Expression of leukotriene biosynthetic enzymes in tonsillar tissue of children with obstructive sleep apnea: a prospective nonrandomized study.

IMPORTANCE: Cysteinyl leukotrienes (CysLTs) potentially promote adenotonsillar hypertrophy in children with obstructive sleep apnea (OSA). Previous studies have identified CysLTs and their receptors in tonsillar tissue from children with OSA. OBJECTIVE: To demonstrate expression of the leukotriene biosynthetic enzymes 5-lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP), leukotriene A(4) hydrolase (LTA(4)H), and leukotriene C(4) synthase (LTC(4)S) in T and B tonsillar lymphocytes from pediatric patients with OSA. It was hypothesized that children with OSA have greater expression of biosynthetic enzymes for CysLTs (5-LO, FLAP, and LTC(4)S) in their tonsillar tissue than do children with recurrent tonsillitis (RT), who were enrolled as controls. DESIGN, SETTING, AND PARTICIPANTS: This prospective, nonrandomized study was performed at a tertiary care university hospital on 13 children with OSA and adenotonsillar hypertrophy undergoing adenotonsillectomy and 12 children without OSA also undergoing tonsillectomy for RT. Tonsillar tissue from children with OSA or RT was examined for 5-LO, FLAP, LTA(4)H, and LTC(4)S expression under real time-quantitative polymerase chain reaction (RT-qPCR), flow cytometry (FC), and confocal laser scanning microscopy (CM). MAIN OUTCOMES AND MEASURES: Expression of biosynthetic enzymes for CysLTs (5-LO, FLAP, and LTC(4)S) was the main outcome measure. Patients with OSA and control patients with RT were compared for numbers of copies of 5-LO, FLAP, and LTC(4)S messenger RNA (by RT-qPCR) in T or B tonsillar lymphocytes and proportions of CD3(+) or CD19(+) tonsillar lymphocytes that expressed 5-LO, FLAP, and LTC(4)S (by FC). RESULTS: Messenger RNA for all 4 enzymes was detected in T and B lymphocytes from both study groups, and expression of all biosynthetic enzymes was demonstrated in participants with OSA and RT by FC. Patients with OSA differed from controls in the proportions (median [10th-90th percentile]) of LTC(4)S(+) CD3(+) T lymphocytes (23.31% [8.64%-50.07%] vs 10.81% [3.48%-23.32%], respectively) (P = .01) and LTC(4)S(+) CD19(+) B lymphocytes (20.66% [14.62%-65.77%] vs 12.53% [2.87%-36.64%], respectively) (P = .01) detected by FC. Immunoreactivity for the 4 enzymes was detected by CM in B lymphocytes of mantle zones and T lymphocytes of extrafollicular areas. CONCLUSIONS AND RELEVANCE: Leukotriene biosynthetic enzymes are expressed in tonsillar lymphocytes, and the previously reported detection of CysLTs in tonsillar tissue from children with OSA may be attributed to endogenous synthesis. Enhanced expression of LTC(4)S is a potential target for pharmacologic interventions in OSA.

Cysteinyl leukotriene receptors in tonsillar B- and T-lymphocytes from children with obstructive sleep apnea.

OBJECTIVES: Cysteinyl leukotrienes have been implicated in the pathogenesis of adenotonsillar hypertrophy in children with obstructive sleep apnea (OSA). This study aimed to quantify the expression of cysteinyl leukotriene receptors (CysLT(1), CysLT(2)) by tonsillar lymphocyte subpopulations from children with OSA and to make comparisons to lymphocyte subpopulations from control subjects with recurrent tonsillitis (RT). METHODS: Tonsillar tissue from children with OSA or RT was studied for CysLT(1) and CysLT(2) expression by RT-PCR, flow cytometry (FC), and immunofluorescence. RESULTS: Ten children with OSA and 10 control subjects were recruited. In OSA participants, CysLT(1)+ fraction of small-size CD19+ B-lymphocytes was similar to the CysLT(1)+ CD3+ T-lymphocytes fraction (FC: 36.5 [16.5-55.4] vs. 14 [2.8-22.1]) (p>0.05) and higher than the CysLT(1)+ moderate/large-size CD19+ B-lymphocytes fraction (6.6 [1.5-14.4]) (p<0.01). Similar trends were recognized for CysLT(2). CysLT(1) and CysLT(2) immunoreactivity was detected by immunofluorescence in the tonsillar mantle zones (small B-lymphocytes) and the extrafollicular areas (T-lymphocytes). Compared to subjects with RT, children with OSA had significantly higher expression of CysLT(1) in small-size CD19+ B-lymphocytes (FC) and in CD3+ T-lymphocytes (RT-PCR and FC) (p<0.05). CONCLUSIONS: Increased expression of leukotriene receptors by immunologically active tonsillar areas in children with OSA is a potential therapeutic target for pediatric sleep apnea.

Associations of tonsillar hypertrophy and snoring with history of wheezing in childhood.

BACKGROUND: Reports in adults and children have correlated history of wheezing or asthma with the presence of obstructive sleep-disordered breathing but the mechanism of this epidemiologic association is unknown. The goal of the present study was to examine whether tonsillar hypertophy can explain this association. METHODS: Children were recruited from the Emergency Department and the Pediatric Pulmonology Clinic. History of wheezing requiring treatment (explanatory variable) and snoring > or = 1 night/week (outcome) were recorded and presence of tonsillar hypertrophy (outcome) was assessed. RESULTS: Four hundred forty-two children were recruited (mean age: 7.6 + or - 3.6 years) and 210 of them had history of wheezing. History of wheezing was significantly associated with the presence of tonsillar hypertrophy and snoring even after adjustment for age, gender, obesity, and passive smoking [odds ratio (95% confidence interval): 2.23 (1.37-3.63); P = 0.001 and 1.73 (1.12-2.67); P = 0.013, respectively]. When only children with tonsillar hypertrophy were considered (n = 92), history of wheezing was significantly related to the presence of snoring, whereas in subjects without tonsillar hypertrophy (n = 350) wheezing did not affect snoring [odds ratio: 2.76 (1.10-6.93); P = 0.031 and 1.49 (0.92-2.43); P = 0.107, respectively]. CONCLUSIONS: Children with history of wheezing have more frequently tonsillar hypertrophy than those without wheezing. Tonsillar hypertrophy may mediate at least in part the reported association between asthma and obstructive sleep-disordered breathing in childhood.

Tonsillar size in 2- to 14-year-old children with and without snoring.

BACKGROUND: Few investigations have assessed tonsillar size in children of variable age, sleep-disordered breathing (SDB) status and degree of adiposity. This study evaluated the size of tonsils in young and older, lean and obese children, without or with snoring. METHODS: Children attending the Emergency Department or Pulmonology Clinic were recruited and tonsillar size was scored 1-4. Snoring >or=1 night/week was considered diagnostic of SDB and body mass index z-score >or=1.645 was defined as obesity. Age was analyzed as dichotomous variable (7 years old). RESULTS: 362 children (2-14 years old) were recruited; 78 (21.5%) were obese and 108 (29.8%) had SDB. SDB-but not age or obesity-was significantly related to tonsillar size (P = 0.001). There was not enough evidence to support the presence of interactions between SDB and age or obesity regarding the size of tonsils (P = 0.157 and P = 0.978, respectively). Young subjects without SDB had larger tonsils than older subjects without SDB (1.9 +/- 0.7 vs. 1.7 +/- 0.8; P = 0.017), whereas age did not affect tonsillar size in children with SDB (P = 0.78). CONCLUSIONS: Young and older children with SDB have similar tonsillar size. In contrast, older subjects without snoring have smaller tonsils than young subjects without snoring. Tonsillar enlargement in children with SDB probably occurs in early childhood without change in older age.