Increase In Leukotriene E4 Research Articles

Clinical course and urinary eicosanoids in patients with aspirin-induced urticaria followed up for 4 years

Little is known about the course of aspirin-induced urticaria. A special regulatory role of cysteinyl leukotrienes and prostaglandin D(2) (PGD(2)) has been postulated. We performed a long-term observation on clinical course, aspirin sensitivity, and urinary eicosanoids in patients with aspirin-induced urticaria. For 4 years, we followed up 22 patients with chronic idiopathic urticaria and aspirin hypersensitivity who restrained from the use of aspirin and other COX-1 inhibitors. Aspirin challenges were performed in 2002 (all results were positive) and repeated in 2006. Levels of urinary leukotriene E(4) (LTE(4)) and the main PGD(2) metabolite, 9 alpha 11 beta PGF(2), were measured at the same time points. During the follow-up period, the severity of urticaria has decreased. In 14 of 22 patients, the results of aspirin challenge remained positive. In 2002, these 14 patients responded to aspirin with a significant increase in urinary LTE(4) and 9 alpha 11 beta PGF(2) levels. When studied 4 years later, they showed a similar response of 9 alpha 11 beta PGF(2) (P = .047) and a tendency toward an increase in LTE(4) level (P = .057). There was a correlation between the urinary LTE(4) concentration after aspirin challenge and the intensity of skin eruptions. The dose of aspirin had no effect on the magnitude of response of both LTE(4) and the PGD(2) metabolite. In the remaining 8 patients, negative aspirin challenge results were not associated with changes in the urinary eicosanoids studied. Aspirin hypersensitivity manifesting as urticaria/angioedema remains present after 4 years in about two thirds of patients. Aspirin-precipitated skin reactions associate with increased excretion of LTE(4) and PGD(2).

Increase in urinary leukotriene B4 glucuronide concentration in patients with aspirin-intolerant asthma after intravenous aspirin challenge.

Aspirin challenge of aspirin-intolerant asthma (AIA) patients causes a significant increase in leukotriene E4 (LTE4) concentration in urine. However, knowledge on leukotriene B4 (LTB4) generation in patients with AIA is insufficient. Recent research has demonstrated that exogenously administered LTB4 is excreted as glucuronide into the urine in human healthy subjects. The purpose of this study is to estimate urinary LTB4 glucuronide (LTBG) concentration in the clinically stable condition in healthy subjects and asthmatic patients and to investigate changes in urinary LTBG concentration in patients with AIA after aspirin challenge. A provocation test was performed by intravenous aspirin challenge. After urine was hydrolysed by beta-glucuronidase, the fraction containing LTB4 was purified by high-performance liquid chromatography and LTB4 concentration was quantified by enzyme immunoassay. Urinary LTBG concentration was calculated as the difference between the concentration obtained with hydrolysis and that without hydrolysis. (1) After hydrolysis, the presence of urinary LTB4 was verified by gas chromatography-mass spectrometry-selected ion monitoring. (2) The urinary LTBG concentration was significantly higher in the asthmatic patients than in the healthy subjects (median, 5.37 pg/mg creatinine [range 1.2-13] vs. 3.32 pg/mg creatinine [range, 0.14-10.5], P = 0.0159). (3) The patients with AIA (n = 7), but not those with aspirin-tolerant asthma (n = 6), showed significant increases in LTBG and LTE4 excretions after aspirin challenge. (4) When the concentrations after aspirin challenge were analysed simultaneously, a significant linear correlation was observed between urinary LTBG concentration and urinary LTE4 concentration in patients with AIA (Spearman's rank correlation test, r = 0.817, P = 0.0003). LTBG is present in human urine, albeit at a concentration lower than urinary LTE4. In addition to a marked increase in cysteinyl-leukotriene production, aspirin challenge induced LTB4 production in AIA patients.

The use of the leukotriene receptor antagonist montelukast (singulair®) in the management of dysmenorrhea in adolescents

PurposePrevious studies have shown an increase in leukotrienes in the uterine tissue as well as in the menstrual flow of adult women with dysmenorrhea. An increase in leukotriene-E4, the major urinary leukotriene, was also reported in adolescent girls with dysmenorrhea, further suggesting a possible involvement of these potent vasoconstrictors and inflammatory mediators in generating dysmenorrhea symptoms. In the present study we examined whether blocking leukotrienes might alleviate symptoms of dysmenorrhea in adolescents. MethodsTwenty-five adolescents (age 16 ± 1 years, 4 ± 1 years post menarche, body mass index 23 ± 1) with dysmenorrhea participated in a randomized, double blind, crossover study. Thirteen girls received one tablet of montelukast (Singulair®, Merck, West Point, PA) 10 mg daily starting on day 21 of the cycle until the last day of the menstrual period for two menstrual cycles, followed by one tablet of placebo (Merck, West Point, PA) daily starting on day 21 of the cycle until the last day of the menstrual period for two additional menstrual cycles. The other 12 girls had a reverse schedule starting with placebo. Participants were instructed to use one or two 200-mg tablets of ibuprofen every 6 h in the event of continuing menstrual symptoms. The Cox Menstrual Symptom Scale was used to assess response to treatment. An intent-to-treat approach was used for data analysis. ResultsTwenty-two girls completed the study. Two girls were noncompliant with the study protocol, and one was withdrawn because of Helicobacter pylori infection. Compared with Cox menstrual score (mean ± SE) before study (46 ± 6), there was no significant change in menstrual symptoms during treatment with placebo (Cox score 42 ± 7) or during treatment with montelukast (Cox score 39 ± 7), and there was no significant difference between montelukast and placebo treatments as well. Likewise, there was no significant difference between the amount of ibuprofen tablets consumed during the menstrual periods before study (4 ± 1), while on placebo (3 ± 1), and while on montelukast (4 ± 1). ConclusionsThis study does not support the use of montelukast, in the current FDA-approved dose (for asthma) and commencing immediately before the menstrual period, for treatment of dysmenorrhea. It remains to be determined in further studies whether a higher dose or a prolonged daily use of montelukast may alleviate symptoms of dysmenorrhea in adolescents.

Early increase in urinary leukotriene E4 (LTE4) is dependent on allergen dose inhaled during bronchial challenge in asthmatic subjects.

Urinary leukotriene E4 (LTE4) excretion is a good marker of the rate of total body production of sulfidopeptide leukotrienes released during allergen challenge. Twenty-three subjects with allergic asthma were challenged with inhaled allergen, and the urinary excretion of LTE4 was determined by immunoenzymatic assay (associated with HPLC separation) at various intervals after challenge. Allergen challenge caused an early airway response (EAR) with a drop in FEV1 of 40.3+/-9.9%. This was associated with an increase in urine LTE4 excretion for 0-3 h after allergen inhalation (296+/-225.25 pg/mg creatinine) in comparison with baseline values obtained during the night before challenge (101.02+/-61.97 pg/mg creatinine). Urinary LTE4 excretion was significantly higher in subjects who inhaled a higher dose of allergen during challenge (LTE4 during EAR: 211+/-192 pg/mg creatinine in subjects with inhaled total dose of allergen <0.1 biologic units; 408+/-223 pg/mg creatinine in subjects with inhaled total dose >0.1 biologic units). All subjects showed a late airway response (LAR) to allergen of different severity, from mild (FEV1 fall: 15-20%) to severe (>30%); no correlation was found between the increase in urine LTE4 excreted during LAR (3-7 h after challenge) and the severity of LAR, but only subjects with severe LAR showed a significant increase in LTE4 during LAR in comparison with baseline value. A release of sulfidopeptide leukotrienes, as evaluated by urinary LTE4 excretion, can be documented during EAR and LAR to allergen in relation to the dose of inhaled allergen, and it can represent a useful index of the events underlying the airway inflammatory responses during allergen challenge.

Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model.

Transfusion-related acute lung injury (TRALI) is a serious complication of hemotherapy. During blood storage, lipids are generated and released into the plasma. In this study, the role of these lipids in TRALI was investigated using an isolated, perfused rat lung model. Rats were pretreated with endotoxin (LPS) or saline in vivo and the lungs were isolated, ventilated, and perfused with saline, or (a) 5% (vol/ vol) fresh human plasma, (b) plasma from stored blood from the day of isolation (D.0) or from the day of outdate (D.42), (c) lipid extracts from D.42 plasma, or (d) purified lysophosphatidylcholines. Lungs from saline or LPS-pretreated rats perfused with fresh (D.0) plasma showed no pulmonary damage as compared with saline perfused controls. LPS pretreatment/D.42 plasma perfusion caused acute lung injury (ALI) manifested by dramatic changes in both pulmonary artery pressure and edema. Incubation of LPS pre-tx rats with mibefradil, a Ca2+ channel blocker, or WEB 2170, a platelet-activating factor (PAF) receptor antagonist, inhibited ALI caused by D.42 plasma. Lung histology showed neutrophil sequestration without ALI with LPS pretreatment/saline or D.0 plasma perfusion, but ALI with LPS pretreatment/D.42 plasma perfusion, and inhibition of D.42 plasma induced ALI with WEB 2170 or mibefradil. A significant increase in leukotriene E4 was present in LPS-pretreated/D.42 plasma-perfused lungs that was inhibited by WEB 2170. Lastly, significant pulmonary edema was produced when lipid extracts of D.42 plasma or lysophosphatidylcholines were perfused into LPS-pretreated lungs. Lipids caused ALI without vasoconstriction, except at the highest dose employed. In conclusion, both plasma and lipids from stored blood produced pulmonary damage in a model of acute lung injury. TRALI, like the adult respiratory distress syndrome, may be the result of two insults: one derived from stored blood and the other from the clinical condition of the patient.

Effects of local and systemic budesonide on allergen-induced airway reactions in the pig.

1. In this study, an attempt was made to distinguish between local and systemic effects of low doses of the topical glucocorticoid, budesonide. The effect of aerosolized budesonide administered to the lower airways versus intravenously administered budesonide on the acute and late response to nebulized Ascaris suum extract in the lung, was evaluated in the minipig after active sensitization with purified A. suum antigen. Budesonide was administered once, 1 h prior to A. suum challenge and airway reactions and mediator release were observed for 8 h after allergen challenge. 2. In the budesonide aerosol group (n = 6), 10.2 +/- 1.2 micrograms kg-1 budesonide was given locally and in the budesonide infusion group (n = 5), 5 micrograms kg-1 was given intravenously. The area under the plasma concentration curve for budesonide during the experiment was 11.4 +/- 1.2 and 10.3 +/- 1.2 nM h in the budesonide aerosol and budesonide infusion group, respectively (no significant difference). The lung tissue content of budesonide in the two groups was 45.2 +/- 4.9 and 18.4 +/- 3.5 nmol kg-1 dry tissue, respectively, 8 h after allergen challenge (P < 0.05). For comparison, 6 pigs were given budesonide vehicle as an infusion prior to A. suum challenge. 3. Total lung resistance (RL) increased acutely (maximal response within 15 min) in the budesonide aerosol, budesonide infusion and budesonide vehicle groups (by 91 +/- 40, 150 +/- 86 and 80 +/- 27%, respectively). The acute reaction partially resolved at about 1 h and was followed by a late increase in RL in the budesonide infusion and budesonide vehicle groups (by 251 +/- 148 and 281 +/- 136% at 8 h, respectively). However, no late change in RL was seen in the budesonide aerosol group (7 +/- 24%). 4. Aerosolized budesonide had a protective effect in that it attenuated the late changes in arterial blood gas and pH as well as the late elevation of plasma catecholamines. Budesonide given as an infusion did not protect against the late changes in these parameters. However, budesonide aerosol or infusion did not inhibit the late vasodilation in the bronchial circulation. 5. Histamine and cysteinyl-leukotrienes were released during the acute reaction as measured by urinary concentration of methylhistamine and leukotriene E4 respectively. There was no release of histamine during the late reaction. A late increase in leukotriene E4 was observed in 2 of the budesonide infusion and 3 of the budesonide vehicle pigs, whereas no such increase was seen in any of the budesonide aerosol pigs. 6. Budesonide concentration in lung tissue, but not in plasma at 8 h correlated negatively with the late increase in RL (P < 0.05, r = -0.53, n = 10), whereas budesonide concentration in plasma but not in lung tissue correlated negatively with the late decrease in dynamic compliance (P < 0.05, r = -0.67, n = 12). 7. This study has shown that a single low dose of locally administered budesonide can inhibit the late allergic reaction in the pig lower airways. If budesonide was given as an intravenous infusion in a dose yielding a plasma concentration similar to that seen after the aerosol treatment, the protective effect of budesonide was poor. It may be suggested that the tissue-bound portion of budesonide affects local mechanisms involved in the development of late changes in the airways (RL), although it does not affect the late increase in bronchial blood flow. We conclude that the inhibitory effect of budesonide on the allergen-induced late reaction in the pig airways relates to tissue-bound steroid, and that the systemic component is of less importance.