Chest
Volume 135, Issue 5, May 2009, Pages 1142-1149
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Original Research
Sleep Medicine
Leukotriene Pathways and In Vitro Adenotonsillar Cell Proliferation in Children With Obstructive Sleep Apnea

https://doi.org/10.1378/chest.08-2102Get rights and content

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]-α, 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-α, 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.

Section snippets

Subjects

The study was approved by the University of Louisville Human Research Committee, and informed consent was obtained from the legal caregiver of each participant. Assent was also obtained from children > 7 years of age. Consecutive children who underwent tonsillectomy for OSA were identified before surgery and recruited into the study. Overnight polysomnography was performed using standard methods that have been published in detail elsewhere.19 OSA was considered to be present when the

Study Population

A total of 52 children out of 54 suitable candidates with a clinical and polysomnographic diagnosis of OSA undergoing T&A agreed to participate and completed the study. The two children who did not participate were similar in every clinical aspect to those included in the study. Of the 52 collected samples, only 49 samples could be processed because in 3 samples, trypan blue exclusion tests showed excessive cell death (> 25%), which in preliminary experiments has been shown to be associated

Discussion

The present study shows that addition of LTD4 to a dissociated mixed cell culture system of adenoids and tonsils derived from children with OSA induces increased proliferative responses and release of proinflammatory cytokines. Furthermore, treatment with LT antagonists not only markedly reduces proliferation in a dose-dependent fashion, but it also reveals striking differences in the potencies of zileuton, montelukast, and the cysLT receptor 1 and 2 antagonist, BAY u9773. Interestingly, the

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  • Cited by (0)

    None of the authors have any conflict of interest to declare.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

    1

    Dr. Gozal is supported by National Institutes of Health grants Nos. HL-065270, HL-086662, and HL-083075, the Commonwealth of Kentucky Research Challenge for Excellence Trust Fund, and the Children's Foundation Endowment for Sleep Research.

    2

    Dr. Kheirandish-Gozal is supported by an investigator-initiated grant from the Merck Company.

    3

    Dr. Bhattacharjee is supported by a fellowship from Jazz Pharmaceuticals.

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