transforming-growth-factor-beta and Sleep-Apnea--Obstructive

To determine the effect of intranasal corticosteroid therapy on T-regulatory cells and other inflammatory cytokines in adenoid tissues in children with obstructive sleep apnea syndrome.. Randomized, prospective, exploratory study.. Academic pediatric otolaryngology practice in a tertiary care children's hospital.. Participants included 24 children between the ages of 2 and 12 years who were undergoing adenotonsillectomy for polysomnogram-documented obstructive sleep apnea syndrome.. Children were randomized to either no treatment (n = 13) or treatment with fluticasone furoate nasal spray, 55 μg/nostril daily (n = 11), for 2 weeks before adenotonsillectomy. Adenoid tissue was obtained at the time of the procedure.. The number of tissue T-regulatory cells, as determined by staining with FOXP3, CD4, and CD25, was the primary outcome measure. Staining for interleukin (IL)-10 and transforming growth factor-β protein by immunohistochemistry, and adenoid mononuclear cell spontaneous and induced release of cytokines (IL-10, IL-6, IL-12, IL-13, tumor necrosis factor, and transforming growth factor β) were secondary outcomes.. Cells isolated from fluticasone furoate nasal spray-treated adenoid tissue released significantly less IL-6 spontaneously as well as upon stimulation with anti-CD3 monoclonal antibody (P = .05) compared with nontreated adenoid tissue. There were no significant differences in the number of CD4/FOXP3-, CD25/FOXP3-, or transforming growth factor β-positive cells. Intensity of staining for IL-10 was also comparable between the groups.. In this study, we show reduction of IL-6, a proinflammatory cytokine, in adenoid tissue obtained from children with obstructive sleep apnea syndrome treated with fluticasone furoate nasal spray. This reduction could contribute to the clinical efficacy of this class of medications in the treatment of childhood obstructive sleep apnea syndrome.

Topics: Adenoidectomy; Adenoids; Administration, Intranasal; Androstadienes; Child; Child, Preschool; Female; Glucocorticoids; Humans; Immunohistochemistry; Interleukins; Male; Prospective Studies; Sleep Apnea, Obstructive; Staining and Labeling; Tonsillectomy; Transforming Growth Factor beta; Tumor Necrosis Factors

In patients with obstructive sleep apnoea (OSA), intermittent hypoxia induces overexpression of paraspeckle component (PSPC)1, a master modulator of transforming growth factor (TGF)-β signalling, which promotes cell cancer progression through epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. However, the persistence of intermittent hypoxia-induced effects on PSPC1, and their consequences in cancer patients are not known. To this effect, circulating PSPC1 levels were compared in patients with cutaneous melanoma with or without OSA, and their relationship with tumour aggressiveness along with the. In 292 cutaneous melanoma patients, sleep studies and serum levels of PSPC1 and TGF-β were evaluated. The effect of PSPC1 on expression of EMT and CSC transcription factors was assessed using melanoma cell lines with patient sera under both normoxia and intermittent hypoxia conditions.. PSPC1 levels were higher in patients with moderate-severe OSA compared with mild OSA or non-OSA patients. Serum levels of PSPC1 were associated with several cutaneous melanoma clinical aggressiveness indicators. Both intermittent hypoxia exposures and serum from OSA patients upregulated TGF-β expression and amplified the expression of transcription factors associated with EMT activation and acquisition of CSC characteristics.. In cutaneous melanoma patients, OSA severity is associated with higher PSPC1 serum levels, which jointly with intermittent hypoxia would enhance the self-reprogramming capabilities of EMT and CSC feature acquisition of melanoma cells, promoting their intrinsic aggressiveness.

Topics: Humans; Hypoxia; Melanoma; Melanoma, Cutaneous Malignant; Paraspeckles; RNA-Binding Proteins; Skin Neoplasms; Sleep Apnea, Obstructive; Transforming Growth Factor beta; Up-Regulation

Obstructive sleep apnea (OSA) is associated with severity of pneumonia; however, the mechanism by which OSA promotes lung cancer progression is unclear.. Twenty-five lung cancer patients were recruited to investigate the relationship between OSA and cancer-associated fibroblast (CAFs) activation. Lung cancer cells (A549) and WI38 fibroblast cells were used to explore the hypoxia-induced TGFβ expression using qPCR, Western blot, and ELISA. Wound healing and transwell assays were performed to evaluate cancer cell migration and invasion. A549 or A549-Luc + WI38 xenograft mouse models were established to detect the intermittent hypoxia (IH) associated with lung tumor growth and epithelial-mesenchymal transition (EMT). OSA promotes CAF activation and enrichment in lung cancer patients. Hypoxia (OSA-like treatment) activated TGFβ signaling in both lung cancer cells and fibroblasts, which promoted cancer cell migration and invasion, and enriched CAFs. IH promoted the progression and EMT process of lung cancer xenograft tumor. Co-inoculation of lung cancer cells and fibroblast cells could further promote lung cancer progression.. IH promotes lung cancer progression by upregulating TGFβ signaling, promoting lung cancer cell migration, and increasing the CAF activation and proportion of lung tumors.

Topics: Animals; Cancer-Associated Fibroblasts; Cell Line, Tumor; Humans; Hypoxia; Lung Neoplasms; Mice; Neoplasm Invasiveness; Sleep Apnea, Obstructive; Transforming Growth Factor beta

Topics: Continuous Positive Airway Pressure; Gene Expression Profiling; Humans; Hypoxia; Inflammation; Interferon-alpha; Interferon-gamma; Leukocytes; NF-kappa B; Oxygen Inhalation Therapy; Sequence Analysis, RNA; Signal Transduction; Sleep Apnea, Obstructive; Transcriptome; Transforming Growth Factor beta; Up-Regulation

Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.Quantitative reverse transcriptase PCR, flow cytometry and

Topics: Continuous Positive Airway Pressure; Cytotoxicity, Immunologic; Female; Humans; Hypoxia; Killer Cells, Natural; Male; Membrane Proteins; Middle Aged; Monocytes; Sleep Apnea, Obstructive; Transforming Growth Factor beta; Treatment Outcome; Tumor Escape

Chronic obstructive sleep apnea syndrome (OSAS) is considered to be associated with pulmonary diseases. However, the roles and mechanisms of OSA in pulmonary remodeling remain ambiguous. Thus, this study was aimed to elucidate the morphological and mechanical action of OSA in lung remodeling. In the present study, we employed a novel OSA model to mimic the OSA patient and investigate the role of OSA in pulmonary remodeling. We showed that pulmonary artery pressure of OSA group has no significant increased compared with the sham group. Nevertheless, we found that fibrotic tissue was predominantly located around the bronchi and vascular in the lung. Additionally, inflammatory cell infiltration was also detected in the peribonchial and perivascular space. The morphological change in OSA canines was ascertained by ultrastructure variation characterized by mitochondrial swelling, lamellar bodies degeneration and vascular smooth muscle incrassation. Moreover, sympathetic nerve sprouting was markedly increased in OSA group. Mechanistically, we showed that several pivotal proteins including collagen type I(CoLA1), GAP-43, TH and NGF were highly expressed in OSA groups. Furthermore, we found OSA could activated the expression of TGF-β, which subsequently suppressed miR-185 and promoted CoL A1 expression. This signaling cascade leads to pulmonary remodeling. In conclusion, Our data demonstrates that OSA can accelerate the progression of pulmonary remodeling through TGF-β/miR-185/CoLA1 signaling, which would potentially provide therapeutic strategies for chronic OSAS.

Topics: Animals; Bronchi; Cell Line; Chronic Disease; Collagen Type I; Disease Models, Animal; Dogs; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Inflammation; Lung; Male; MicroRNAs; Muscle, Smooth, Vascular; Sleep Apnea, Obstructive; Transforming Growth Factor beta

Obstructive sleep apnea (OSA) associated with chronic intermittent hypoxia (CIH) increases the morbidity and mortality of ischemic heart disease in patients. Yet, there is a paucity of preventive measures targeting the pathogenesis of CIH-induced myocardial injury. We examined the cardioprotective effect of melatonin against the inflammation, fibrosis and the deteriorated sarcoplasmic reticulum (SR) Ca(2+) homeostasis, and ischemia/reperfusion (I/R)-induced injury exacerbated by CIH. Adult male Sprague Dawley rats that had received a daily injection of melatonin (10 mg/kg) or vehicle were exposed to CIH treatment mimicking a severe OSA condition for 4 wk. Systolic pressure, heart weights, and malondialdehyde were significantly increased in hypoxic rats but not in the melatonin-treated group, when compared with the normoxic control. Levels of the expression of inflammatory cytokines (TNF-α, IL-6, and COX-2) and fibrotic markers (PC1 and TGF-β) were significantly elevated in the hypoxic group but were normalized by melatonin. Additionally, infarct size of isolated hearts with regional I/R was substantial in the hypoxic group treated with vehicle but not in the melatonin-treated group. Moreover, melatonin treatment mitigated the SR-Ca(2+) homeostasis in the cardiomyocyte during I/R with (i) Ca(2+) overloading, (ii) decreased SR-Ca(2+) content, (iii) lowered expression and activity of Ca(2+) -handling proteins (SERCA2a and NCX1),and (iv) decreased expressions of CAMKII and phosphorylated eNOS(ser1177). Furthermore, melatonin ameliorated the level of expression of antioxidant enzymes (CAT and MnSOD) and NADPH oxidase (p22 and NOX2). Results support a prophylactic usage of melatonin in OSA patients, which protects against CIH-induced myocardial inflammation and fibrosis with impaired SR-Ca(2+) handling and exacerbated I/R injury.

Topics: Animals; Antioxidants; Biomarkers; Cardiotonic Agents; Chronic Disease; Cytokines; Gene Expression Regulation; Heart Diseases; Hypoxia; Male; Melatonin; Myocardium; Rats; Sleep Apnea, Obstructive; Transforming Growth Factor beta

This study aims to explore the role of the Th17 to Treg cell ratio in children with OSA and its relationship with allergic rhinitis.. The study included 127 children diagnosed with OSA by polysomnography (PSG) testing and 29 children without OSA. The 127 children with OSA were divided into the following groups: OSA with moderate adenoidal hypertrophy (n=47), OSA with severe adenoidal hypertrophy (n=49), and OSA complicated by allergic rhinitis (AR) (n=31). The adenoids of the 29 children without OSA were mildly hypertrophic. We measured the number of Th17 and Treg cells, the levels of related serum cytokines in cellular secretions, and the expression of key transcription factors in both the peripheral blood and adenoid tissue. The Th17/Treg ratio was calculated and analyzed between groups. The numbers of Th17 and Treg cells were measured by flow cytometry; the secreted IL-17, IL-10, and TGF-β were measured by ELISA; and the expression levels of RORγt and Foxp3 were measured by RT-PCR.. Compared with the control group, OSA children exhibited a significant increase in the number of peripheral Th17 cells, Th17-related cytokine secretion (IL-17), and RORγt mRNA levels, whereas they exhibited a decrease in the number of Treg cells, Treg-related cytokine secretions (IL-10, TGF-β) and Foxp3 mRNA levels. The Th17/Treg ratio was higher (p<0.05) in the OSA groups than in the control group. The Th17/Treg ratio was correlated with the size of the adenoids. We also found that the Th17/Treg balance in OSA patients was complicated by allergic rhinitis; the increase was significantly larger in the AR group (p<0.05, p=0.021) than in OSA groups without AR. These results were observed in both the peripheral blood and local adenoid tissue.. The Th17/Treg imbalance may increase the risk of developing OSA, and AR may promote the development of the disease. These results provide an alternative explanation for OSA pathogenesis that warrants additional research and presents new directions for the prevention and treatment of OSA in children.

Topics: Adenoids; Child; Child, Preschool; Female; Flow Cytometry; Forkhead Transcription Factors; Humans; Hypertrophy; Interleukin-10; Interleukin-17; Lymphocyte Count; Male; Nuclear Receptor Subfamily 1, Group F, Member 3; Organ Size; Rhinitis, Allergic; RNA, Messenger; Sleep Apnea, Obstructive; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

Obstructive sleep apnea syndrome (OSAS) has emerged as a risk factor for cardiovascular disease. A prothrombotic state may affect coagulation and participate in the atherosclerotic process in subjects with OSAS. These alterations in coagulation seem to involve the plasminogen activation system. We evaluated the imbalances of the plasminogen activation system related to OSAS, and we assessed the effects of CPAP on the plasminogen activation system.. Thirty-nine subjects were submitted to a home-based cardiorespiratory sleep study, and 14 healthy subjects (apnea-hypopnea index < 5) were used as controls. Serum levels of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and active transforming growth factor-β (TGF-β) were measured. These molecules were reassessed in only 17 of the subjects after 1 month of CPAP.. PAI-1 and tPA were significantly higher in the subjects with OSAS compared with the controls, whereas TGF-β and uPA levels were lower. PAI-1 showed a significant positive correlation with the apnea-hypopnea index, percentage of time spent at O2 saturation < 90%, and oxygen desaturation index, whereas TGF-β was inversely related to all 3 of these parameters. After the CPAP therapy, PAI-1 significantly decreased, whereas TGF-β showed a significant increase, although the values did not reach those of the controls. uPA and tPA did not show significant differences after the treatment.. Our results suggest an imbalance of fibrinolysis related to OSAS and an improvement of the prothrombotic state after the CPAP treatment.

Topics: Aged; Case-Control Studies; Continuous Positive Airway Pressure; Female; Humans; Male; Middle Aged; Oxygen; Plasminogen Activator Inhibitor 1; Severity of Illness Index; Sleep Apnea, Obstructive; Thrombophilia; Tissue Plasminogen Activator; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator

Inflammation may contribute to upper airway pathophysiology in obstructive sleep apnoea (OSA). Our objective was to compare upper airway pro-inflammatory cytokine expression, oxidative stress and connective tissue deposition in severe (n = 25) versus mild (n = 17) OSA patients. Upper airway surgical specimens were separated by predominance of either mucosal or muscle tissue. Expression levels of interleukin (IL)-1α, IL-6, interferon-γ, RANTES (regulated on activation, normal T-cell expressed and secreted), transforming growth factor (TGF)-β and l-selectin were measured by ribonuclease protection assay. Oxidative stress was assessed via protein carbonyl group detection by immunoblotting. Histochemistry was employed for immunolocalisation of selected cytokines and connective tissue morphometry. In the severe OSA group, expression of IL-1α, IL-6 and TGF-β was significantly higher in mucosa-predominant tissues, whereas in muscle-predominant specimens, RANTES expression was greater in severe OSA. Increased protein carbonylation was observed in severe OSA within both mucosal and muscle compartments. Immunohistochemistry localised TGF-β to submucosal and perimuscular inflammatory cells, while IL-6 was primarily localised to myocytes. Consistent with the pro-fibrotic cytokine profile observed in mucosa-predominant tissue, morphometric analysis revealed greater submucosal and perimuscular connective tissue in severe OSA subjects. There is increased pro-inflammatory and pro-fibrotic cytokine expression, oxidative stress, and connective tissue deposition in upper airway tissues from severe versus mild OSA patients.

Topics: Adult; Cytokines; Female; Fibrosis; Gene Expression Regulation; Humans; Inflammation; Interleukin-1alpha; Interleukin-6; Male; Middle Aged; Oxidative Stress; Polysomnography; Sleep Apnea, Obstructive; Transforming Growth Factor beta

Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O(2) profile in patients with OSA. We exposed adult C57BL/6J mice to 3 mo of IH with a fraction of inspired oxygen (F(I)(O(2))) nadir of 5% 60 times/h during the 12-h light phase. Control mice were exposed to room air. Lung volumes were measured by quasistatic pressure-volume (PV) curves under anesthesia and by water displacement postmortem. Lungs were processed for morphometry, and the mean airspace chord length (Lm) and alveolar surface area were determined. Lung tissue was stained for markers of proliferation (proliferating cell nuclear antigen), apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling), and type II alveolar epithelial cells (surfactant protein C). Gene microarrays were performed, and results were validated by real-time PCR. IH increased lung volumes by both PV curves (air vs. IH, 1.16 vs. 1.44 ml, P < 0.0001) and water displacement (P < 0.01) without changes in Lm, suggesting that IH increased the alveolar surface area. IH induced a 60% increase in cellular proliferation, but the number of proliferating type II alveolocytes tripled. There was no increase in apoptosis. IH upregulated pathways of cellular movement and cellular growth and development, including key developmental genes vascular endothelial growth factor A and platelet-derived growth factor B. We conclude that IH increases alveolar surface area by stimulating lung growth in adult mice.

Topics: Animals; Base Sequence; Chronic Disease; Disease Models, Animal; DNA Primers; Gene Expression Profiling; Hypoxia; Lung; Male; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sleep Apnea, Obstructive; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Adenoid hypertrophy is the most common cause of upper airway obstruction and sleep-disordered breathing in children, yet its pathogenesis remains unclear. The identification of the novel helper T cell subsets, Th17 cells and regulatory T cells (Tregs) could provide new insight into our understanding of the mechanisms involved in the development of this condition. The purpose of this study is to evaluate the adenoidal lymphocyte subsets to describe the percentage of various lymphocyte subsets in hypertrophied adenoids and correlate them with symptom severity. Twenty consecutive children undergoing adenoidectomy were included, and lymphocytes were isolated from their adenoids. T cell subpopulations were detected by flow cytometry using a fluoresceinated monoclonal antibody directed against a number of cell markers (CD4+, CD8+, CD25+, FOXP3 IL17+, and others). We found a significant negative linear correlation between the Th17/Treg ratio and the patients' clinical scores (R = -0.71 p < 0.005). The correlation was independent of age and gender. Decreased ratios of Th17/Treg subpopulations may play a role in the pathogenesis of adenoid hypertrophy.

Topics: Adenoidectomy; Adenoids; Age Factors; B-Lymphocytes; CD3 Complex; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Child; Child, Preschool; Female; Forkhead Transcription Factors; Humans; Hypertrophy; Infant; Interferon-gamma; Interleukins; Lymphocyte Subsets; Male; Sex Characteristics; Sleep Apnea, Obstructive; Surveys and Questionnaires; T-Lymphocytes, Regulatory; Th17 Cells; Transforming Growth Factor beta

The levels of some pro- and anti-inflammatory cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-10, and transforming growth factor (TGF)-beta], were measured by enzyme-linked immunosorbent assay (ELISA) method in the plasma of patients affected by obstructive sleep apnea syndrome (OSAS) at 22:00 hours before polysomnographic recording and immediately after the first obstructive apnea causing an SaO2 below 85%. Significantly higher levels of TNF-alpha were found in OSAS patients assessed before polysomnography compared with the control group (P < 0.01). A slight but significant increase in the plasma levels of IL-6 was also present (P < 0.05). Conversely, a significant decrease in the plasma levels of IL-10 was evident at baseline in OSAS patients (P < 0.04). No significant difference emerged between the mean values of IL-1alpha and TGF-beta between OSAS patients and controls. The present data support a prevailing activation of the Th1-type cytokine pattern in OSAS patients, which is not associated with the severity and duration of OSAS. This can have important consequences for the outcome of OSAS patients, especially with regard to the increased risk for developing atherosclerosis and cardiovascular and cerebrovascular diseases. Immediately after the first obstructive apnea causing an SaO2 <85%, a significant variation was observed in the plasma levels of TNF-alpha in OSAS patients compared with those measured before the beginning of polysomnographic recording (P < 0.001). The role played by this further increase in TNF-alpha levels after the obstructive apnea in OSAS patients remains to be established in the light of the pathogenic mechanisms of this sleep disorder.

Topics: Analysis of Variance; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-1; Interleukin-10; Interleukin-6; Male; Middle Aged; Polysomnography; Sleep Apnea, Obstructive; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha