1/DC2 dendritic cells between the OSAHS and control groups. CONCLUSION: Our study showed differential responses of various types of immune cells in the peripheral blood in patients with OSAHS and their correlation with severity of oxygen desaturation.

Exosome and Macrophage Crosstalk in Sleep-Disordered Breathing-Induced Metabolic Dysfunction.

Obstructive sleep apnea (OSA) is a highly prevalent worldwide public health problem that is characterized by repetitive upper airway collapse leading to intermittent hypoxia, pronounced negative intrathoracic pressures, and recurrent arousals resulting in sleep fragmentation. Obesity is a major risk factor of OSA and both of these two closely intertwined conditions result in increased sympathetic activity, oxidative stress, and chronic low-grade inflammation, which ultimately contribute, among other morbidities, to metabolic dysfunction, as reflected by visceral white adipose tissue (VWAT) insulin resistance (IR). Circulating extracellular vesicles (EVs), including exosomes, are released by most cell types and their cargos vary greatly and reflect underlying changes in cellular homeostasis. Thus, exosomes can provide insights into how cells and systems cope with physiological perturbations by virtue of the identity and abundance of miRNAs, mRNAs, proteins, and lipids that are packaged in the EVs cargo, and are secreted from the cells into bodily fluids under normal as well as diseased states. Accordingly, exosomes represent a novel pathway via which a cohort of biomolecules can travel long distances and result in the modulation of gene expression in selected and targeted recipient cells. For example, exosomes secreted from macrophages play a critical role in innate immunity and also initiate the adaptive immune response within specific metabolic tissues such as VWAT. Under normal conditions, phagocyte-derived exosomes represent a large portion of circulating EVs in blood, and carry a protective signature against IR that is altered when secreting cells are exposed to altered physiological conditions such as those elicited by OSA, leading to emergence of IR within VWAT compartment. Consequently, increased understanding of exosome biogenesis and biology should lead to development of new diagnostic biomarker assays and personalized therapeutic approaches. Here, the evidence on the major biological functions of macrophages and exosomes as pathophysiological effectors of OSA-induced metabolic dysfunction is discussed.

[Effect of resection of adenoids and tonsillectomy on immune function in children with obstructive sleep apnea hypopnea syndrome].

Objective:To remove the immune function of children with obstructive sleep apnea hypopnea syndrome by resection of adenoids and tonsillar. Method: The fasting peripheral venous blood of children with OSAHS and healthy children were collected. The lymphocyte subsets, NK cells and immunoglobulin levels were compared between the two groups. The fasting blood samples of OSAHS children were collected again after 2d, 30d, 60d and 90d after operation. The changes of lymphocyte subsets, NK cells and immunoglobulin levels were observed after operation. Result: Before operation, at the 0.05 test level, it was not yet clear that the levels of IgG, IgM, IgA, NK, CD3+, CD4+ and CD8+ in OSAHS children were significantly different from those in the control group. The levels of IgA, CD3+ and CD4+ decreased significantly in children at 2d and OSAHS after operation, and IgG, IgM, IgA, NK, CD3+ and IgA continued to rise after 60d until ninetieth day after operation. Conclusion: There is no statistical disorder of immune level in children with OSAHS compared with healthy children. The implementation of adenoidectomy and tonsillectomy in children with OSAHS, the level of immunity in 90 days can be restored to the preoperative level.

The level of lipopolysaccharide-binding protein is elevated in adult patients with obstructive sleep apnea.

BACKGROUND: lipopolysaccharide-binding protein (LBP) has been to be a surrogate marker of inflammation in OSA. This study aimed to test the hypothesis that the concentration of LBP is elevated in adult patients with obstructive sleep apnea (OSA). METHODS: A total of 90 patients were enrolled into the study, 50 subjects were divided into OSA groups and 40 in healthy control according to PSG examination. Subsequently, patients with apnea-hypopnea index (AHI) ≧ 5, were divided into different subgroups according to blood pressure, gender, body mass index (BMI) and AHI. Venous blood samples were collected for detection after polysomnography. The serum levels of LBP and proinflammatory cytokines (interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α) were tested by ELISA. RESULTS: The present study demonstrated that the serum levels of both LBP and proinflammatory cytokines were elevated in OSA patients. A stratified analysis conducted to analyze differences among subgroups indicated that OSA patients with a higher AHI or BMI had an increased level of LBP and proinflammatory cytokines (all p < 0.05). Furthermore, a significant correlations were observed between LBP and inflammation and AHI. Multivariate regression analysis also demonstrated that AHI, LSaO2 and BMI had impact on the concentration of LBP. CONCLUSION: The research showed that the serum level of LBP and proinflammatory cytokines were elevated in adult patients with OSA, and an association with severity of disease and BMI were established. Furthermore, sleep apnea and BMI had effect on the concentration of LBP.

Circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1): A potential biomarker for coronary artery disease in patients with obstructive sleep apnea.

OBJECTIVE: Although severe obstructive sleep apnea (OSA) is an important risk factor for atherosclerosis-related diseases including coronary artery disease (CAD), there is no reliable biomarker of CAD risks in patients with OSA. This study aimed to test our hypothesis that circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1-Abs) are associated with the prevalence of CAD in patients with OSA. METHODS: Eighty-two adults diagnosed with OSA by polysomnography, 96 patients with a diagnosis of acute coronary syndrome (ACS) and 64 healthy volunteers (HVs) were consecutively enrolled. Serum samples were collected from patients with OSA at diagnostic polysomnography and from patients with ACS at disease onset. Serum NBL1-Ab level was measured by amplified luminescence proximity homogeneous assay and its association with clinical variables related to atherosclerosis was evaluated. RESULTS: NBL1-Ab level was significantly elevated in patients with both OSA and ACS compared with HVs. Subgroup analyses showed that NBL1-Ab level was markedly higher in patients with severe OSA and OSA patients with a history of CAD. Weak associations were observed between NBL1-Ab level and apnea-hypopnea index, age, mean SpO2 and arousal index, whereas significantly higher NBL1-Ab levels were observed in OSA patients with a history of CAD than in those without a history of CAD. Sensitivity analysis using a logistic regression model also demonstrated that increased NBL1-Ab levels were associated with the previous history of CAD in patients with OSA. CONCLUSIONS: Elevated NBL1-Ab levels may be associated with the prevalence of CAD in patients with OSA, which needs to be confirmed further.

Sleep Apnea Morbidity: A Consequence of Microbial-Immune Cross-Talk?

OSA has emerged as a highly prevalent public health problem that imposes important mid- and long-term consequences, namely cardiovascular, metabolic, cognitive, and cancer-related alterations. OSA is characterized by increased upper airway resistance, alveolar hypoventilation, and recurrent upper airway obstruction during sleep. Recurrent collapse of the upper airway develops with sleep onset and is associated with both intermittent hypoxemia and sleep fragmentation. The microbiome is a vast and complex polymicrobial ecosystem that coexists with the human organism, and it has been identified as playing significant roles in the development of host immunologic phenotypes. In humans and animal models, changes in gut microbial communities occur with lifestyle behaviors, such as smoking, long-distance travel, dietary preferences, physical exercise, and circadian rhythm disturbances. In parallel, diseases previously attributed in part to lifestyle such as obesity, coronary heart disease, depression, and asthma (also associated with OSA) are now claimed as microbiota related. We therefore posit that altered patterns of sleep and oxygenation, as seen in OSA, will promote specific alterations in gut microbiota that in turn will elicit the immunologic alterations that lead to OSA-induced end-organ morbidities. The present article assesses the potential mechanistic links between OSA-induced changes in gut microbiota and its morbid phenotypes.

The complex associations between obstructive sleep apnea and auto-immune disorders: A review.

Obstructive sleep apnea is known to be associated with diseases such as hypertension, metabolic disorder, and cancer. A more controversial and less understood association is that of sleep apneas and the development and worsening of autoimmune and rheumatologic disorders. Through the main pathways of intermittent hypoxia and sleep deprivation, we hypothesize that obstructive sleep apnea creates a chronic inflammatory state that worsens or incites autoimmune disorders. This thorough review of the available literature highlights our current understanding of the relationship between these disease processes in order to demonstrate the importance of diagnosis and appropriate management of sleep disorders in patients suffering from rheumatologic diseases.