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      Plasma Extracellular Vesicles in Children with OSA Disrupt Blood–Brain Barrier Integrity and Endothelial Cell Wound Healing In Vitro

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          Abstract

          Pediatric obstructive sleep apnea (P-OSA) is associated with neurocognitive deficits and endothelial dysfunction, suggesting the possibility that disruption of the blood–brain barrier (BBB) may underlie these morbidities. Extracellular vesicles (EVs), which include exosomes, are small particles involved in cell–cell communications via different mechanisms and could play a role in OSA-associated end-organ injury. To examine the roles of EVs in BBB dysfunction, we recruited three groups of children: (a) absence of OSA or cognitive deficits (CL, n = 6), (b) OSA but no evidence of cognitive deficits (OSA-NC(−), n = 12), and (c) OSA with evidence of neurocognitive deficits (OSA-NC(+), n = 12). All children were age-, gender-, ethnicity-, and BMI-z-score-matched, and those with OSA were also apnea–hypopnea index (AHI)-matched. Plasma EVs were characterized, quantified, and applied on multiple endothelial cell types (HCAEC, HIAEC, human HMVEC-D, HMVEC-C, HMVEC-L, and hCMEC/D3) while measuring monolayer barrier integrity and wound-healing responses. EVs from OSA children induced significant declines in hCMEC/D3 transendothelial impedance compared to CL ( p < 0.001), and such changes were greater in NC(+) compared to NC(−) ( p < 0.01). The effects of EVs from each group on wound healing for HCAEC, HIAEC, HMVED-d, and hCMEC/D3 cells were similar, but exhibited significant differences across the three groups, with evidence of disrupted wound healing in P-OSA. However, wound healing in HMVEC-C was only affected by NC(+) ( p < 0.01 vs. NC(−) or controls (CO). Furthermore, no significant differences emerged in HMVEC-L cell wound healing across all three groups. We conclude that circulating plasma EVs in P-OSA disrupt the integrity of the BBB and exert adverse effects on endothelial wound healing, particularly among OSA-NC(+) children, while also exhibiting endothelial cell type selectivity. Thus, circulating EVs cargo may play important roles in the emergence of end-organ morbidity in pediatric OSA.

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          Most cited references61

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          Diagnosis and management of childhood obstructive sleep apnea syndrome.

          This technical report describes the procedures involved in developing recommendations on the management of childhood obstructive sleep apnea syndrome (OSAS). The literature from 1999 through 2011 was evaluated. A total of 3166 titles were reviewed, of which 350 provided relevant data. Most articles were level II through IV. The prevalence of OSAS ranged from 0% to 5.7%, with obesity being an independent risk factor. OSAS was associated with cardiovascular, growth, and neurobehavioral abnormalities and possibly inflammation. Most diagnostic screening tests had low sensitivity and specificity. Treatment of OSAS resulted in improvements in behavior and attention and likely improvement in cognitive abilities. Primary treatment is adenotonsillectomy (AT). Data were insufficient to recommend specific surgical techniques; however, children undergoing partial tonsillectomy should be monitored for possible recurrence of OSAS. Although OSAS improved postoperatively, the proportion of patients who had residual OSAS ranged from 13% to 29% in low-risk populations to 73% when obese children were included and stricter polysomnographic criteria were used. Nevertheless, OSAS may improve after AT even in obese children, thus supporting surgery as a reasonable initial treatment. A significant number of obese patients required intubation or continuous positive airway pressure (CPAP) postoperatively, which reinforces the need for inpatient observation. CPAP was effective in the treatment of OSAS, but adherence is a major barrier. For this reason, CPAP is not recommended as first-line therapy for OSAS when AT is an option. Intranasal steroids may ameliorate mild OSAS, but follow-up is needed. Data were insufficient to recommend rapid maxillary expansion.
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            The dynamic blood-brain barrier.

            With the endothelium as its central unit, the blood-brain barrier (BBB) is a complex multicellular structure separating the central nervous system (CNS) from the systemic circulation. Disruption of the BBB has now been implicated in a multitude of acute and chronic CNS disorders indicating the potentially devastating effects of BBB breakdown on brain function. However, the healthy BBB is not an impermeable wall, but rather a communication 'centre', responding to and passing signals between the CNS and blood. New studies are identifying BBB-specific transport pathways that tightly regulate the entry and exit of molecules to and from the brain. They are revealing a highly plastic barrier in which dynamic changes in BBB components like paracellular tight junction complexes can contribute to BBB maintenance. Here, we provide a succinct overview of the current state-of-play in BBB research and summarize novel findings into BBB regulation in homeostatic regulation of the brain.
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              The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications.

              Human pathologies such as vascular malformations, hemorrhagic stroke, and edema have been associated with defects in the organization of endothelial cell junctions. Understanding the molecular basis of these diseases requires different integrated approaches which include basic cell biology, clinical studies, and studies in animal models such as mice and zebrafish. In this review we discuss recent findings derived from these approaches and their possible integration in a common picture.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                10 December 2019
                December 2019
                : 20
                : 24
                : 6233
                Affiliations
                Child Health Research Institute, Department of Child Health, University of Missouri School of Medicine, Columbia, MO 65201, USA; khalyfaa@ 123456missouri.edu (A.K.); gozald@ 123456health.missouri.edu (D.G.)
                Author notes
                [* ]Correspondence: gozall@ 123456health.missouri.edu ; Tel.: +1-573-882-6882
                Author information
                https://orcid.org/0000-0002-5811-5148
                https://orcid.org/0000-0001-8195-6036
                Article
                ijms-20-06233
                10.3390/ijms20246233
                6941040
                31835632
                1a00474f-1557-4db1-818f-da2b425103db
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 November 2019
                : 08 December 2019
                Categories
                Article

                Molecular biology
                pediatric osa,extracellular vesicles (evs), exosomes,neurocognitive deficits,wound healing,hcmec/d3 cells,electric cell–substrate impedance sensing (ecis)

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