Leukotriene pathways and in vitro adenotonsillar cell proliferation in children with obstructive sleep apnea.
BACKGROUND
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.
Dayyat
Ehab
E
Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY.
Serpero
Laura D
LD
Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY.
Kheirandish-Gozal
Leila
L
Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY.
Goldman
Julie L
JL
Department of Surgery, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY; Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY.
Snow
Ayelet
A
Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY.
Bhattacharjee
Rakesh
R
Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY.
Gozal
David
D
Department of Pediatrics, Division of Sleep Medicine and Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY. Electronic address: dgozal@peds.bsd.uchicago.edu.
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000234:Adenoids / Q000166:cytology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007378:Interleukins / Q000032:analysis; D020024:Leukotriene Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D017998:Leukotriene D4 / Q000494:pharmacology; D014066:Palatine Tonsil / Q000166:cytology*; D017286:Polysomnography; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D020181:Sleep Apnea, Obstructive / Q000188:drug therapy / Q000378:metabolism*; D013440:Sulfides
D000085:Acetates; C071435:BAY u9773; D003521:Cyclopropanes; D007378:Interleukins; D020024:Leukotriene Antagonists; D011804:Quinolines; D013189:SRS-A; D013440:Sulfides; D017998:Leukotriene D4; C093875:montelukast; C063449:zileuton; D006918:Hydroxyurea