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Background: Maternal obesity is known to affect human milk composition. Long-chain polyunsaturated fatty acids (LCPUFA) are vital nutrients to the nervous system development and precursors of eicosanoids related to obesity (prostaglandin E 2 -PGE 2 -and leukotriene E 4 -LTE 4 ). The aim of the present research was to study the lipid profiles, with particular emphasis to LCPUFAs, and the concentrations of eicosanoids PGE 2 and LTE 4 , involved in adipose tissue development, in human milk from overweight mothers compared with normal weight mothers. Materials and Methods: Study including 46 overweight and 86 normal weight breastfeeding volunteers was carried out. Fatty acids and eicosanoids (PGE 2 and LTE 4 ) were analyzed in mature human milk. Fatty acids quantification was determined by gas chromatography and mass spectrometry. PGE 2 and LTE 4 were measured by immununoassay. Results: Human milk of overweight mothers had lower contents of n-3 LCPUFA, including eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) and higher levels of total n-6 LCPUFA, compared with normal weight mothers (0.45 ± 0.23 versus 0.58 ± 0.38, p  = 0.016; 0.05 ± 0.04 versus 0.08 ± 0.08, p  = 0.005; 0.26 ± 0.15 versus 0.34 ± 0.22, p  = 0.015; 0.84 ± 0.25 versus 0.74 ± 0.20, p  = 0.029; respectively). Multiple regression analyses showed that maternal overweight was associated with human milk fatty acid profile. The levels of PGE 2 and LTE 4 in human milk did not show significant differences between groups. Conclusions: Our findings support the hypothesis that mother weight status influences human milk n-3 LCPUFA lipid composition, but not its relationship with PGE 2 and LTE 4 levels.

Background: Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma., Methods: Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model-building and validation phases., Results: Exhaled LTB 4 , LTE 4 , PGE 2, and LXA 4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB 4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB 4 , LXA 4 , together with FeNO and FEV 1 , distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as "asthma classification ratio" was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively., Conclusions: In a pediatric study population in Taiwan, the levels of exhaled LTB 4 , LTE 4 , LXA 4, and PGE 2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB 4 and LXA 4 , together with FeNO and FEV 1 , best characterized childhood asthma., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: The impact of air pollution on the respiratory system has been estimated on the basis of respiratory symptoms and lung function. However; few studies have compared lung inflammation in healthy and asthmatics children exposed to high levels of air pollution. The aim of the study was to elucidate the modulatory effect of air pollution on Cysteinyl-leukotrienes (Cys-LTs) levels in exhaled breath condensate (EBC) among healthy and asthmatic children., Methods: We performed a cross-sectional comparative study. Children between 7-12 years of age, asthmatics and non-asthmatics, residents of a city with high levels of PM10 were included. In all cases, forced spirometry, Cys-LTs levels in EBC, and the International Study of Asthma and Allergies in Childhood questionnaire were evaluated. We also obtained average of PM10, CO, SO2 and O3 levels during the period of the study by the State Institute of Ecology., Results: We studied 103 children (51 asthmatics and 52 non-asthmatics). Cys-LTs levels were higher in asthmatics than in non-asthmatics (77.3 ± 21.6 versus 60.3 ± 26.8 pg/ml; p = 0.0005). Also, Cys-LTs levels in children with intermittent asthma were lower than in children with persistent asthma (60.4 ± 20.4 versus 84.7 ± 19.2 pg/ml; p = 0.0001). In the multiple regression model, factors associated with levels of Cys-LTs were passive smoking (β = 13.1, p 0.04) and to be asthmatic (β = 11.5, p 0.03)., Conclusions: Cys-LTs levels are higher in asthmatic children than in healthy children in a contaminated city and its levels are also associated with passive smoking.

Background: Acetylsalicylic acid (ASA; aspirin) is a well-known inducer of pseudoallergic response in patients with chronic rhinosinusitis with polyps (CRSwPs). The mechanism that leads to this response remains unclear. This study was designed to measure and compare the local and systemic inflammatory response to aspirin challenge in patients with CRSwPs who develop either a nasobronchial response (NBR) or a nasal response (NR), and compare it with nonresponders (non-Rs)., Methods: The three groups underwent nasal wash before ASA challenge, and inflammatory mediators were measured in the nasal wash as well as in serum., Results: A total of 25 CRSwP patients were enrolled. The NBR patients (n = 13) had a significantly longer mean disease duration and a higher mean serum leukotriene E4 (LTE4) level than the NR (n = 6) and non-R (n = 6) patients (39.2 ± 9.7 months, 21 ± 8.8 months, and 22.8 ± 11.2 months, respectively, and 4221 ± 1205 pg/mL, 1430 ± 605 pg/mL, and 857 ± 461 pg/mL, respectively). The NBR and NR patients had a larger mean number of nasal eosinophils than the non-R group (52.8 ± 28.8 cells/μL, 47 ± 21.3 cells/μL, and 19.3 ± 13.4 cells/μL, respectively). The tryptase, albumin, nasal LTE4, and prostaglandin E2 levels were not significantly different between the three groups in any examined combination., Conclusion: The nasal eosinophil and serum LTE4 levels correlate with aspirin sensitivity.

A sensitive and precise method for simultaneous quantification of cysteinyl leukotrienes (=cys LTs) - leukotriene C4 (=LTC4), leukotriene D4 (=LTD4) and leukotriene E4 (=LTE4) - essential biomarkers of bronchial asthma present in exhaled breath condensate (=EBC) was developed. An immunomagnetic molecular probe was prepared by anchoring cysteinyl leukotrienes antibody on the surface of functionalized monodispersed magnetic particles and used to selectively isolate cys LTs from biological matrices - EBC, plasma and urine. Immobilization and the immunoaffinity capture procedures were optimized to maximize the amount of separated cys LTs, which were detected "off-beads" after acidic elution by UHPLC-ESI-MS/MS operated in a multiple reaction monitoring mode. The developed method was characterized with high precision ≤13.6% (intra-day precision determined as RSD) and ≤14.5% (inter-day precision determined as RSD), acceptable accuracy ≤18.5% (determined as RE), and high recovery of immunoseparation (≥93.1%) in aforementioned biological matrices. The applicability of the method was demonstrated on EBC, plasma and urine clinical samples of patients with various subtypes of bronchial asthma (occupational, steroid-resistant, moderate with and without corticosteroids therapy) and healthy subjects where reasonable differences in cys LTs concentration levels were found. Combining extremely selective immunomagnetic separation with highly sensitive and precise detection step, the developed method was used to aid diagnosis, predict the most effective therapy, and monitor the response to treatment. The detection of elevated inflammatory mediators (cys LTs) in EBC of subjects with relatively asymptomatic asthma and normal pulmonary function tests could offer a novel way for monitoring the lung inflammation and perhaps initiating treatment in an earlier stage., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Leukotrienes (LTs) are involved in the pathogenesis of lung fibrosis and were increased in exhaled breath condensate (EBC) of the patients with pneumoconiosis. However the possible influence of extra-pulmonary disorders on the EBC markers is not known. Therefore in parallel with EBC, LTs' levels in the plasma and urine were measured in patients with pneumoconiosis (45 × asbestos exposure, 37 × silica exposure) and in 27 controls. Individual LTs B4, C4, D4 and E4 were measured by liquid chromatography - electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS). In EBC, LT D4 and LT E4 were increased in both groups of patients (p<0.001 and p<0.05), comparing with the controls. Both LT B4 and cysteinyl LTs were elevated in asbestos-exposed subjects (p<0.05). Asbestosis with more severe radiological signs (s1/s2-t3/u2) and lung functions impairment has shown higher cysteinyl LTs and LT C4 in the EBC (p<0.05) than mild asbestosis (s1/s0-s1/s1). In addition, in the subjects with asbestosis, cysteinyl LTs in EBC correlated with TLC (-0.313, p<0.05) and TLCO/Hb (-0.307, p<0.05), and LT C4 with TLC (-0.358, p<0.05). In pneumoconioses, EBC appears the most useful from the 3 fluids studied.

Background: Female hormones play an important role in women's lung health, especially in asthma pathophysiology. Although a growing interest has recently been aroused in asthma related to short-term reproductive states, menopausal asthma has been little studied in the past. The aim of the present study was to explore airway inflammation in menopausal asthmatic women in a noninvasive manner., Methods: Forty consecutive women with menopausal asthma, 35 consecutive women with premenopausal asthma and 30 age-matched healthy controls were enrolled in the study. Urinary LTE-4, induced sputum inflammatory cells, and exhaled LTE-4, IL-6, pH, and NO levels were measured in all the subjects enrolled., Results: Women with menopausal asthma showed decreased estradiol concentrations, high sputum neutrophils, and exhaled IL-6. Women with premenopausal asthma presented instead an essentially eosinophilic inflammatory pattern. Higher urine and breath condensate LTE-4 concentrations were found in premenopausal and menopausal asthma compared to controls., Conclusion: Our results substantiate the existence of a new biological phenotype of menopausal asthma that is mainly characterized by neutrophilic airways inflammation and shares several characteristics of the severe asthma phenotype.

Objective: To assess the clinical significance of three different noninvasive airway inflammatory indices in induced sputum and exhaled breath condensate (EBC) from persistent asthmatic patients., Methods: Moderate and severe asthmatic patients were prescribed inhaled corticosteroids combined with long-acting beta(2) agonists for a month. The symptom scores and percentage of predicted value of forced expiratory volume in one second (FEV(1)) (FEV(1)%pred) were measured while the concentrations of H(2)O(2), NO(3)(-)/NO(2)(-), and cysteinyl-leukotriene E(4) (LTE(4)) in induced sputum and EBC were detected before and after therapy., Results: A total of twenty-five subjects with moderate and severe asthma were enrolled. By combined therapy for one month the asthma symptoms relieved and FEV(1)%pred improved significantly (P < 0.01). The concentrations of H(2)O(2), NO(3)(-)/NO(2)(-) and LTE(4) in induced sputum and EBC declined significantly (P < 0.01) although the concentrations were still higher than those at normal baseline. More marked reduction of H(2)O(2) and NO(3)(-)/NO(2)(-) compared to LTE(4) was observed. It was revealed that the concentrations of H(2)O(2)and NO(3)(-)/NO(2)(-) but not of LTE(4) in EBC were negatively correlated with FEV(1)%pred (P < 0.01) and positively with symptom scores. Such correlations were also found in H(2)O(2) in induced sputum with FEV(1)%pred and symptom scores as well as NO(3)(-)/NO(2)(-) in induced sputum with FEV(1)%pred. The improvement of FEV(1)%pred after treatment was positively correlated with the reduction of H(2)O(2) and NO(3)(-)/NO(2)(-) both in induced sputum and EBC. Correlation analysis also demonstrated three inflammatory indices were equivalent in induced sputum and EBC (correlation coefficient of H(2)O(2), NO(3)(-)/NO(2)(-) and LTE(4), 0.759, 0.826 and 0.653, respectively. P < 0.01)., Conclusions: (1) Combined therapy with inhaled corticosteroid plus long-acting beta(2) agonist significantly improves the clinical symptoms and lung function of patients with moderate and severe asthma companies with marked suppression of airway inflammation. (2) Both of EBC and induced sputum sampling are valuable noninvasive procedures for detecting asthma airway inflammation, however, EBC technique is superior in safety and reproducibility. (3) H(2)O(2) and NO(3)(-)/NO(2)(-) seem to be more sensitive indices in diagnosis and monitoring asthma compared to LTE(4).

Background: Allergic rhinitis and bronchial asthma can coexist and affect each other., Objective: To investigate the relationship between the postseasonal increase in the concentration of leukotriene (LT) B4 and LTE4 in exhaled breath condensate (EBC) and bronchial responsiveness to methacholine (BRM) in patients with seasonal allergic rhinitis (SAR)., Methods: In 28 patients with SAR and 50 healthy study patients, the leukotrienes were measured in EBC during and after the pollen season by gas chromatography/mass spectrometry. The BRM was determined after the pollen season., Results: In 7 patients with SAR, significantly increased concentrations of both the leukotrienes were found in EBC during and 5 months after the pollen season. The following seasonal and postseasonal median values were measured in patients with SAR in comparison with control patients: LTB4: 131 and 90 pg/mL vs 80 and 79 pg/mL, P < .001 and P = .03, respectively; LTE4: 122 and 86 pg/mL vs 76 and 74 pg/mL, P < .001 and P = .02, respectively. Five months after the pollen season, the concentrations of LTB4 and LTE4 decreased with respect to their seasonal values (90 and 86 pg/mL, respectively, P < .001, for both leukotrienes). In 7 patients with SAR and leukotriene levels exceeding the reference limits, significantly increased BRM was also found (LTB4: P = .02; LTE4: P = .002)., Conclusions: The seasonal and postseasonal increases in LTB4 and LTE4 concentrations in EBC of the patients with SAR correlated significantly with the later increase in BMR. This relationship could provide a useful predictive parameter for early inflammatory processes in the lower airways of patients with allergic rhinitis.

Background: Chronic airway inflammation is a feature of asthma. Increased levels of cysteinyl leukotrienes (cys-LTs; leukotriene [LT]C(4), LTD(4), LTE(4)) have been shown in the exhaled breath condensate (EBC) of children with moderate-to-severe asthma. The aim of this study was to examine the relationship between EBC cys-LTs (LTE(4)) levels and bronchial hyperreactivity in children with mild asthma in order to evaluate the clinical utility of measuring EBC cys-LTs levels., Methods: We measured LTE(4) levels in the EBC of children aged 8 to 18 years, including healthy nonasthmatic children (n = 6) and children with mild asthma (n = 37). Patients with mild asthma were classified into the following three groups: group 1, participants who had been asymptomatic (no wheezing/symptoms of asthma) for > 6 months prior to examination (n = 12); group 2, participants who were asymptomatic but had had wheezing/symptoms of asthma within 6 months before examination (n = 18); and group 3, patients with current wheeze and/or mild symptoms of asthma exacerbation at the time of examination., Results: Exhaled LTE(4) levels were increased in all children with mild asthma compared with nonasthmatic control subjects (5.69 +/- 9.62 pg/20 min vs 0.74 +/- 0.79 pg/20 min, p < 0.05) [mean +/- SD]. In particular, the EBC LTE(4) levels in group 2 (4.99 +/- 6.70 pg/20 min) and group 3 (14.66 +/- 17.11 pg/20 min) were increased compared with control subjects and group 1 (1.50 +/- 1.69 pg/20 min). The EBC LTE(4) levels negatively correlated with the provocative concentration of methacholine causing a 15% fall in FEV(1) (r = - 0.454, p = 0.012)., Conclusion: EBC cys-LTs may be useful as a noninvasive marker assessing airway inflammation and hyperreactivity in children with asthma.

Purpose: To ensure the suitable preservation of isolated lungs, a super-cooling system was used to cool water to temperatures as low as -5 degrees C without freezing., Description: After lung tissues were obtained from patients with lung cancer, they were kept at -5 degrees C or 4 degrees C for as many as 5 days, and then they were histologically and biochemically examined. To evaluate biochemical stability, tissues after storage were passively sensitized with immunoglobulin E and then incubated with anti-immunoglobulin-E antibody., Evaluation: Although tissues preserved at -5 degrees C for 5 days had an almost normal appearance with intact cilia on bronchial epithelium and normal endothelium, tissues stored at 4 degrees C showed degradation of these structures. Single-stranded DNA, a sign of DNA cleavage, was frequently noted in tissues stored at 4 degrees C, but only rarely observed at -5 degrees C. A significant amount of cysteinyl-leukotrienes was generated from tissues stored at -5 degrees C for 3 days, but there was no response to antibody stimulation from tissues stored at 4 degrees C., Conclusions: Super-cooling systems may provide useful applications as a novel preserving method.

Background: Leukotriene (LT) E(4) and 8-isoprostane concentrations are elevated in exhaled breath condensate in children with asthma. The effects of leukotriene receptor antagonists (LTRAs) on exhaled leukotriene and prostanoids in children with asthma are unknown., Objective: (1) To study the effect of montelukast, a LTRA, on exhaled LTE(4), 8-isoprostane, and prostaglandin E(2) in children with asthma and atopic children; (2) to measure exhaled nitric oxide., Methods: An open-label study with oral montelukast (5 mg once daily for 4 weeks) was undertaken in 17 atopic children with asthma and 16 atopic children without asthma., Results: Pretreatment exhaled LTE(4) (P < .0001) and 8-isoprostane (P < .0001) values were higher in atopic children with asthma than in atopic children without asthma. In atopic children with asthma, montelukast reduced exhaled LTE(4) by 33% (P < .001), and this reduction was correlated with pretreatment LTE(4) values (r = -0.90; P = .0001). Posttreatment exhaled LTE(4) levels in children with asthma were higher than pretreatment LTE(4) values in atopic children without asthma (P < .004). Montelukast had no effect on exhaled LTE(4) in atopic children without asthma (P = .74), or on exhaled 8-isoprostane (atopic children with asthma, P = .94; atopic children without asthma, P = .55) and PGE(2) (atopic children with asthma, P = .56; atopic children without asthma, P = .93) in both groups. In atopic children with asthma, exhaled nitric oxide concentrations were reduced by 27% (P < .05) after montelukast., Conclusion: Leukotriene receptor antagonists decrease exhaled LTE(4) in atopic children with asthma. This reduction is dependent on baseline exhaled LTE(4) values., Clinical Implications: Measurement of exhaled LTE(4) might help identify children with asthma most likely to benefit from LTRAs.

To evaluate the levels of leukotrienes (LTs), interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-gamma (IFN-gamma) in patients with eczema and observe the effects inversed by mizolastine. Serum LTB4, LTC4, IL-2, IL-4, IFN-gamma and urinary LTE4 levels were detected by enzyme-linked immunosorbent assay (ELISA) and LTB4, LTC4, LTE4 concentrations of cutis tissue were measured by reverse-phase high-pressure liquid chromatography (RP-HPLC) in 10 eczema patients and 10 healthy volunteers. Eczema patients received mizolastine 10 mg once a day for 5 days, respectively, for comparison between before and after treatment. The above markers were assayed again after treatment. Serum LTB4, LTC4, IL-2, IFN-gamma and urinary LTE4 and skin tissue LTB4, LTC4, LTE4 levels in patients are higher than those in healthy volunteers significantly (P < 0.05). But serum IL-4 level did not show significant difference between patients and normal controls (P > 0.05). Mizolastine significantly reduced serum LTB4 and IFN-gamma levels as well as skin lesion LTB4, LTC4, LTE4 concentrations. LTs are involved in the pathogenesis of eczema. Mizolastine clearly reduces LTs levels in skin lesion.

Background: After in vitro allergen-specific stimulation, basophils become activated and release sulfidoleukotrienes LTC4, LTD4 and LTE4. This can be detected by means of the CAST assay. We assessed the positivity criteria and the reliability of antigen-specific sulfidoleukotriene production (CAST) in the in vitro diagnosis of betalactam (BL) allergic patients., Material and Methods: We studied a sample of 67 patients (age 48.94 +/- 15.76 years) who had presented with anaphylaxis or urticaria-angioedema within the first 60 minutes after administration of Amoxicillin (54/67), Penicillin G (7/67), Cefuroxime (5/67) or Cefazoline (1/67). All of them had a positive skin test to at least one of the antigenic determinants of Penicillin. As control group 30 adults with negative skin tests who tolerated BL were included. All of them underwent skin tests, oral provocation tests, specific IgE (CAP-FEIA, Pharmacia) and CAST., Results: Positivity criteria were established by means of ROC curves: a sLT release induced by Betalactams of at least 100 pg/ml and greater than or equal to 3 times the basal value. The overall sensitivity of CAST is 47.7% and specificity 83.3%. Sensitivity of specific IgE is 37.8% and specificity 83.3%., Conclusions: We have established validated positivity criteria for the CAST technique in patients allergic to Betalactams. This technique is a useful in vitro diagnostic method in patients with IgE-mediated allergy to Betalactam antibiotics.

Prostaglandins and leukotrienes are implicated in conditions of both the upper and lower airways. In the former they are deranged in nasal polyposis, intrinsic rhinitis and allergic rhinitis while in the latter they are involved in the pathogenesis of asthma. The aim of the present study was to measure mucosal eicosanoid levels in the three types of rhinitis and compare with controls. In addition, the effect of topical steroids on eicosanoid levels in rhinitis was examined. The levels of prostaglandins E(2) (PGE(2)) and D(2) (PGD(2)) and of leukotrienes E(4) (LTE(4)) and B(4) (LTB(4)) were measured in nasal biopsies from the inferior turbinates of patients suffering from perennial rhinitis and a control group. Rhinitis patients were classified into three categories: perennial allergic rhinitis (PAR), non-allergic rhinitis with eosinophilia (NARES) and noneosinophilic non-allergic rhinitis (NENAR) on the basis of symptoms, secretion eosinophilia, nasal resistance and allergy testing. Patients with rhinitis were randomized into two groups. One received fluticasone propionate nasal spray (FPANS) and the other a placebo (PNS) over a period of six weeks prior to the biopsies. One hundred and one patients with PAR, NARES or NENAR were recruited sequentially and the control group consisted of 21 patients with no evidence of rhinitis but with nasal obstruction due to septal deviation. Untreated rhinitics had significantly lower levels of PGE(2), PGD(2) and LTE(4) than non-rhinitic controls. Six-weeks' treatment with FPANS significantly increased the levels of those eicosanoids in patients with PAR and NARES but they were still significantly below normal. Levels of LTB(4) in all three rhinitis groups were not significantly different from controls and treatment with topical steroids had no effect. Their findings are contrary to current thinking that increased levels of eicosanoids, in particular cysteinyl-leukotrienes, play an important role in the pathogenesis of chronic, non-infective upper airway inflammation.

Objective: To evaluate changes in cysteinyl leukotriene (LT) concentrations in urine and bronchoalveolar lavage fluid (BALF) in cats with experimentally induced asthma., Animals: 19 cats with experimentally induced asthma and 5 control cats., Procedure: Cats were sensitized to Bermuda grass or house dust mite allergen, and phenotypic features of asthma were confirmed with intradermal skin testing, evaluation of BALF eosinophil percentages, and pulmonary function testing. A competitive ELISA kit for LTC4, LTD4, and LTE4 was used for quantitative analysis of LTs. Urinary creatinine concentrations and BALF total protein (TP) concentrations were measured, and urinary LT-to-creatinine ratios and BALF LT-to-TP ratios were calculated., Results: Mean urinary LT-to-creatinine ratios did not differ significantly between control cats and allergen-sensitized cats before or after sensitization and challenge exposure with saline (0.9% NaCl) solution or allergen, respectively. In BALF the mean LT-to-TP ratio of control cats did not differ significantly before or after sensitization and challenge exposure with saline. Asthmatic cats had BALF LT-to-TP ratios that were significantly lower than control cats at all time points, whereas ratios for asthmatic cats did not differ significantly among the various time points., Conclusions and Clinical Relevance: Although LTs were readily detectable in urine, no significant increases in urinary LT concentrations were detected after challenge in allergen-sensitized cats. Spot testing of urinary LT concentrations appears to have no clinical benefit for use in monitoring the inflammatory asthmatic state in cats. The possibility that cysteinyl LTs bind effectively to their target receptors in BALF and, thus, decrease free LT concentrations deserves further study.

Objective: The leukotrienes are a family of arachidonic acid-derived lipid mediators with proinflammatory and profibrotic properties. The aim of this study was to analyze the role of leukotriene B(4) (LTB(4)) and LTE(4) in the pathogenesis of scleroderma lung disease (SLD)., Methods: Nineteen systemic sclerosis (SSc) patients with SLD, 11 SSc patients without SLD, and 10 healthy controls were studied. Bronchoalveolar lavage (BAL) fluid was obtained during routine bronchoscopy of the right middle lobe in all study subjects. Levels of LTB(4) and LTE(4) were measured using enzyme immunoassay kits., Results: Levels of LTB(4) and LTE(4) were significantly higher in SSc patients with SLD (251 +/- 170 pg/ml and 479 +/- 301 pg/ml, respectively), than those in patients without SLD (114 +/- 86 and 159 +/- 149 pg/ml) and those in normal controls (86 +/- 49 and 110 +/- 67 pg/ml). In the total group of patients with SSc, levels of both leukotrienes correlated positively with the total number of cells in the BAL fluid and correlated negatively with the forced vital capacity. After intravenous pulse therapy with cyclophosphamide in 6 patients, there was a significant reduction in the concentration of LTB(4) (from 380 +/- 196 pg/ml to 155 +/- 123 pg/ml) but no significant difference in the levels of LTE(4) (from 697 +/- 325 pg/ml to 418 +/- 140 pg/ml)., Conclusion: Our findings show that LTB(4) and LTE(4) levels are elevated in SSc patients with SLD and correlate with parameters of inflammation in the lungs. These results indicate that leukotrienes may contribute to the pathogenesis of SLD and may represent a new therapeutic target.

Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A(2) (cPLA(2)). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA(2). In the present study, we hypothesized that pharmacological intervention of cPLA(2) could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA(2) could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.

Background: Most of the studies investigating the role of leukotrienes (LTs) and prostaglandins (PGs) in asthma have used invasive (eg, bronchoalveolar lavage fluid) or semi-invasive (eg, sputum induction) techniques. Others have measured eicosanoids in plasma or urine, probably reflecting systemic rather than lung inflammation. Collection of exhaled breath condensate (EBC) is a noninvasive method to collect airway secretions., Objective: We sought to investigate whether eicosanoids are measurable in EBC, to show possible differences in their concentrations in asthmatic patients and healthy subjects, and to investigate whether exhaled eicosanoids correlate with exhaled nitric oxide (NO), a marker of airway inflammation., Methods: Twelve healthy nonsmokers and 15 steroid-naive patients with mild asthma were studied. Subjects attended on one occasion for pulmonary function tests, collection of EBC, and exhaled NO measurements. Exhaled LTB(4)-like immunoreactivity, LTE(4)-like immunoreactivity, PGE(2)-like immunoreactivity, PGD(2)-methoxime, PGF(2)(alpha)-like immunoreactivity, and thromboxane B(2)-like immunoreactivity were measured by means of enzyme immunoassays., Results: LTE(4)-like immunoreactivity and LTB(4)-like immunoreactivity were detectable in EBC in healthy subjects, and their levels in asthmatic patients were increased about 3-fold (P <.0001) and 2-fold (P <.0005), respectively. Exhaled NO was increased in asthmatic patients compared with healthy subjects (P <.0001). There was a correlation between exhaled LTB(4) and exhaled NO (r = 0.56, P <.04) in patients with asthma. When measurable, prostanoid levels were similar in asthmatic patients and control subjects., Conclusions: Exhaled LTE(4) and LTB(4) are increased in steroid-naive patients with mild asthma. EBC may be proved to be a novel method to monitor airway inflammation in asthma.

Inhalation of heparin attenuates hyperventilation-induced bronchoconstriction in humans and dogs. The purpose of this study was to determine whether heparin inhibits the late-phase response to hyperventilation, which is characterized by increased peripheral airway resistance (RP), eicosanoid mediator production, neutrophilic/ eosinophilic inflammation, and airway hyperreactivity (AHR) at 5 h after dry air challenge (DAC). Fiberoptic bronchoscopy was used to record RP and airway reactivity (DeltaRP) to aerosol and intravenous histamine before and 5 h after DAC. Bronchoalveolar lavage fluid (BALF) cells and eicosanoid mediators were also measured approximately 5 h after DAC. DAC of vehicle-treated bronchi resulted in late-phase airway obstruction (approximately 120% increase over baseline RP), inflammation, increased BALF concentrations of leukotriene (LT) C(4), LTD(4), and LTE(4) and prostaglandin (PG)D(2), and AHR. Pretreatment with aerosolized heparin attenuated late-phase airway obstruction by approximately 50%, inhibited eosinophil infiltration, reduced BALF concentrations of LTC(4), LTD(4), and LTE(4) and PGD(2), and abolished AHR. We conclude that heparin inhibits hyperventilation-induced late-phase changes in peripheral airway function, and does so in part via the inhibition of eosinophil migration and eicosanoid mediator production and release.

Background: Cysteinyl leukotrienes (LTs) are potent proinflammatory mediators. They are predominantly excreted from blood by hepatobiliary elimination. To explore the clinical significance of biliary cysteinyl LTs, we determined their concentration changes in bile during treatment in patients with obstructive jaundice., Methods: Bile samples were obtained during endoscopic or transhepatic biliary drainage. Leukotrienes C(4), D(4), and E(4) were quantified by two-step reversed-phase high-performance liquid chromatography and subsequent radioimmunoassay., Results: The increased excretion of cysteinyl LTs (LTC(4) + LTD(4) + LTE(4)) decreased between day 1 and 14 after drainage (means, 171 pmol/h to 79 pmol/h; P < 0.02). During drainage, the excretion was higher when there was additional cholangitis (mean, 225 and 86 pmol/h, with and without cholangitis, respectively; P < 0.001). The concentrations of LTD(4) and LTE(4) were also higher with additional cholangitis than without (LTD(4), mean 6.0 vs 2.0 nM; P < 0.05; LTE(4), 6.8 vs 2.4 nM; P < 0.02, respectively). Biliary LTC(4) was detected only in patients with cholangitis. The biliary excretion of cysteinyl LTs was positively correlated with leukocyte concentration ( r = 0.68; P < 0.005) and C-reactive protein ( r = 0.73; P < 0.005) in blood. Furthermore, only in the absence of cholangitis, the excretion was positively correlated with serum gamma-glutamyl transferase ( r = 0.76; P < 0.02) and alanine aminotransferase ( r = 0.72; P < 0.02)., Conclusions: The excretion of biliary cysteinyl LTs increases with the severity of cholestasis and hepatic inflammation in patients with obstructive jaundice. An additional increase of cysteinyl LTs was observed during bacterial cholangitis. The increased biliary excretion of biologically active cysteinyl LTs may contribute to the aggravation of cholestasis and inflammatory reaction in obstructive jaundice.

Background: Leukotrienes (LTs) are important in asthma, and LT modifiers modulate antigen-induced asthma. Overproduction of LT by suppression of cyclooxygenase activity is involved in patients with aspirin-intolerant asthma (AIA)., Methods: House dust mite (HDM) inhalation provocation tests were performed in HDM-sensitive asthmatic inpatients without AIA (HDM group; n = 6), and aspirin oral provocation tests were performed in AIA patients (ASA group; n = 7). Tests were repeated using the same regimen after 7 days of treatment with pranlukast, an LT receptor antagonist (LTRA). The effects of pranlukast on changes in sputum LTC(4)-LTD(4), eosinophil cationic protein (ECP), eosinophil count, urinary LTE(4)/creatinine, 11-dehydrothromboxane B(2) (11-dhTXB(2))/creatinine, serum LTC(4)-LTD(4), ECP, and peripheral blood eosinophil count, during immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) in the HDM group and during IAR in the ASA group for each test, were compared in each group., Results: In the HDM group, IAR and LAR were observed. Sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine increased significantly both during IAR and LAR. Sputum ECP increased during IAR and further increased during LAR. Eosinophil count in the sputum did not increase during IAR but significantly increased during LAR. Pranlukast suppressed the fall in FEV(1) both during IAR and LAR (73.8% and 51.9%, respectively) and inhibited the increase in sputum eosinophil count during LAR and sputum ECP during IAR and LAR. In the ASA group, aspirin-induced IAR was associated with a fall in urinary 11-dhTXB(2)/creatinine, increased the levels of sputum LTC(4)-LTD(4) and ECP and urinary LTE(4)/creatinine. Pranlukast suppressed IAR and inhibited the increase of the level of sputum ECP, but failed to change aspirin-induced LT production in the sputum and urine. The levels of sputum LTC(4)-LTD(4) and urinary LTE(4)/creatinine in the stable phase in the ASA group were significantly greater than those in the HDM group., Conclusion: Our results indicated that HDM-provoked asthma is associated with overproduction of LT with an antigen-antibody reaction, while AIA is associated with overproduction of LT with a shift to the 5-lipoxygenase series of the arachidonate cascade. LTRA may be useful against both types of asthma through inhibition of LT activity and eosinophilic inflammation of the airways.

Exercise-induced asthma is a common phenomenon, the mechanism of which is undetermined. Eosinophils have been suggested as playing a role in its occurrence. We studied the effect of exercise-induced asthma on the cellular and mediator composition of spontaneously obtained sputum. Twenty-five patients with bronchial asthma were investigated by studying sputum spontaneously obtained before and following challenge. One group with (n=9) and one without (n=9) exercise-induced asthma performed exercise challenge. A third group (n=7) performed methacholine challenge. The sputum was analysed using Giemsa staining for differential cell count, measuring eosinophil cationic proteins and mixtures of leukotrienes (D4, E4 and C4) in the liquid phase using ELISA. The group with exercise-induced asthma had a mean drop of 23.7+/-7.4% in FEV1, significantly (P=0.001) higher than the group without it. Following challenges, there were significant increases in sputum eosinophils only in the group with exercise-induced asthma (from 8.1+/-13.9% to 18.3+/-20.2%, P=0.0017) and not in control groups (from 0.9+/-0.9% to 1.5+/-15%) or in those who had methacholine challenge (from 23.6+/-27.2% to 22.3+/-23.8%). Eosinophil cationic proteins did not change significantly in any group. In the liquid phase of the sputum, the amount of leukotrienes increased following exercise in six of the seven patients with exercise-induced asthma in whom it was measured. The influx of eosinophils to the airway in patients who develop exercise-induced asthma can be partially explained by the leukotrienes in the airways of those patients.

We have used the relatively noninvasive technique of induced sputum to measure allergen-induced changes in the concentration of eicosanoid mediators in bronchial secretions from atopic asthmatics. Sputum induction was performed before and 24 h after inhalational allergen challenge in 14 atopic asthmatics who developed a late asthmatic reaction (LAR). Differential cell counts were made on sputum cytospins and eicosanoid (cysteinyl leukotrienes [cys LTs], prostaglandin D(2) [PGD(2)], and PGE(2)) concentrations were measured in the sputum supernatants. The percentage of eosinophils at baseline correlated with the concentration of cys LTs (r = 0.84, p < 0.001) but not prostanoid mediators. Allergen challenge produced a significant increase in the concentration of sputum cys LTs from 3. 45 ng/ml sputum to 11.95 ng/ml (p = 0.002), which correlated with the increase in sputum eosinophils (r = 0.55, p < 0.05). There were no significant changes in PGD(2) or PGE(2) concentrations in sputum supernatants in response to challenge. Thus, the noninvasive technique of induced sputum has been used to demonstrate increased cys LTs, but not prostanoids associated with LAR after allergen challenge. The correlation between eosinophil numbers and cys LT concentrations at baseline values and 24 h after allergen challenge is consistent with these cells being a principal source of cys LTs within the airways at these time points.

During recent years, the role of inflammatory lipid mediators in the pathophysiology of Helicobacter pylori (H. pylori) infections has been investigated in several studies. The concentrations of leukotrienes (LTs) in gastric juice from H. pylori positive (n = 13) and negative (n = 18) children with recurrent abdominal pain were studies in order to determine whether these lipid inflammatory mediators are involved in local and systemic biological actions. Gastric juice samples and biopsy specimens of mucosa were obtained endoscopically from 31 patients with recurrent abdominal pain for assessment of LTs and histopathological examination. In this study, all children with recurrent abdominal pain were investigated by rapid urease test and histological assessment for H. pylori colonization. Leukotriene levels were measured by high performance liquid chromatography (HPLC) and radioimmunoassay (RIA) in gastric juice samples. Gastric juice LTB4, LTC4, and LT4 levels were significantly higher in patients with H. pylori colonization than in children without H. pylori colonization. These results indicate that increased gastric content of proinflammatory mediators (LTB4, LTC4, and LT4) may be related to the pathogenesis of H. pylori-associated gastritis.

Bronchoalveolar lavage (BAL) was used to sample lung cells and biochemical components in the lung air spaces at various times from 1 to 91 d after intrapulmonary instillation of 2.6 microm-diameter iron oxide particles in human subjects. The instillation of particles induced transient acute inflammation during the first day post instillation (PI), characterized by increased numbers of neutrophils and alveolar macrophages as well as increased amounts of protein, lactate dehydrogenase, and interleukin-8 in BAL fluids. This response was subclinical and was resolved within 4 d PI. A similar dose-dependent response was seen in rats 1 d after intratracheal instillation of the same particles. The particles contained small amounts of soluble iron (240 ng/mg) and possessed the capacity to catalyze oxidant generation in vitro. Our findings indicate that the acute inflammation after particle exposure may, at least partially, be the result of oxidant generation catalyzed by the presence of residual amounts of ferric ion, ferric hydroxides, or oxyhydroxides associated with the particles. These findings may have relevance to the acute health effects associated with increased levels of ambient particulate air pollutants.

An automated on-line sampling method was developed using microdialysis as the simultaneous sampling and sample pre-treatment technique. The extraction fraction values of microdialysis probes sampling different eicosanoids were investigated. The impact of cyclodextrins in the perfusion liquid used for sampling hydrophobic eicosanoids in biological systems was also studied. The total time for one analysis was 7.6 min allowing seven measurements per hour for monitoring kinetic changes in biological systems.

Antibodies against integrins have been shown to inhibit allergic airway responses. The purpose of this study was to test the hypothesis that the beta1 integrin, very late antigen-4 (VLA-4), is involved in mast cell activation triggered by allergen exposure in sensitized animals. To do this we studied Brown Norway rats that were sensitized to ovalbumin (OA; 1 mg subcutaneously) using Bordetella pertussis as an adjuvant. Two weeks later rats were challenged with OA, pulmonary resistance (RL) was determined, and the concentrations of histamine and tryptase in bronchoalveolar lavage fluid and N-acetyl-leukotriene (LT)E4 in bile were measured. Pretreatment with a monoclonal antibody against VLA-4 (TA-2) attenuated the early response after OA challenge (342.9 +/- 24.4% baseline RL versus 153.3 +/- 19.4%; p < 0.01). There were significantly lower concentrations of histamine (67.11 +/- 11.90 microgram/ml versus 26.69 +/- 1.84; p < 0.01) and tryptase (0.143 +/- 0. 035 microgram/ml versus 0.053 +/- 0.022 microgram/ml; p < 0.01) in TA-2-treated animals. The increases in the concentrations of biliary N-acetyl-LTE4 after OA challenge were also significantly lower in TA-2-treated animals. These data suggest that a selective anti-VLA-4 monoclonal antibody prevents early responses through inhibition of mast cell activation.

This study investigated the post-treatment effect of isoproterenol (ISO) on pulmonary parameters in rabbits whole-body-exposed to a lethal dose of the toxic gas phosgene. Phosgene is widely used in industry as a chemical intermediate for the production of plastics, drugs and polyurethane products. The results of this study are from five study groups: 10-min perfused baseline; uninjured controls exposed to air; phosgene-exposed; phosgene-exposed isoproterenol-treated intravascularly and intratracheally (ISO i.v.+i.t.); and phosgene-exposed isoproterenol-treated intratracheally (ISO i.t.). Treatment with ISO was administered as either a continuous intravascular infusion (24 microg min(-1)) from the beginning to end of perfusion (i.v.) and a 24-microg intratracheal bolus (i.t.) or just an i.t. bolus immediately prior to the start of perfusion. Rabbits of 2.5-3 kg were exposed to a cumulative dose of phosgene to attain a concentration x time exposure-effect of 1500 ppm x min. Lungs were isolated in situ and perfused 50-60 min after the start of exposure with Krebs-Henseleit buffer at 40 ml min(-1). Pulmonary artery pressure (Ppa), tracheal pressure (Pt) and lung weight gain (lwg) were continuously measured. Leukotrienes (LT) C4/D4/E4 were measured in the perfusate every 20 min during perfusion. At the immediate conclusion of the experiment, lung tissue was frozen in liquid N2 and analyzed for glutathione (GSH) and cyclic 3',5'-adenosine monophosphate (cAMP). Post-treatment with ISO by either i.v.+i.t. or i.t. routes 50+ min after phosgene exposure significantly lowered Ppa, Pt and lwg. Phosgene-exposed rabbits post-treated with ISO i.t. had significantly higher levels of reduced GSH (3 +/- 0.4 nmol mg(-1) protein), GSH/GSSG ratios (3.3 +/- 0.6 nmol mg(-1) protein) and percentage of total as reduced GSH (75 +/- 2.5%) compared with phosgene-exposed rabbits: 1.9 +/- 0.3, 2 +/- 0.3 and 58 +/- 6.3%, respectively. The ISO (i.v.+i.t.) post-treatment route significantly increased reduced GSH (6.2 +/- 1.7 nmol mg(-1) protein), GSH/GSSG ratio (5.9 +/- 0.8 nmol mg(-1) protein) and percentage of total as reduced GSH (85 +/- 1.7%) when compared to the phosgene-only group. The ISO i.t. and ISO i.v.+i.t. treatments significantly reduced perfusate LTC4/D4/E4 150 min after the start of exposure by 90% and 48%, respectively. These data suggest that protective mechanisms for ISO involve reduced vascular pressure, decreased LTC4/D4/E4-mediated pulmonary capillary permeability and a favorable lung tissue redox state compared with untreated phosgene-exposed rabbits.

The kinetic profiles of leukotriene B4 (LTB4) and E4 (LTE4) after intravenous administration (30 nmol/kg) of the inflammatory peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) were evaluated in male rabbits. LTB4 and LTE4 reached the maximal concentration of 84.2 +/- 60.0 and 162.2 +/- 51.4 nmol/L (mean +/- s.d.), at 2 and 5 min, respectively. The first elimination phase for LTB4 and LTE4, after FMLP administration, showed an apparent half-life of 24.6 +/- 6.7 and 36.9 +/- 13.0 min, respectively. The area under the blood concentration-time curve (AUC, nmol min/L) of LTB4 and LTE4 was 2178 +/- 1591 and 7627 +/- 3052, respectively. LTE4 and N-ac-LTE4 were the major components excreted in the urine, mostly in the first time interval (0-12 h) of urinary collection after FMLP treatment; 11-trans-LTE4 was recovered in the second interval (12-24 h). Two other more polar compounds, potential metabolites, were recovered in the first interval of urine collection. Knowledge of the kinetic characteristics of endogenously produced leukotrienes may be useful in understanding the role of these eicosanoids in inflammatory and thrombotic disease, as well as in evaluating the efficacy of drugs designed to modulate their production and effect.

Cysteinyl leukotrienes (C-LTs) are local inflammatory mediators involved in bronchial asthma. Seventeen asthmatic patients (FEV1 ranging from 41 to 99.8% of predicted values) and 11 healthy subjects were studied. The clinical severity of asthma was assessed by the Aas score. Plasma C-LTs were measured by enzyme immunoassay (EIA) after sample purification by solid-phase extraction (SPE), to investigate whether differences may exist between asthmatic and control subjects and whether leukotriene E4 (LTE4) levels were related to the severity of disease. LT measurements showed that 87.6 +/- 1.2% was recovered as LTE4 and 9.4 +/- 1.3% as LTC4. In asthmatic subjects, LTE4 plasma levels were found to be significantly higher than those in the control group (1.073 +/- 0.133 and 0.53 +/- 0.19 ng/ml of plasma, respectively; P < 0.002). Moreover, there was a significant correlation between LTE4 plasma levels and the Aas clinical score (P < 0.005). These data suggest that plasma LTE4 levels might be used to assess the severity of asthma.

To investigate the contribution of leukotrienes (LTs) to inflammation and bronchoconstriction in nocturnal asthma, we performed a randomized trial in 12 asthmatic patients and 6 normal control subjects. This study involved pulmonary function testing, methacholine challenge, bronchoscopy for cell counts, LT and thromboxane (TX) levels in bronchoalveolar lavage (BAL) fluid, and collection of urine for LTs at 4:00 P.M. and 4:00 A.M. At 4:00 P.M. BAL fluid LTB4 and sulfidopeptide LT levels in asthmatic and control subjects were not statistically different. At 4:00 A.M. alone, LTB4 and cysteinyl LT levels increased to become significantly greater in asthmatic than in control subjects, LTB4 levels correlating significantly (r = -0.66, p < 0.0001) with nocturnal fall in FEV1. Nocturnal asthmatic urinary LTE4 levels were also significantly higher than those of control subjects. The 4:00 A.M. testing was repeated during treatment with a 5-lipoxygenase inhibitor, zileuton. In asthmatic subjects, zileuton decreased BAL fluid LTB4 (p = 0.01) and urinary LTE4 (p = 0.01) while showing a trend for improving nocturnal FEV1 (p = 0.086). These decreases in LTB4 levels and improvement in FVE1 were associated with significant reductions in 4 A.M. BAL fluid and blood eosinophil percentages on zileuton compared with placebo administration. These findings demonstrate the importance of LTs in both the inflammation and the physiology of nocturnal asthma.

We have recently reported that the 5-lipoxygenase (5-LO) inhibitor, zileuton, alters lung inflammation produced by segmental antigen challenge in ragweed-allergic human subjects. Specifically, zileuton inhibited the urinary excretion of leukotriene E4 produced by antigen challenge, and the significant increase in bronchoalveolar lavage (BAL) eosinophils observed in subjects on placebo was not seen in subjects on zileuton. In this manuscript, we report additional data obtained during that study which provide information about mechanisms important during IgE-mediated inflammatory reactions in the lung. Three different areas are addressed: 1) the time to recovery of the lung from an IgE-mediated inflammatory response; 2) mechanisms related to the generation of cyclooxygenase products in the lung after antigen challenge and the effect of 5-LO inhibition on the production of cyclooxygenase metabolites; and 3) mechanisms responsible for the production of peptide leukotrienes in the lung and lung injury (as shown by albumin influx into the alveolar air space) 24 h after antigen challenge. We observed the following: 1) a significant BAL eosinophilia and basophilia remained 31 days (range 21-48) after segmental antigen challenge and bronchoalveolar lavage; 2) a decreased quantity of BAL cyclooxygenase products, as well as lipoxygenase products, in the presence of 5-LO inhibition; and 3) correlative analyses which suggest that while eosinophils appear most important for the production of peptide leukotrienes and lung injury 24 h after antigen challenge in subjects taking placebo, other effector mechanisms, perhaps those involving basophils and the initial mast cell triggering event, appear to gain in importance when the IgE-mediated inflammatory reaction is blunted by 5-LO inhibition.

Proinflammatory mediators, including leukotriene (LT) B4, are elevated in the intestinal mucosa in active chronic inflammatory bowel diseases (IBD). LTE4 is the major peptidoleukotriene metabolite and it is stable in urine. The aim of this study was to measure LTE4 levels in the urine of 27 children with Crohn's disease and 27 control subjects including 12 children with functional recurrent abdominal pain and 15 unaffected siblings of IBD patients. LTE4 levels were measured in urine using high-performance liquid chromatography separation and radioimmunoassay with specific antibody. The Pediatric Crohn's Disease Activity Index and physician global assessment were used to categorize patient groups. C-reactive protein, orosomucoid, and erythrocyte sedimentation rate were employed as laboratory markers of mucosal inflammation. Urinary LTE4 levels were elevated in the 13 children with active Crohn's disease (160.5 +/- 59.4 pg/ml; mean +/- SEM) compared with both levels in the 14 patients with inactive disease (67.1 +/- 18.1 pg/ml; p < 0.05) and controls (45.0 +/- 10.9 pg/ml; p < 0.05). We conclude that measurement of urinary LTE4 is a useful test for monitoring the activation of peptidoleukotrienes in patients with Crohn's disease. It provides a noninvasive, objective adjunct for assessment of disease activity and could be employed in future trials examining the role of the leukotriene inhibitors in the medical therapy of IBD.

We have developed methods to measure LTE4, the index metabolite of cysteinyl leukotrienes, by HPLC/RIA and GC/MS. Urinary LTE4 appears to be a reliable parameter to assess whole body cysteinyl leukotriene synthesis in man from all evidence available at this time. Measurement of this metabolite can be used to monitor effects of diseases and drugs on cysteinyl leukotriene synthesis in man.