The FOXP3 gene, which regulates expression of T regulatory lymphocytes, is more likely to display increased methylation among children with OSA who exhibit increased systemic inflammatory responses. Thus, epigenetic modifications may constitute an important determinant of inflammatory phenotype in OSA, and FOXP3 DNA methylation levels may provide a potential biomarker for end-organ vulnerability.

Obesity has emerged as one of the most prevalent diseases in the western hemisphere, and its prevalence continues to increase. Obese children are at increased risk for several disorders, particularly affecting the cardiovascular and metabolic systems. The mechanisms leading to obesity-related morbidities are likely multifactorial, and include activation of inflammatory pathways ultimately leading to end-organ injury. Furthermore, the concurrent presence of obesity and other diseases facilitated by increased fat deposition poses a theoretical risk of accentuating obesity-related complications. One of the conditions whose prevalence is increased by obesity in childhood is the obstructive sleep apnea syndrome (OSAS). OSAS in non-obese children may lead to co-morbidities that are not only remarkably similar to those associated with obesity but recruit similar inflammatory mechanisms as those activated by obesity, suggesting that the two disorders may amplify each other and synergistically augment the magnitude of their respective adverse consequences. The objective of this review is to critically review the effects of both obesity and OSAS in inducing systemic inflammation in children and will examine the latest evidence pertaining to the up-regulation of specific inflammatory mediators.

Rationale: Sleep studies are laborious, expensive, inaccessible, and inconvenient for diagnosing obstructive sleep apnea (OSA) in children. Objectives: To examine whether the urinary proteome uncovers specific clusters that are differentially expressed in the urine of children with OSA. Methods: Two-dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry proteomics followed by validation with western blot of ELISA. Measurements and Main Results: Morning urine proteins from 60 children with polysomnographically confirmed OSA and from matched children with primary snoring (n 5 30) and control subjects (n 5 30) were assessed. A total of 16 proteins that are differentially expressed in OSA were identified, and 7 were confirmed by either immunoblots or ELISA. Among the latter, receiver-operator curve analyses of urinary concentrations of uromodulin, urocortin-3, orosomucoid-1, and kallikrein assigned favorable predictive properties to these proteins. Furthermore, combinatorial approaches indicated that the presence of values beyond the calculated cutoff concentrations for three or more of the proteins yielded a sensitivity of 95% and a specificity of 100%. Conclusions: Proteomic approaches reveal that pediatric OSA is associated with specific and consistent alterations in urinary concentrations of specific protein clusters. Future studies aiming to validate this approach as a screening method of habitually snoring children appears warranted.

Adenotonsillar hypertrophy is the major pathophysiological mechanism underlying obstructive sleep apnea (OSA) and recurrent tonsillitis (RI) in children. The increased expression of various mediators of the inflammatory response in tonsils of patients with OSA prompted our hypothesis that the enhanced local and systemic inflammation in children with OSA would promote tonsillar proliferation. Mixed cell cultures from tonsils recovered during adenotonsillectomy in children with OSA and RI were established, and proliferative rates were assessed. Cells were also cultured to determine the levels of proinflammatory cytokines and antioxidant protein levels and mRNA expression. Global cell proliferative rates from OSA tonsils were significantly higher than RI (p Ͻ 0.01), with CD3 ϩ , CD4 ϩ , and CD8 ϩ cell proliferation being higher in OSA (p Ͻ 0.05). Moreover, proinflammatory cytokines, such as TNF-␣, IL-6, and IL-1␣, were highly expressed in OSA-derived tonsils. Furthermore, thioredoxin (TRX), an antioxidant protein, was also highly expressed in OSA tonsils at the mRNA and protein levels (p Ͻ 0.01). Thus, T cells are in a highly proliferative state in the tonsils of children with OSA and are associated with increased production of proinflammatory cytokines and TRX, when compared with children with RI. (1). In a series of previous studies from our and other laboratories, it has become apparent that children with OSA are at increased risk for a vast array of morbidities, principally affecting the CNS and cardiovascular systems (2-9). Adenotonsillar hypertrophy has been recognized as the major pathophysiological contributor of OSA in children (10), and it plays an important role as well in recurrent tonsillitis (RI) (11). Consequently, adenotonsillectomy (T&A) is currently the first line of treatment for children with these conditions (12,13). However, the exact mechanisms underlying follicular lymphoid proliferation and hyperplasia remain extremely poorly understood. In adults, there are several lines of evidence, suggesting that both local upper airway and systemic inflammation are implicated in the pathophysiology of this a priori mechanical dysfunction of the upper airway. For example, the number of immune cells is substantially increased in the upper airway mucosa and the muscle of adults with OSA (14). Similar increases in regional and systemic inflammatory markers have also been reported in children with OSA (15-17). In addition, increased expression of mediators of the inflammatory response, such as cysteinyl leukotrienes and glucocorticoid receptors, is consistently found in tonsillar tissues of children with OSA (18 -20). Therefore, we hypothesized that cellular proliferation of tonsillar tissues in children with OSA would differ from that of children with RI, possibly reflecting different pathologic mechanisms and cell type involvement leading to the enlargement of upper airway lymphoid tissue in these two conditions. METHODS Subjects. The study was approved by the University of Louisville HumanRese...

Endothelial dysfunction is frequently present in OSAS. Variance in endothelial functional phenotype may not only reside in the individual susceptibility but also in the ability to recruit endothelial repair mechanisms.