Obstructive Sleep Apnea Plasma-Derived Exosomes Mediate Cognitive Impairment Through Hippocampal Neuronal Cell Pyroptosis.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with impaired cognitive function. Exosomes are secreted by most cells and play a role in OSA-associated cognitive impairment (CI). The aim of this study was to investigate whether OSA plasma-derived exosomes cause CI through hippocampal neuronal cell pyroptosis, and to identify exosomal miRNAs in OSA plasma-derived. MATERIALS AND METHODS: Plasma-derived exosomes were isolated from patients with severe OSA and healthy comparisons. Daytime sleepiness and cognitive function were assessed using the Epworth Sleepiness Scale (ESS) and the Beijing version of the Montreal Cognitive Assessment Scale (MoCA). Exosomes were coincubated with mouse hippocampal neurons (HT22) cells to evaluate the effect of exosomes on pyroptosis and inflammation of HT22 cells. Meanwhile, exosomes were injected into C57BL/6 male mice via caudal vein, and then morris water maze was used to evaluate the spatial learning and memory ability of the mice, so as to observe the effects of exosomes on the cognitive function of the mice. Western blot and qRT-PCR were used to detect the expressions of Gasdermin D (GSDMD) and Caspase-1 to evaluate the pyroptosis level. The expression of IL-1ß, IL-6, IL-18 and TNF-α was detected by qRT-PCR to assess the level of inflammation. Correlations of GSDMD and Caspase-1 expression with clinical parameters were evaluated using Spearman's rank correlation analysis. In addition, plasma exosome miRNAs profile was identified, followed by Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. RESULTS: Compared to healthy comparisons, body mass index (BMI), apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and ESS scores were increased in patients with severe OSA, while lowest oxygen saturation during sleep (LSaO2), mean oxygen saturation during sleep (MSaO2) and MoCA scores were decreased. Compared to the PBS group (NC) and the healthy comparison plasma-derived exosomes (NC-EXOS), the levels of GSDMD and Caspase-1 and IL-1ß, IL-6, IL-18 and TNF-α were increased significantly in the severe OSA plasma-derived exosomes (OSA-EXOS) coincubated with HT22 cells. Compared to the NC and NC-EXOS groups, the learning and memory ability of mice injected with OSA-EXOS was decreased, and the expression of GSDMD and Caspase-1 in hippocampus were significantly increased, along with the levels of IL-1ß, IL-6, IL-18 and TNF-α. Spearman correlation analysis found that clinical AHI in HCs and severe OSA patients was positively correlated with GSDMD and Caspase-1 in HT22 cells from NC-EXOS and OSA-EXOS groups, while negatively correlated with clinical MoCA. At the same time, clinical MoCA in HCs and severe OSA patients was negatively correlated with GSDMD and Caspase-1 in HT22 cells from NC-EXOS and OSA-EXOS groups. A unique exosomal miRNAs profile was identified in OSA-EXOS group compared to the NC-EXOS group, in which 28 miRNAs were regulated and several KEGG and GO pathways were identified. CONCLUSIONS: The results of this study show a hypothesis that plasma-derived exosomes from severe OSA patients promote pyroptosis and increased expression of inflammatory factors in vivo and in vitro, and lead to impaired cognitive function in mice, suggesting that OSA-EXOS can mediate CI through pyroptosis of hippocampal neurons. In addition, exosome cargo from OSA-EXOS showed a unique miRNAs profile compared to NC-EXOS, suggesting that plasma exosome associated miRNAs may reflect the differential profile of OSA related diseases, such as CI.

Clinical characteristics of IgG4-related disease with lung involvement in 14 patients. / 14例累及肺部的IgG4ç›¸å ³æ€§ç–¾ç— çš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: Immunoglobulin G4-related diseases (IgG4-RD) is a rare autoimmune disease, and there is no specific diagnostic test for patients with lung involvement yet. This study aims to summarize the clinical characteristics of IgG4-RD with lung involvement and improve the understanding and diagnosis of this disease. METHODS: All patients diagnosed with IgG4-RD in the Second Xiangya Hospital from December 2014 to February 2022 were re-diagnosed according to the recommendations of Chinese Expert Consensus on the Diagnosis and Treatment of IGG4-Related Diseases in 2021. The clinical data of 14 IgG4-RD patients with pulmonary abnormalities were collected and analyzed. RESULTS: Among the 14 patients, 11 were males and 3 were females, and the median age of diagnosis was 66 (22-82) years old. Six cases had respiratory symptoms such as cough, sputum and short breath. Extrapulmonary involvement was the most common in the glands of head and neck (6/14), followed by pancreas and bile duct (4/14). Elevated serum IgG4 level was found in all patients, and most (11/14) were accompanied by abnormal inflammatory markers. Patients' pulmonary imaging findings were diverse, the most common performances were mediastinal/hilar lymphadenopathy (12/14), followed by multiple pulmonary nodules (9/14), patchy density enhancement (7/14) and the increased broncho vascular bundles (6/14). Lung biopsy was performed in 9 patients, their pathology results showed lymphoplasmic cell infiltration, 5 cases of them had interstitial fibrosis, 2 cases with phlebitis, and extrapulmonary biopsy was performed in 8 patients. Immunohistochemical results of all the patients showed that the number of IgG4+ plasma cells was more than 10 per high magnification, and the ratio of IgG4/IgG was more than 40%. For treatment, 12 patients received hormone therapy, and 5 patients combined immunosuppressive therapy with hormone. 10 patients were in remission after treatment, while 2 patients were progressed. CONCLUSIONS: IgG4-RD with lung involvement is rare and has no specific clinical manifestation. Its pulmonary imaging is diverse. Diagnosis for it should combine with serum IgG4 level and pathological examination. Glucocorticoid is the first line treatment, and combination with immunosuppressant can help prevent disease recurrence.

Residents' cognition and attitude towards obstructive sleep apnea hypopnea syndrome. / ä½é™¢åŒ»å¸ˆå¯¹é˜»å¡žæ€§ç¡çœ å‘¼å¸æš‚åœä½Žé€šæ°”ç»¼åˆå¾çš„è®¤çŸ¥åŠæ€åº¦.

OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSAHS) may cause damage to many organs of the body and is a potentially fatal disease, which has a serious impact on health and quality of life for patients. Residents play an important role in the screening of OSAHS. This study aims to evaluate the cognition and attitude level of residents towards OSAHS, and to provide evidence for the intervention and diagnosis of the disease. METHODS: A cross-sectional survey of residents at a teaching hospital was conducted from December 1, 2021 to December 1, 2022. A questionnaire was used to assess residents' knowledge, attitudes, and confidence in dealing with OSAHS patients. RESULTS: Of the 200 residents who responded to the questionnaire, 183(91.5%) completed it. The average score on the knowledge scale of Obstructive Sleep Apnea Knowledge and Attitudes Questionnaire (OSAKA) for all residents in this study was 13.12±2.46. The knowledge score of internal medicine residents was higher than that of non-internal medicine residents (13.46±2.22 vs 12.33±2.83, P<0.05), and the mean knowledge score of residents with respiratory rotation experience was higher than that of residents without respiratory rotation experience (13.46±2.35 vs 12.69±2.56, P<0.05). The average score of the attitude/confidence scale on the OSAKA questionnaire for all residents in this study was 3.64±0.62. Of the 183 residents, 60.7% of residents considered OSAHS to be extremely important as a clinical disorder, 72.7% of residents were confident in the identification of OSAHS patients, but only 50.3% were confident in the management of OSAHS patients, and only 42.6% were confident in the management of patients treated with continuous positive pressure ventilation. There was a weak positive correlation among levels of knowledge, attitude, and confidence. CONCLUSIONS: Most residents are aware of the clinical importance of OSAHS, but their knowledge and confidence for OSAHS diagnosis and management are still insufficient, and they need to be trained to manage OSAHS patients.

Clinical characteristics of 32 cases of diffuse panbronchiolitis. / 32例弥漫性泛细支气管炎的临床特征.

OBJECTIVES: Diffuse panbronchiolitis (DPB) is a chronic airway inflammation with low specificity and its diagnosis is often missed or delayed. This study aims to summarize the clinical characteristics and treatment of DPB in order to improve the understanding and diagnosis of the disease. METHODS: The clinical data of 32 DPB patients were collected, analyzed and summarized from March 1, 2013 to March 1, 2022 in the Second Xiangya Hospital of Central South University. The basic information, clinical manifestations, laboratory tests, pulmonary function, imaging tests, treatment, and regression of patients were analyzed. RESULTS: A total of 32 patients were enrolled in the final analysis, with a male-to-female ratio at 1.67. The median age at symptom onset was 26.5 (11.0-69.0) years, and the median age of diagnosis was 47.5 (16.0-77.0) years. All patients presented with chronic cough and copious sputum production. A total of 26 patients had post activity shortness of breath and 14 patients had a positive result (blood cold agglutination test titer≥1꞉64). Pulmonary function examination was performed in 31 patients, 18 patients showed mixed pulmonary ventilation dysfunction, 12 patients showed obstructive pulmonary ventilation, and 1 patient had normal pulmonary ventilation function. A total of 31 patients had a bilateral, diffuse, small nodule pattern on chest CT. All patients were treated with macrolides. A total of 31 patients showed improvement, and 20 patients showed improvement in partial pressure of oxygen and blood oxygen saturation compared with before at discharge. A total of 12 patients were re-examined by chest CT after completing macrolides treatment, 6 cases showed less diffuse nodules, 5 cases showed no significant changes, and 1 case showed more diffuse nodules, which indicated the disease progression. Seven patients received pulmonary function tests after completing macrolides treatment, forced expiratory volume in one second (FEV1) and FEV1/forced vital capacitywere improved, but forced expiratory flow at 25% of vital capacity did not change significantly. CONCLUSIONS: The clinical manifestations of DPB are nonspecific. Early diagnosis and treatment are very important for the prognosis of patients.

Clinical characteristics of eosinophilic granulomatosis with polyangiitis involving the lung in 13 patients. / 13ä¾‹ç´¯åŠè‚ºéƒ¨çš„å—œé ¸æ€§è‚‰èŠ½è‚¿æ€§å¤šè¡€ç®¡ç‚Žçš„ä¸´åºŠç‰¹å¾.

OBJECTIVES: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis, which often starts with respiratory symptoms such as asthma, and it is difficult to make early clinical diagnosis.This study aims to improve the therapeutic level of EGPA with lung involvement via analyzing the clinical characteristics, diagnosis, and treatment . METHODS: We retrospectively analyzed the clinical data of 13 EGPA patients with lung involvement who were diagnosed from February 1, 2014 to July 31, 2021 in the Second Xiangya Hospital, Central South University. RESULTS: The ratio of male to female in 13 patients was 7꞉6. The patients were diagnosed at median age 52 (46-68) years old and 6 had been diagnosed as "bronchial asthma". Pulmonary clinical manifestations mainly included cough, expectoration, wheezing, and shortness of breath; while extra-pulmonary manifestations mainly included rash and subcutaneous mass, fever, limb numbness, muscle and joint pain, abdominal pain, etc. Peripheral blood tests of all patients showed that 11 patients had eosinophils ≥10%, 10 had elevated inflammatory indicators, and 3 were anti-neutrophil cytoplasmic antibody (ANCA) positive. The major lung imaging features were patches or strips of increased density, multiple nodules, bronchiectasis, bronchial wall thickening, exudation, mediastinal lymph nodes, and so on. Eight patients had sinusitis and 9 with abnormal electromyography. Extravascular eosinophil infiltration was found in 9 patients. Six patients with lung biopsy showed eosinophil, lymphocyte, and plasma cell infiltration, 3 patients were involved in small blood vessels, and 1 had granuloma. Pulmonary function tests were performed in 7 patients, 5 of them showed different degrees of pulmonary ventilation dysfunction, and 4 of them had diffusion dysfunction. Almost all patients respond well to glucocorticoid and immunosuppressant. CONCLUSIONS: EGPA is rare in clinical, often involving multiple systems with great harm and may combine with asthmatic manifestations. Pulmonary involvement is relatively common. However, due to insufficient recognition of this disease and huge heterogeneity of pulmonary imaging manifestations, misdiagnosis and missed diagnosis are easy to occur. Relevant laboratory, imaging, and biopsy examination should be performed as early as possible with comprehensive consideration of extrapulmonary involvement. Early identification has great significance to improve the diagnosis rate and prognosis of diseases.

TDP43/HDAC6/Prdx1 signaling pathway participated in the cognitive impairment of obstructive sleep apnea via regulating inflammation and oxidative stress.

Neuroinflammation and oxidative stress induced by intermittent hypoxia (IH) are associated with cognitive dysfunction in patients with obstructive sleep apnea (OSA). Recently, TAR DNA-binding protein 43 (TDP-43), histone deacetylase 6 (HDAC6), and peroxiredoxin 1 (Prdx1) have been reported to be involved in cognitive impairment in many degenerative diseases; however, the underlying mechanisms remain unclear. In the present study, subjects underwent polysomnography to diagnose OSA. Cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA) and peripheral blood samples were collected. HMC3 cells were treated with lipopolysaccharide (LPS) to mimic in vitro neuroinflammation. Western blotting was used to assess protein expression and ELISA to assess inflammation and oxidative stress levels. Participants were divided into three groups: healthy control (n = 20); mild to moderate OSA (n = 20); and severe OSA (n = 20). The MoCA scores in mild-moderate OSA and severe OSA were lower than those in healthy controls. Continuous positive airway pressure therapy was found to be effective for cognitive impairment in subjects with severe OSA (24.70 ± 1.81). Expression of TDP-43 and HDAC6 was increased in subjects with OSA, whereas Prdx1 expression was decreased. Alterations in these proteins were partially reversed after 12 weeks of CPAP treatment. Protein expression of TDP-43 and HDAC6 was negatively correlated with MoCA scores in patients with OSA, while Prdx1 expression exhibited the opposite trend. In LPS-treated HMC3 cells, TDP-43 and HDAC6 were upregulated, whereas Prdx1 expression was reduced. TDP-43 influenced the expression of Prdx1 by regulating HDAC6, and inflammation and oxidative stress varied with the expression of TDP-43. When a specific inhibitor of HDAC6 was used, LPS-induced inflammation and oxidative stress were alleviated by an elevated level of Prdx1. In summary, findings of the present study suggest that TDP-43 influenced Prdx1 by regulating HDAC6 expression and promoting neuroinflammation and oxidative stress. This process may be involved in the cognitive impairment experienced by patients with OSA and may provide potential therapeutic targets.

Role of epigenetic abnormalities and intervention in obstructive sleep apnea target organs.

ABSTRACT: Obstructive sleep apnea (OSA) is a common condition that has considerable impacts on human health. Epigenetics has become a rapidly developing and exciting area in biology, and it is defined as heritable alterations in gene expression and has regulatory effects on disease progression. However, the published literature that is integrating both of them is not sufficient. The purpose of this article is to explore the relationship between OSA and epigenetics and to offer better diagnostic methods and treatment options. Epigenetic modifications mainly manifest as post-translational modifications in DNA and histone proteins and regulation of non-coding RNAs. Chronic intermittent hypoxia-mediated epigenetic alterations are involved in the progression of OSA and diverse multiorgan injuries, including cardiovascular disease, metabolic disorders, pulmonary hypertension, neural dysfunction, and even tumors. This article provides deeper insights into the disease mechanism of OSA and potential applications of targeted diagnosis, treatment, and prognosis in OSA complications.

Prevalence and characteristics of pain in moderate-to-severe obstructive sleep apnea patients and effect of CPAP treatment.

Pain problems are common in patients with obstructive sleep apnea (OSA), but few studies have thoroughly evaluated pain in these patients. The objective of this study was to examine the prevalence and characteristics of pain in moderate-to-severe OSA patients and the effect of continuous positive airway pressure (CPAP) treatment. Moderate-to-severe OSA patients and healthy controls (HC) completed the Short Form McGill Pain Questionnaire (SF-MPQ) and a portion of the Brief Pain Inventory (BPI) Short Form to assess pain characteristics. The Epworth Sleepiness Scale (ESS), the Short Form-36 (SF-36), and the Hospital Anxiety and Depression Scale (HADS) were used to measure daytime sleepiness, health-related quality of life (HRQoL), and psychological status, respectively. The OSA patients with pain were divided into a CPAP-treated group and a CPAP-untreated group based on their adherence to CPAP. The subjects' pain intensity was reassessed after 3 months. The prevalence of pain was 57.5% in OSA versus 27.1% in HC (p < 0.001). Head (39.0%) accounted for the highest proportion of overall pain locations in subjects with OSA, with 28.8% of OSA patients experiencing headaches. Pain in OSA was associated with impaired HRQoL and psychological problems. Patients with very severe OSA had an increased risk for pain problems (OR: 7.000, p = 0.041). Associated factors for pain intensity in OSA included age, ESS ≥ 9.0, and lowest pulse oximetry (LSpO2) < 80.0%. Pain intensity in OSA decreased significantly after CPAP treatment (p < 0.001). Pain was prevalent among patients with moderate-to-severe OSA and was associated with depression, anxiety, and a lower HRQoL. Patients with very severe OSA had an increased risk for pain problems. The intensity of pain in OSA can be predicted by age, ESS ≥ 9.0, and LSpO2 < 80.0%, and it can be alleviated through CPAP treatment.

IL-33/ST2 mediating systemic inflammation and neuroinflammation through NF-kB participated in the neurocognitive impairment in obstructive sleep apnea.

Increasing evidence has noted that neuroinflammation contributes to the pathological processes of cognitive impairment of obstructive sleep apnea (OSA) patients. Interleukin (IL) -33/suppression of tumorigenicity 2 (ST2) signaling pathway plays well-defined roles in the inflammatory progression. The study aims to elucidate whether IL-33/ST2 signaling pathway plays a role in the cognitive dysfunction in patients with OSA via regulating neuroinflammation. We found that compared with control subjects, patients with OSA showed significantly elevated IL-33, ST2 and p65 nuclear factor-kappa B (NF-κB) levels in peripheral blood mononuclear cells (PBMCs) and inflammatory cytokines IL-6, IL-8 in serum, which were positively correlated with disease severity. Meanwhile, OSA patients exhibited a decline in Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, suggesting mild cognitive impairment. Continuous positive airway pressure (CPAP) treatment for 12 weeks significantly decreased the expression of IL-33, ST2, p65NF-κB, IL-6 and IL-8, as well as improved cognitive function of OSA patients. Moreover, the IL-33/ST2 signaling was closely correlated with sleep respiratory parameters and cognitive dysfunction. To further explore the underlying mechanism of IL-33/ST2 signaling pathway, we stimulated human microglial clone 3 (HMC3) cells with lipopolysaccharide (LPS) to mimic neuroinflammatory response in vitro. The results showed that LPS treatment led to an increase in IL-33 and ST2 expression in a dose- dependent manner, along with an increased secretion of IL-6 and IL-8. Functional experiments showed that knockdown of IL-33 ameliorated LPS-induced neuroinflammation via suppressing NF-κB signaling. Overall, current findings suggest that IL-33/ST2 signaling participated in the cognitive impairment of OSA patients by promoting neuroinflammation via activating NF-κB signaling. These results may provide a novel therapeutic target for treating OSA- associated cognitive dysfunction.