leukotriene-e4 and Dermatitis--Atopic

Cysteinyl-leukotrienes (cysteinyl-LTs), that is, LTC4, LTD4, and LTE4, trigger contractile and inflammatory responses through the specific interaction with G protein-coupled receptors (GPCRs) belonging to the purine receptor cluster of the rhodopsin family, and identified as CysLT receptors (CysLTRs). Cysteinyl-LTs have a clear role in pathophysiological conditions such as asthma and allergic rhinitis (AR), and have been implicated in other inflammatory conditions including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. Molecular cloning of human CysLT1R and CysLT2R subtypes has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Interestingly, recent data provide evidence for the immunomodulation of CysLTR expression, the existence of additional receptor subtypes, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Furthermore, genetic variants have been identified for the CysLTRs that may interact to confer risk for atopy. Finally, a crosstalk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize and attempt to integrate recent data derived from studies on the molecular pharmacology and pharmacogenetics of CysLTRs, and will consider the therapeutic opportunities arising from the new roles suggested for cysteinyl-LTs and their receptors.

Topics: Adult; Animals; Asthma; Cardiovascular Diseases; Child; Child, Preschool; Dermatitis, Atopic; Female; Humans; Hydroxyurea; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Membrane Proteins; Pharmacogenetics; Receptors, Leukotriene; Receptors, Purinergic; Recombinant Proteins; Rhinitis, Allergic, Seasonal; SRS-A; Tissue Distribution

Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s.. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD. Human ILC2s expressed the LT receptor CysLT. CysLTs, particularly LTE

Topics: Adult; Cells, Cultured; Cytokines; Dermatitis, Atopic; Eicosanoic Acids; Epithelial Cells; Female; Humans; Immunity, Innate; Leukotriene E4; Lymphocytes; Male; Mast Cells; Prostaglandin D2; Th2 Cells

Leukotrienes are thought to play a role in the pathogenesis of atopic eczema/dermatitis syndrome (AEDS). Urinary leukotriene E4 (U-LTE4) is a marker of whole-body cysteinyl-leukotriene production.. To evaluate the role of leukotrienes in children with AEDS by measuring levels of U-LTE4, and to evaluate whether levels of U-LTE4 may reflect disease activity and allergic sensitization in AEDS.. U-LTE4 was measured by enzyme-linked immunosorbent assay in 87 children with mild (n=32), moderate (n=34) and severe (n=21) AEDS, as well as in 72 nonatopic healthy controls. Fifty-eight of the children with AEDS were sensitized to common allergens, and 29 were not.. Levels of U-LTE4 were higher in children with severe AEDS (140; 66-166 microg/mmol creatinine, median; quartiles) than in controls (52; 30-90, P <0.05), whereas levels of U-LTE4 in moderate and mild disease were similar to controls. U-LTE4 levels were similar in children with or without sensitization to common allergens, but severe AEDS children with sensitization had higher levels of U-LTE4 than those without sensitization.. The results suggest a role for leukotrienes in the pathogenesis of severe AEDS, and may support a role for leukotriene-antagonists in the treatment of this disorder. Levels of U-LTE4 may reflect the disease severity and sensitization to allergens in AEDS.

Topics: Case-Control Studies; Child, Preschool; Dermatitis, Atopic; Female; Humans; Infant; Leukotriene E4; Male; Severity of Illness Index; Syndrome

Leukotriene E4 (LTE(4)) is elevated in adults with atopic dermatitis (AD). We evaluated whether urinary LTE(4) as a noninvasive marker correlates with clinical indices of disease activity in children with AD. AD patients aged 18 years or younger were eligible for inclusion in the study. Disease severity over the preceding 3 days was evaluated by the SCORing Atopic Dermatitis (SCORAD) index. Severity of AD over the past 12 months was evaluated by the Nottingham Eczema Severity Score (NESS) in Chinese. Urinary LTE(4) concentration was measured by competitive enzyme immunoassay. One hundred and twenty-six children with AD (82 boys and 44 girls) and 45 controls were recruited. The mean +/- SD urinary log-transformed LTE(4) concentration in AD patients and controls was 2.94 +/- 0.32 and 2.62 +/- 0.20 pg/mg creatinine, respectively (P < 0.0001). SCORAD significantly correlated with NESS (r = 0.681, P < 0.0001). There were significant correlations between urinary LTE(4) concentration and overall SCORAD score (r = 0.270, P = 0.002) and its extent (r = 0.185, P = 0.038) and intensity components (r = 0.247, P = 0.005), but not with NESS. When compared with mild AD, urinary LTE(4) concentrations were higher in patients with moderate-to-severe disease (P = 0.049). Urinary LTE(4) measurement is noninvasive and may be useful in supplementing the SCORAD for following longitudinal changes in AD severity in children. However, the practical value of this assay in a clinical setting remains to be determined.

Topics: Adolescent; Biomarkers; Child; Creatinine; Dermatitis, Atopic; Female; Humans; Leukotriene E4; Male; Severity of Illness Index

Synthesis of cysteinyl leukotrienes (LTs) is known to play a part in the pathogenesis of inflammatory diseases.. To define the involvement of cysteinyl LTs in atopic dermatitis (AD).. Synthesis of cysteinyl LTs was assessed in patients with AD and healthy volunteers by measuring urinary LTE4, a useful index of systemic cysteinyl LT synthesis, using liquid chromatography/tandem mass spectrometry.. Mean +/- SD urinary LTE4 levels in patients with AD (125 +/- 69 pg mg(-1) creatinine, n = 20) were significantly higher (P < 0.01) than in healthy volunteers (60 +/- 19 pg mg(-1) creatinine, n = 17). A significant correlation between urinary LTE4 and total serum IgE levels in patients with AD was observed (r = 0.643, P < 0.05).. Our findings demonstrate an enhanced synthesis of cysteinyl LTs in patients with AD and suggest that cysteinyl LTs are involved in the pathophysiology of AD.

Topics: Adolescent; Adult; Chromatography, Liquid; Dermatitis, Atopic; Female; Humans; Immunoglobulin E; Leukotriene E4; Male; Mass Spectrometry

To evaluate the significance of peptide leukotrienes in children with atopic dermatitis, we measured urinary LTE4 levels which are thought to reflect in vivo production of peptide LTs. Urine was collected in the early morning. There was no significant difference in urinary LTE4 levels among atopic children with different severities. On the other hand, urinary LTE4 levels were significantly elevated in the patients who had severe nocturnal itches compared with the patients who had mild nocturnal itches and normal controls. These results suggested that increased production of peptide LTs may be relevant to nocturnal itch of atopic dermatitis.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Circadian Rhythm; Dermatitis, Atopic; Female; Humans; Leukotriene E4; Male; Pruritus; Severity of Illness Index

Leukotriene synthesis may be increased in a variety of inflammatory diseases. Urinary leukotriene E4 is a stable metabolite of leukotrienes C4 and D4 which has previously been found to be increased in exacerbations of severe asthma and after antigen inhalation. Levels of urinary LTE4 in seven patients during and after a severe flare of atopic dermatitis were measured by high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Mean urinary LTE4 levels (+/- SEM) were not increased during (16.7 +/- 3.7 pg/mumol) or after (16.9 +/- 4.8 mumol) the acute exacerbation of atopic dermatitis when compared with the normal range (mean = 23.8 [95% confidence interval 19.9-28.2] pg/mumol creatinine). These findings do not provide evidence of cysteine leukotriene involvement in the pathogenesis of atopic dermatitis.

Topics: Acute Disease; Dermatitis, Atopic; Humans; Leukotriene E4

Synthesis of cysteinyl leukotrienes was assessed in patients with atopic dermatitis (AD; n = 8) and healthy volunteers (n = 8) by measuring urinary excretion of leukotriene E4 (LTE4), the main index metabolite of cysteinyl leukotrienes in man. Using this non-invasive method we demonstrated a significant (P < 0.05) 4.5-fold increase in excretion of LTE4 compared with healthy volunteers. The identity of LTE4 was unequivocally demonstrated by gas chromatography-mass spectrometry/mass spectrometry (GC-MS/MS). LTE4 was routinely measured by radioimmunoassay (RIA), and quantitative measurement of LTE4 by RIA was validated by GC-MS/MS. There was a linear correlation between LTE4 measured by RIA and by GC-MS/MS (r = 0.994). In representative samples, LTE4 was also quantitatively assessed by GC-MS/MS. In these samples, LTE4 values obtained by GC-MS/MS differed < 10% from those obtained by RIA. The present findings suggest that cysteinyl leukotrienes play a role in AD.

Topics: Adult; Dermatitis, Atopic; Female; Gas Chromatography-Mass Spectrometry; Humans; Leukotriene E4; Leukotrienes; Male; Radioimmunoassay; SRS-A