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1.
Sleep Med ; 67: 278-285, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32057628

RESUMO

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a sleep disorder caused by transient obstruction of the upper airway and results in intermittent hypoxia, sleep fragmentation, sympathetic nervous system activation, and arousal which can have an adverse effect on cardiovascular disease. It is theorized that OSA might intensify stroke injury. Our goal here was to develop a new model of experimental OSA and test its ability to aggravate behavioral and morphological outcomes following transient brain ischemia/reperfusion. METHODS: We used a 3D printed OSA device to expose C57BL6 mice to 3 h of OSA (obstructive apnea index of 20 events per hour) for three days. These mice were then subjected to ischemia/reperfusion using the middle cerebral artery occlusion model (MCAO) stroke and examined for overall survival, infarct size and neurological scoring. RESULTS: We found that OSA transiently decreased respiration and reduced oxygen saturation with bradycardia and tachycardia typical of human responses during apneic events. Brain injury from MCAO was significantly increased by OSA as measured by infarct size and location as well as by intensification of neurological deficits; mortality following MCAO was also increased in OSA animals. CONCLUSIONS: Our findings suggest that our new model of OSA alters respiratory and cardiovascular physiological functions and is associated with enhanced ischemia/reperfusion mediated injury in our non-invasive, OSA intensified model of stroke.

2.
Int J Obes (Lond) ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071426

RESUMO

The interest on a potential association between cancer and sleep-disordered breathing (SDB) has clearly gained substantial traction over the last several years. This novel relationship was initially explored in experimental models of obstructive sleep apnea (OSA) and showed that both intermittent hypoxia and sleep fragmentation, the two main hallmarks of OSA, promoted alterations in both tumorigenesis and tumor malignant properties. In parallel, an intriguing role of obesity as a major interactive player in the relationship between cancer and OSA was postulated in the following contextual settings: (1) obesity (with or without OSA) is associated with increased risk of some types of cancer (both incidence and aggressiveness), whereas obesity could be protective for others ("obesity paradox"); (2) OSA has been associated with increased risk for some types of cancer (independent of obesity), but not with others; (3) More than 80% of adult patients with OSA are overweight and >50% are obese; (4) both OSA and obesity exhibit oscillations in tissue oxygen tensions in peripheral organs such as adipose tissues. Further understanding these complex relationships become all the more important considering that the prevalence of obesity, cancer and OSA are all increasing worldwide. In parallel, experimental models of OSA provide biological plausibility constructs to the clinical and epidemiological findings, suggesting that the metabolic and inflammatory changes induced by chronic intermittent hypoxia and sleep fragmentation may foster or exacerbate immune and biomechanical alterations of the tumor microenvironment, including the expression of extracellular matrix components facilitating tumor progression.

3.
Menopause ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32108736

RESUMO

OBJECTIVE: Intermittent hypoxia (IH)-a hallmark of obstructive sleep apnea (OSA)-enhances lung cancer progression in mice via altered host immune responses that are also age and sex-dependent. However, the interactions of menopause with IH on tumor malignant properties remain unexplored. Here, we aimed to investigate lung cancer outcomes in the context of ovariectomy (OVX)-induced menopause in a murine model of OSA. METHODS: Thirty-four female mice (C57BL/6, 12-week-old) were subjected to bilateral OVX or to Sham intervention. Six months after surgery, mice were pre-exposed to either IH or room air (RA) for 2 weeks. Then, 10 lung carcinoma (LLC1) cells were injected subcutaneously in the left flank, with IH or RA exposures continued for 4 weeks. Tumor weight, tumor invasion, and spontaneous lung metastases were assessed. Tumor-associated macrophages (TAMs) were isolated and subjected to flow cytometry polarity evaluation along with assessment of TAMs modulation of LLC1 proliferation in vitro. To determine the effect of IH and OVX on each experimental variable, a two-way analysis of variance was performed. RESULTS: IH and OVX promoted a similar increase in tumor growth (∼2-fold; P = 0.05 and ∼1.74-fold; P < 0.05, respectively), and OVX-IH further increased it. Regarding lung metastasis, the concurrence of OVX in mice exposed to IH enhanced the number of metastases (23.7 ±â€Š8.0) in comparison to those without OVX (7.9 ±â€Š2.8; P < 0.05). The pro-tumoral phenotype of TAMS, assessed as M2/M1 ratio, was increased in OVX (0.06 ±â€Š0.01; P < 0.01) and IH (0.06 ±â€Š0.01; P < 0.01) compared with sham/RA conditions (0.14 ±â€Š0.03). The co-culture of TAMS with naive LLC1 cells enhanced their proliferation only under IH. CONCLUSION: In female mice, both the IH that is characteristically present in OSA and OVX as a menopause model emerge as independent contributors that promote lung cancer aggressiveness and seemingly operate through alterations in the host immune response.

4.
Respirology ; 25(3): 312-320, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31215129

RESUMO

BACKGROUND AND OBJECTIVE: Chronic intermittent hypoxia (CIH) is a major determinant of the cardiovascular morbidity associated with obstructive sleep apnoea (OSA), and the magnitude of CIH impact may be influenced by ageing. Here, we assessed the role of ageing in the early cardiovascular structural remodelling induced by severe CIH in a murine model of OSA. METHODS: Cardiovascular remodelling was assessed in young (2 months old, n = 20) and aged (18 months old, n = 20) C57BL/6 female mice exposed to CIH (20% O2 for 40 s, 5% O2 for 20 s) or normoxia (room air) for 8 weeks (6 h/day). RESULTS: Early vascular remodelling was observed in young mice exposed to CIH as illustrated by intima-media thickening (mean change: 4.6 ± 2.6 µm; P = 0.02), elastin fibre disorganization (mean change: 9.2 ± 4.5%; P = 0.02) and fragmentation (mean change: 2.5 ± 0.8%; P = 0.03), and collagen (mean change: 3.2 ± 0.6%; P = 0.001) and mucopolysaccharide accumulation (mean change: 2.4 ± 0.8%; P = 0.01). In contrast, vascular remodelling was not apparent in aged mice exposed to CIH. Furthermore, left ventricular perivascular fibrosis (mean change: 0.71 ± 0.1; P < 0.001) and hypertrophy (mean change: 0.17 ± 0.1; P = 0.038) were increased by CIH exposure in young mice, but not in aged mice. Principal component analysis identified similar cardiovascular alterations among the young mice exposed to CIH and both older mouse groups, suggesting that CIH induces premature cardiovascular senescence. CONCLUSION: Cardiovascular remodelling induced by severe CIH is affected by the age at which CIH onset occurs, suggesting that the deleterious cardiovascular effects associated with CIH may be more pronounced in younger populations, and such changes resemble chronological age-related declines in cardiovascular structural integrity.

6.
Sleep ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782790

RESUMO

Immunosurveillance is compromised in obstructive sleep apnea (OSA) patients as reflected by overexpression of the programmed death cell receptor and its ligand (PD-1/PD-L1) co-inhibitory axis. However, the contributions of intermittent hypoxia (IH) and sleep fragmentation (SF) are unclear. We therefore evaluated the expression of PD-1 and PD-L1 on immune cells from mice subjected to IH or SF, and in human cells exposed to IH, oxidative stress, or both conditions. Six-week-old male C57BL/6J mice were exposed to either IH or SF using previously established in vivo models. Moreover, human peripheral blood mononuclear cells (PBMC) were cultured overnight under normoxia, IH, hydrogen peroxide (H2O2) or both. Murine splenocytes and human PBMC were isolated, and labeled using surface-specific antibodies for flow cytometry analysis. Compared to control mice, IH induced higher expression of PD-L1 on F4/80 cells and of PD-1 on CD4+ and CD8+ T-cells, while no significant changes emerged after SF. In vitro models of IH and oxidative stress showed similar changes for expression of PD-L1 on human monocytes and PD-1 on CD4+ T-cells. Furthermore, H2O2 increased PD-1 expression on CD8+ T-cells, compromising their cytotoxic capacity assessed by perforin expression, similar to IH. No evidence of synergistic effects was apparent. Therefore, PD-1/PD-L1 upregulation reported in OSA patients appears to be preferentially mediated by IH rather than SF.

8.
Breathe (Sheff) ; 15(3): 234-240, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31508161

RESUMO

The Lung Science Conference and the Sleep and Breathing Conference 2019 brought together leading experts in the field to discuss the latest cutting-edge science, as well as various career development opportunities for early career members http://bit.ly/2XNX6V6.

9.
Front Physiol ; 10: 1047, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474879

RESUMO

Increasing evidence shows that lungs can be damaged by inhalation of nanoparticles (NPs) at environmental and occupational settings. Recent findings have associated the exposure to iron oxide (Fe2O3) and titanium dioxide (TiO2) - NPs widely used in biomedical and clinical research - with pulmonary oxidative stress and inflammation. Although changes on cellular mechanics could contribute to pulmonary inflammation, there is no information regarding the effects of Fe2O3 and TiO2 on alveolar epithelial cell biomechanics. The aim was to investigate the NPs-induced biomechanical effects in terms of cell stiffness and traction forces exerted by human alveolar epithelial cells. Cell Young's modulus (E) measured by atomic force microscopy in alveolar epithelial cells significantly decreased after exposure to Fe2O3 and TiO2 (∼28 and ∼25%, respectively) compared to control conditions. Moreover, both NPs induced a similar reduction in the traction forces exerted by the alveolar epithelial cells in comparison to the control conditions. Accordingly, immunofluorescence images revealed a reduction of actomyosin stress fibers in response to the exposure to NPs. However, no inflammatory response was detected. In conclusion, an acute exposure of epithelial pulmonary cells to Fe2O3 and TiO2 NPs, which was mild since it was non-cytotoxic and did not induce inflammation, modified cell biomechanical properties which could be translated into damage of the epithelial barrier integrity, suggesting that mild environmental inhalation of Fe2O3 and TiO2 NPs could not be innocuous.

10.
Sci Rep ; 9(1): 11443, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391506

RESUMO

Obstructive sleep apnea syndrome (OSA) promotes aortic dilatation, increased stiffness and accelerated atherosclerosis, but the mechanisms of vascular remodelling are not known. We aimed to assess vascular remodelling, its mechanisms, and the effect of mesenchymal stem cells (MSC) infusions in a clinically relevant rat model of chronic OSA involving recurrent airway obstructions leading thoracic pressure swings and intermittent hypoxia/hypercapnia (OSA-rats). Another group of rats were placed in the same setup without air obstructions (Sham-rats) and were considered controls. Our study demonstrates that chronic, non-invasive repetitive airway obstructions mimicking OSA promote remarkable structural changes of the descending thoracic aorta such as eccentric aortic hypertrophy due to an increased wall thickness and lumen diameter, an increase in the number of elastin fibers which, in contrast, get ruptured, but no changes in tunica media fibrosis. As putative molecular mechanisms of the OSA-induced vascular changes we identified an increase in reactive oxygen species and renin-angiotensin system markers and an imbalance in oxide nitric synthesis. Our results also indicate that MSC infusion blunts the OSA-related vascular changes, most probably due to their anti-inflammatory properties.

11.
J Appl Physiol (1985) ; 127(3): 745-752, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369330

RESUMO

Obstructive sleep apnea (OSA), characterized by events of hypoxia-reoxygenation, is highly prevalent in pregnancy, negatively affecting the gestation process and particularly the fetus. Whether the consequences of OSA for the fetus and offspring are mainly caused by systemic alterations in the mother or by a direct effect of intermittent hypoxia in the fetus is unknown. In fact, how apnea-induced hypoxemic swings in OSA are transmitted across the placenta remains to be investigated. The aim of this study was to test the hypothesis, based on a theoretical background on the damping effect of oxygen transfer in the placenta, that oxygen partial pressure (Po2) swings resulting from obstructive apneas mimicking OSA are mitigated in the fetal circulation. To this end, four anesthetized ewes close to term pregnancy were subjected to obstructive apneas consisting of 25-s airway obstructions. Real-time Po2 was measured in the maternal carotid artery and in the umbilical vein with fast-response fiber-optic oxygen sensors. The amplitudes of Po2 swings in the umbilical vein were considerably smaller [3.1 ± 1.0 vs. 21.0 ± 6.1 mmHg (mean ± SE); P < 0.05]. Corresponding estimated swings in fetal and maternal oxyhemoglobin saturation tracked Po2 swings. This study provides novel insights into fetal oxygenation in a model of gestational OSA and highlights the importance of further understanding the impact of sleep-disordered breathing on fetal and offspring development.NEW & NOTEWORTHY This study in an airway obstruction sheep model of gestational sleep apnea provides novel data on how swings in oxygen partial pressure (Po2) translate from maternal to fetal blood. Real-time simultaneous measurement of Po2 in maternal artery and in umbilical vein shows that placenta transfer attenuates the magnitude of oxygenation swings. These data prompt further investigation of the extent to which maternal apneas could induce similar direct oxidative stress in fetal and maternal tissues.

13.
ERJ Open Res ; 5(3)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31304175

RESUMO

The 2018 European Respiratory Society (ERS) International Congress held in Paris, France, served as a platform to discover the latest research on respiratory diseases, the improvement in their treatments and patient care. Specifically, the scientific sessions organised by ERS Assembly 4 provided novel insights into sleep disordered breathing and fresh knowledge in respiratory physiology, stressing its importance to understanding and treating respiratory diseases. This article, divided by session, will summarise the most relevant studies presented at the ERS International Congress. Each session has been written by early career members specialised in the different fields of this interdisciplinary assembly.

14.
Breathe (Sheff) ; 15(2): 128-130, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31191724

RESUMO

The #ERSCongress is the largest respiratory conference worldwide. This article points out why @ERSTalk Early Career Members can especially benefit from attending this huge event and gives upcoming fellowship deadlines. http://ow.ly/3GQ530o8Ezh.

16.
Breathe (Sheff) ; 15(1): 60-63, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30838061

RESUMO

Preview for Early Career Members on the Sleep and Breathing Conference 2019 and report on international collaboration between the European Respiratory Society and the Chinese Thoracic Society http://ow.ly/IUpi30n2DSL.

17.
Front Oncol ; 9: 43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30788287

RESUMO

Hypoxia is a common characteristic of many solid tumors that has been associated with tumor aggressiveness. Limited diffusion of oxygen generates a gradient of oxygen availability from the blood vessel to the interstitial space and may underlie the recruitment of macrophages fostering cancer progression. However, the available data based on the recruitment of circulating cells to the tumor microenvironment has been so far carried out by conventional co-culture systems which ignore the hypoxic gradient between the vessel to the tumor interstitium. Here, we have designed a novel easy-to-build cell culture device that enables evaluation of cellular cross-talk and cell migration while they are being simultaneously exposed to different oxygenation environments. As a proof-of-concept of the potential role of differential oxygenation among interacting cells we have evaluated the activation and recruitment of macrophages in response to hypoxic melanoma, breast, and kidney cancer cells. We found that hypoxic melanoma and breast cancer cells co-cultured with normoxic macrophages enhanced their directional migration. By contrast, hypoxic kidney cells were not able to increase their recruitment. We also identified well-described hypoxia-induced pathways which could contribute in the immune cell recruitment (VEGFA and PTGS2 genes). Moreover, melanoma and breast cancer increased their proliferation. However, oxygenation levels affected neither kidney cancer cell proliferation nor gene expression, which in turn resulted in no significant changes in macrophage migration and polarization. Therefore, the cell culture device presented here provides an excellent opportunity for researchers to reproduce the in vivo hypoxic gradients in solid tumors and to study their role in recruiting circulating cells to the tumor in specific types of cancer.

18.
Respirology ; 24(7): 684-692, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30656807

RESUMO

BACKGROUND AND OBJECTIVE: In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death-1 (PD-1) receptor and its ligand (PD-L1). Because the risk of OSA-related cancer depends on age, we assessed PD-L1/PD-1 expression in middle-aged and older patients with OSA as well as in a murine model. METHODS: PD-L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD-L1 expression on monocytes and plasma PD-L1 protein levels. Moreover, we analysed PD-L1 expression on an in vivo IH model with old and young mice. RESULTS: In subjects up to 55 years of age, severe OSA increased PD-L1 surface protein and mRNA level expression on monocytes and soluble-PD-L1 protein concentration in plasma compared to HV. PD-L1 and hypoxia-induced factor (HIF)-1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD-L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF-1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD-L1 expression in monocytes was related to HIF-1α expression in young patients with OSA. CONCLUSION: PD-L1 upregulation in patients with OSA as a consequence of HIF-1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity.

19.
Eur Respir J ; 53(2)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30487198

RESUMO

Obstructive sleep apnoea (OSA) upregulates the programmed cell death-1 receptor and its ligand (PD-L1) pathway, potentially compromising immunosurveillance. We compared circulating levels of soluble PD-L1 (sPD-L1) in patients with cutaneous melanoma according to the presence and severity of OSA, and evaluated relationships with tumour aggressiveness and invasiveness.In a multicentre observational study, 360 patients with cutaneous melanoma underwent sleep studies, and serum sPD-L1 levels were assayed using ELISA. Cutaneous melanoma aggressiveness indices included mitotic rate, Breslow index, tumour ulceration, Clark level and tumour stage, and sentinel lymph node (SLN) metastasis was recorded as a marker of invasiveness.sPD-L1 levels were higher in severe OSA compared to mild OSA or non-OSA patients. In OSA patients, sPD-L1 levels correlated with Breslow index and were higher in patients with tumour ulceration, advanced primary tumour stages or with locoregional disease. The incorporation of sPD-L1 to the classic risk factors to SLN metastasis led to net improvements in the classification of 27.3%.Thus, sPD-L1 levels are increased in melanoma patients with severe OSA, and, in addition, might serve as a potential biomarker of cutaneous melanoma aggressiveness and invasiveness in this group of subjects.

20.
J Biomech ; 83: 315-318, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30527389

RESUMO

INTRODUCTION: Application of lipopolysaccharide (LPS) is a widely employed model to mimic acute respiratory distress syndrome (ARDS). Available data regarding LPS-induced biomechanical changes on pulmonary epithelial cells are limited only to P. aeruginosa LPS. Considering that LPS from different bacteria could promote a specific mechanical response in epithelial cells, we aim to assess the effect of E. coli LPS, widely employed as a model of ARDS, in the biomechanics of alveolar epithelial cells. METHODS: Young's modulus (E) of alveolar epithelial cells (A549) was measured by atomic force microscopy every 5 min throughout 60 min of experiment after treatment with LPS from E. coli (100 µg/mL). The percentage of cells presenting actin stress fibers (F-actin staining) was also evaluated. Control cells were treated with culture medium and the values obtained were compared with LPS-treated cells for each time-point. RESULTS: Application of LPS induced significant increase in E after 20 min (77%) till 60 min (104%) in comparison to controls. Increase in lung epithelial cell stiffness induced by LPS was associated with a higher number of cells presenting cytoskeletal remodeling. CONCLUSIONS: The observed effects of E. coli LPS on alveolar epithelial cells suggest that this widely-used LPS is able to promote a quick formation of actin stress fibers and stiffening cells, thereby facilitating the disruption of the pulmonary epithelial barrier.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Escherichia coli/química , Lipopolissacarídeos/farmacologia , Fenômenos Mecânicos/efeitos dos fármacos , Células A549 , Células Epiteliais Alveolares/metabolismo , Fenômenos Biomecânicos/efeitos dos fármacos , Humanos
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