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Leukotriene pathways and in vitro adenotonsillar cell proliferation in children with obstructive sleep apnea
Ehab Dayyat1, Laura D Serpero1, Leila Kheirandish-Gozal1
1Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY.
Introduction:
The abundant expression of leukotrienes (LTs) and their receptors in adenotonsillar tissues of children with obstructive sleep apnea (OSA) suggest that LT antagonists could be useful in treating OSA.
Methods:
The effects of LTD4 and of LT receptor antagonists zileuton, montelukast, and BAY u9773 were examined on mixed cell cultures prepared from dissociated tonsils or adenoids harvested intraoperatively from children with polysomnographically diagnosed OSA. Proliferation was assessed by (3)[H]-thymidine incorporation, and inflammatory cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, IL-8, IL-10, and IL-12) was assessed in supernatants using enzyme-linked immunosorbent assay.
Results:
LTD4 elicited dose-dependent increases in adenotonsillar cell proliferation (p < 0.001; n = 12). All LT antagonists exhibited dose-dependent reductions in adenotonsillar cellular proliferation rates, with montelukast more than BAY u9773 more than zileuton (n = 14/group; p < 0.001). However, BAY u9773 showed partial agonist effects and increased cellular proliferation at higher concentrations (10(-4) mmol/L; p < 0.01; n = 12). LTD4 effects were partially blocked by montelukast and BAY u9773 but not by zileuton. All three antagonists reduced TNF-alpha, IL-6, and IL-12 concentrations, with selective changes in IL-8 and no effects on IL-10 levels.
Conclusions:
LT pathways mediate intrinsic proliferative and inflammatory signaling pathways in adenotonsillar tissues from children with OSA, and targeted pharmacologic disruption of these pathways may provide nonsurgical alternatives for prevention and treatment of this disease.
Insights
Leukotriene (LT) antagonists may treat obstructive sleep apnea (OSA) in children by reducing adenotonsillar cell proliferation and inflammation. These findings suggest potential non-surgical treatment options for pediatric OSA.
Area of Science:
- Pediatric Pulmonology
- Immunology
- Pharmacology
Background:
- Obstructive sleep apnea (OSA) in children is linked to high leukotriene (LT) expression in adenotonsillar tissues.
- LT antagonists show potential as a therapeutic strategy for pediatric OSA.
Purpose of the Study:
- To investigate the effects of LTD4 and LT receptor antagonists on adenotonsillar cell proliferation and inflammatory cytokine production in pediatric OSA.
- To evaluate the efficacy of zileuton, montelukast, and BAY u9773 in modulating these cellular responses.
Main Methods:
- Adenotonsillar cells from children with OSA were cultured and exposed to LTD4 and LT antagonists.
- Cell proliferation was measured using [3H]-thymidine incorporation.
- Inflammatory cytokine levels (TNF-alpha, IL-6, IL-8, IL-10, IL-12) were quantified via ELISA.
Main Results:
- LTD4 significantly increased adenotonsillar cell proliferation.
- Montelukast, BAY u9773, and zileuton dose-dependently reduced proliferation, with montelukast being most effective.
- All antagonists decreased TNF-alpha, IL-6, and IL-12 levels, indicating anti-inflammatory effects.
Conclusions:
- Leukotriene pathways are involved in the proliferation and inflammation of adenotonsillar tissues in pediatric OSA.
- Targeting these LT pathways with antagonists offers a potential non-surgical approach for managing pediatric OSA.
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