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Biomedical subjects

M Kumlin

Publications and source records attributed to M Kumlin.

At least 37 records · Page 2Linked to original sources
PubMed1998

Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics.

From bronchoprovocation studies and investigations of the acute effects of drugs that inhibit leukotrienes (LT), the hypothesis has emerged that leukotrienes are important mediators of airway obstruction and other symptoms in aspirin-intolerant asthma (AIA). However, it has yet not been shown if subjects with AIA respond favorably to clinical treatment with leukotriene inhibitors. Therefore, in a double-blind placebo-controlled crossover study, we examined the effects of 6 wk of treatment with the leukotriene-pathway inhibitor zileuton (600 mg, four times daily) in 40 patients with well-characterized AIA. The treatment was added to existing therapy, which included medium to high doses of inhaled (average daily dose 1,030 microg of beclomethasone or budesonide) or oral glucocorticosteroids (4 to 25 mg/d) for all but one of the patients. On top of this treated baseline, there were no significant effects of adding placebo, indicating that their asthma was kept relatively stable. However, there was an acute and chronic improvement in pulmonary function after treatment with zileuton, expressed both as increased FEV1 from baseline compared with placebo, and higher morning and evening peak expiratory flow rate (PEFR) values on zileuton treatment compared with placebo. The improvements occurred despite lower use of rescue bronchodilator with zileuton. Zileuton also diminished nasal dysfunction, which is one of the cardinal signs of AIA. There was a remarkable return of smell, less rhinorrhea, and a trend for less stuffiness and higher nasal inspiratory flow during treatment with zileuton. Zileuton caused a small but distinct reduction of bronchial hyperresponsiveness to histamine and inhibited aspirin-induced bronchoconstriction. Zileuton inhibited urinary excretion of LTE4 but did not change airway reactivity to inhaled LTD4, supporting that zileuton specifically inhibited leukotriene biosynthesis. The findings indicate that leukotrienes are important mediators of persistent airway obstruction and chronic nasal dysfunction in AIA. The study also suggests that addition of a leukotriene pathway inhibitor such as zileuton may bring about greater control of asthma than what is achieved by treatment with medium to high doses of glucocorticosteroids alone.

Adrenergic beta-Agonists↗
PubMed1998

Evidence for mast cell activation during exercise-induced bronchoconstriction.

Controversy remains about the causative mediators in the bronchoconstrictive response to exercise in asthma. This study examined whether mast cell activation is a feature of exercise-induced bronchoconstriction by measuring urinary metabolites of mast cell mediators. Twelve nonsmoking subjects with mild asthma and a history of exercise-induced bronchoconstriction exercised on a stationary bicycle ergometer for 5 min at 80% maximum work load. Pulmonary function was monitored and urine was collected before and 30 and 90 min after the provocation. The urinary concentrations of the mast cell markers 9alpha,11beta-prostaglandin (PG)F2 and Ntau-methylhistamine, as well as leukotriene E4 (LTE4) were determined by immunoassay. Seven of the 12 subjects (responders) experienced bronchoconstriction (>15% fall in the forced expiratory volume in one second) following exercise, whereas the pulmonary function of the remaining five subjects (nonresponders) remained stable. The urinary excretion (mean+/-SE) of 9alpha,11beta-PGF2 in the responders increased significantly compared with the nonresponders at 30 (77.1+/-14.4 versus 37.2+/-5.6; p<0.05) and 90 min (79.3+/-8.6 versus 40.4+/-8.5, p<0.05) after exercise challenge. The urinary excretion of Ntau-methylhistamine and LTE4 was not significantly different between the two groups at 30 or 90 min after exercise. The findings represent the first documentation of increased urinary levels of 9alpha,11beta-prostaglandin F2 in adults following exercise challenge and provides clear evidence for mast cell activation during exercise-induced bronchoconstriction in asthmatics.

Adult↗
PubMed1997

Inhibition of allergen-induced airway obstruction and leukotriene generation in atopic asthmatic subjects by the leukotriene biosynthesis inhibitor BAYx 1005.

BACKGROUND: Leukotriene receptor antagonists significantly blunt allergen-induced bronchoconstriction in asthmatic subjects. Inhibitors of leukotriene synthesis should theoretically provide similar protection, but conflicting results have been obtained when synthesis inhibitors have been tested in allergen challenge. BAYx 1005, a new inhibitor of leukotriene synthesis, was therefore evaluated in an allergen bronchoprovocation study. METHODS: Ten men with mild allergic asthma and bronchial hyperresponsiveness to histamine were recruited. On two different occasions each subject inhaled a single dose of allergen, previously determined to cause at least a 20% fall in forced expiratory volume in one second (FEV1) four hours after ingestion of 750 mg BAYx 1005 or placebo in a double blind crossover design. Urinary excretion of leukotriene E4 was measured before and during the challenges. RESULTS: The mean (SE) maximal fall in FEV1 was 7.1 (1.7)% after BAYx 1005 and 21.0 (3.0)% after placebo (p < 0.001). The mean difference between treatments was 13.9 (95% CI 7.0 to 20.8) for the maximal fall in FEV1. All subjects were protected by BAYx 1005, the mean inhibition of the fall in FEV1 being 70.0 (7.0)%. The mean area under the curve (AUC) for urinary excretion of leukotriene E4 in the first two hours after the challenge was 1.7 (0.9) after placebo and 0.4 (0.6) after BAYx 1005 (difference = 1.3 (95% CI-0.1 to 2.7); p < 0.05). CONCLUSIONS: These results indicate that BAYx 1005 is a potent inhibitor of allergen-provoked leukotriene synthesis in asthmatic subjects and lend further support to the suggestion that leukotrienes are important mediators of allergen-induced bronchoconstriction.

Adult↗
PubMed1997

Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics.

We defined the contribution of histamine and leukotrienes to allergen-induced airway obstruction in asthmatics; 12 subjects with allergic asthma underwent identical allergen bronchoprovocations on four occasions. At a control session, all subjects displayed early (EAR) and late asthmatic (LAR) reactions. The mean (+/- SE) drop in FEV1 during EAR (0-2 h) and LAR (2-12 h) was 29 +/- 2% and 28 +/- 4%, respectively. Thereafter, the influence of 1 wk randomized pretreatment with the leukotriene receptor antagonist zafirlukast (Accolate) (80 mg twice daily), the antihistamine loratadine (10 mg twice daily), and the combination of both antagonists was assessed. Expressed as AUC FEV1 in percent of the control reaction, zafirlukast reduced the response during EAR and LAR by 62 +/- 11% and 55 +/- 12%, respectively (p < 0.05 versus control). Loratadine inhibited EAR and LAR by 25 +/- 14% and 40 +/- 16%, respectively (p < 0.05 versus control). Zafirlukast was significantly more effective than loratadine during EAR but not during LAR. The combination of zafirlukast and loratadine reduced the AUC FEV1 during EAR and LAR further, by 75 +/- 8% and 74 +/- 14%, respectively (p < 0.05 versus control). The combination was significantly (p < 0.05) more effective than either drug alone during the LAR. The findings indicate that leukotrienes and histamine together mediate the major part of both the EAR and the LAR following exposure of asthmatics to allergen. Combination of leukotriene antagonism and antihistamines may represent a new strategy for treatment of airway obstruction in asthma.

Adolescent↗
PubMed1996

Analytical methods for the measurement of leukotrienes and other eicosanoids in biological samples from asthmatic subjects.

This paper summarizes methodological aspects of measurements of eicosanoids in biological samples and describes some applications of such methods in studies on leukotriene formation in the human airways and the effects of drugs interfering with these compounds in asthmatic subjects. For estimations of in vivo production of eicosanoids, major, stable metabolites were selected for analysis in biological fluids. An enzyme immunoassay for LTE4 was validated for use in unextracted urine samples. To monitor thromboxane production, a radioimmunoassay for 11-dehydro-TXB2 was developed and used for measurements in samples of human plasma and urine. In vitro production of leukotrienes in chopped human lung was measured by UV-spectroscopy after extraction and separation on RP-HPLC. Corrections for losses during purification were performed with individually selected internal standards.

Asthma↗
PubMed1996

Increased urinary excretion of the prostaglandin D2 metabolite 9 alpha, 11 beta-prostaglandin F2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction.

Prostaglandin (PG)D2 is a major product of arachidonic acid metabolism in pulmonary mast cells. We therefore attempted to determine whether measurement of the stable urinary metabolite of PGD2, 9 alpha, 11 beta-PGF2, could serve as a marker of mast cell activation in the lungs. A commercially available enzyme immunoassay was validated and found to be specific and sensitive when applied to unpurified urine. There was no diurnal variation in the levels of 9 alpha, 11 beta-PGF2 in healthy volunteers. Morning baseline values of urinary 9 alpha, 11 beta-PGF2 were measured in three groups--healthy volunteers (n = 9), patients with atopic asthma (n = 14), and aspirin-intolerant patients with asthma (n = 12)--and found to be very similar, 54 +/- 9, 62 +/- 6, and 71 +/- 15 ng/mmol creatinine, respectively (means +/- SEM). Urinary excretion of 9 alpha, 11 beta-PGF2 was increased threefold immediately after allergen-induced bronchoconstriction in nine patients with atopic asthma. Bronchial challenge with inhaled lysine aspirin in eight aspirin-intolerant patients with asthma produced bronchoconstriction without extrapulmonary symptoms and was also followed by a significant increase in the urinary excretion of 9 alpha, 11 beta-PGF2. In addition, challenge with a higher dose of aspirin produced an even greater increase in urinary 9 alpha, 11 beta-PGF2, supporting dose-dependent release of PGD2 during aspirin-induced bronchoconstriction. In contrast, the postchallenge levels of urinary 9 alpha, 11 beta-PGF2 were not increased when bronchoconstriction was induced by histamine challenge in the aspirin-intolerant patients with asthma. The study confirms mast cell involvement in allergen-induced bronchoconstriction and provides novel data, which strongly support the hypothesis that pulmonary mast cells are activated during aspirin-induced airway obstruction. It is finally suggested that measurement of urinary 9 alpha, 11 beta-PGF2 with enzyme immunoassay may be used as a new noninvasive strategy to monitor mast cell activation in vivo.

Adult↗
PubMed1996

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.

Administration, Inhalation↗
PubMed1995

Arachidonic acid metabolism in the human mast cell line HMC-1: 5-lipoxygenase gene expression and biosynthesis of thromboxane.

Metabolism of arachidonic acid was studied in the unique human mast cell line HMC-1. By HPLC and/or gas chromatography mass spectrometry (GC-MS), 19 oxygenated metabolites were identified, including monohydroxy acids, leukotrienes, prostaglandins, and thromboxane. Intact cells incubated with the calcium ionophore A23187 and arachidonic acid expressed 5-lipoxygenase activity and produced 5-hydroxyeicosatetraenoic acid (5-HETE) as the major metabolite (745 pmol/10(7) cells) followed by leukotriene (LT) C4 (245 pmol/10(7) cells) and 11-trans-LTC4 (74 pmol/10(7) cells). Low but clearly detectable levels of LTB4 were also observed. The total amounts of 5-LO products were comparable to those obtained with RBL-1 cells and corresponded to approx. 30% of the levels obtained with isolated human polymorphonuclear leukocytes. Time-course experiments revealed that HMC-1 cells contained the enzyme activities required to metabolize LTC4 into LTD4 and further into LTE4. The profile of prostanoids included, prostaglandin (PG) E2, PGF2 alpha, and PGD2, whereas 6-keto-PGF1 alpha, reflecting prostacyclin formation, could not be detected. Furthermore, we were able to unambiguously establish that HMC-1 cells could produce substantial amounts of thromboxane (TX) A2, measured as TXB2 (0.1-2.2 nmol/10(7) cells). Generation of TXA2 in such quantities, exceeding those of LTC4, suggests that mast cells may be an important source of thromboxane and points to a possible role for these cells in hemostasis and thrombosis. After approx. 10 passages in culture, 5-lipoxygenase activity in HMC-1 cells drastically declined concomitantly with changes in growth behavior and cell morphology. Analysis by Northern and Western blots revealed that loss of 5-lipoxygenase activity correlated well with a reduced 5-lipoxygenase gene expression at both a transcriptional and translational level. This loss of enzyme activity and gene expression may be related to a genetic abnormality propagated in HMC-1 cells, i.e., a 10;16 translocation, which thus involves the chromosome containing the 5-lipoxygenase gene.

Arachidonate 5-Lipoxygenase↗
PubMed1995

Validation and application of a new simple strategy for measurements of urinary leukotriene E4 in humans.

To monitor endogenous production of cysteinyl-containing leukotrienes, the end-metabolite leukotriene E4 (LTE4) was analysed in urine. Results obtained with a sensitive enzyme immunoassay (EIA), performed on crude urine samples correlated well with data obtained from a previously reported radioimmunoassay. Enzyme immunoassay analysis of unextracted urine was justified by an excellent agreement between analyses in crude samples and measurements achieved after purification on solid phase extraction followed by separation on reversed-phase high performance liquid chromatography. Moreover, LTE4 was stable in urine samples stored at -20 degrees C, for months without the addition of preservatives. The stability of LTE4 in urine was not improved by addition of the antioxidant 4-hydroxy-TEMPO and pH adjustment to 9. As assessed by EIA analysis in crude urine samples, baseline values for urinary leukotriene E4 were not significantly different between atopic asthmatic subjects and non-asthmatic individuals, and there was no diurnal variation in urinary excretion of LTE4 in healthy subjects. However, we confirmed earlier data on significantly higher basal levels of urinary LTE4 in aspirin-intolerant asthmatics. In addition, a post-challenge increase in urinary LTE4 levels was detected in association with allergen-induced airway obstruction in atopic asthmatics. The per cent increase in urinary LTE4 was similar, irrespective of whether the samples were purified or not prior to EIA. Thus, combined with random validation by high performance liquid chromatography, the strategy of direct EIA of serially diluted urine samples was found to be a good index of in vivo production of leukotrienes. This was further reinforced by the demonstration that pretreatment with the leukotriene biosynthesis inhibitor Bay x 1005 inhibited the post allergen-challenge increase in urinary LTE4, as shown both with unpurified and purified samples.

Allergens↗
PubMed1995

Effects of oxygen radicals on cysteinyl leukotriene metabolism and pulmonary circulation in young pigs.

The effects of oxygen radicals, generated by the hypoxanthine-xanthine oxidase (XO) system, on pulmonary circulation and release of cysteinyl-containing leukotrienes (LTs) were studied in pigs after XO infusion into the right atrium. A 2.3-fold increase in pulmonary vascular resistance (PVR) (p < 0.05 vs. baseline) and a 2.1-fold increase in LT release (p < 0.05 vs. baseline) was observed. Pretreatment with indomethacin and allopurinol attenauted the vascular response (p < 0.01 and p < 0.05 vs. XO), and the LT release was inhibited by allopurinol and catalase (p < 0.01 and p < 0.02 vs. XO). We conclude that oxygen radicals stimulate lipoxygenase metabolism. This coincides with the observed increase in PVR, however, no causal relationship can be derived from the data presented.

Animals↗
PubMed1995

Allergen-induced late-phase airways obstruction in the pig: mediator release and eosinophil recruitment.

The aim of this study was to develop a novel model for studies of mediator mechanisms involved in the late asthmatic reaction in the lower airways, by using the sensitized pig. The release of histamine and cysteinyl-containing leukotrienes (cys-LTs), as well as the levels of inflammatory cells in blood and bronchoalveolar lavage fluid, were determined and their relationship to plasma cortisol levels and pulmonary airways obstruction was noted. Specific-pathogen free pigs were actively sensitized with Ascaris suum allergen, and one group of animals was treated with a cortisol-synthesis inhibitor (metyrapone) by constant intravenous infusion. Ascaris suum allergen was nebulized into the lower airways and total lung resistance, blood leucocyte count and urinary levels of methylhistamine and leukotriene E4 (LTE4) were followed for 8 h, whereafter bronchoalveolar lavage was performed for analysis of leucocytes. An increase in urinary methylhistamine and LTE4 was seen during the acute allergic reaction in both groups of pigs. Metyrapone treatment prolonged the acute release of histamine, and this was seen together with a prolonged acute bronchoconstrictor response. In metyrapone-treated pigs, a continuous release over 8 h was seen for cys-LTs, but not for histamine. A late blood eosinophilia was also seen in metyrapone-treated animals, starting 4-6 h after allergen challenge. Late cys-LT release and eosinophilia were absent in non-metyrapone-treated animals. These results suggest that allergen-induced late release of cys-LTs as well as blood eosinophilia occur simultaneously with late-phase airways obstruction in the pig, and that all these reactions are prevented by high levels of endogenous cortisol.

Allergens↗
PubMed1995

D-penicillamine inhibits the action of reactive oxygen species in the pig pulmonary circulation.

Oxygen radicals produced by the hypoxanthine-xanthine oxidase (Hyp-XO) system potently constrict the pulmonary circulation of pigs. D-penicillamine (DPA) is thought to be a free radical scavenger. In the present work we have studied if DPA may influence the vasoactive action of Hyp-XO in pig lungs. Further, we have measured how this drug influences the output of cyclooxygenase and lipoxygenase products from the left atrium in pigs infused with XO into the pulmonary circulation. Twelve young pigs were divided into two groups. Group 1, the XO group, was infused 1 U/kg XO into right atrium. Group 2, the DPA group, was pretreated with DPA, 100 mg/kg intravenously before XO infusion as in group 1. Pulmonary artery pressure, left atrial pressure, pulmonary artery blood flow and systemic blood flow and pressure were recorded continuously. Plasma tromboxane B2 and prostaglandin (6-keto-PGF1 alpha) were determined with a radioimmunoassay method. Cysteinyl containing leukotrienes LTC4, LTD4, and LTE4, were measured together by RIA analyses of plasma samples, using a monoclonal antibody. There was a significant parallel decrease in paO2 and saO2 during the 130 minutes duration of the experiments in both groups without differences between the groups. Pulmonary vascular pressure and resistance increased sharply with a peak found after 25 minutes in the XO group. DPA attenuated the hemodynamic response. DPA inhibited the XO induced pulmonary blood pressure changes with 80% and inhibited the increase in pulmonary vascular resistance 68%. Plasma TXB2 increased two folds in the XO group reaching a maximum after 40 minutes, this effect was completely inhibited by DPA (92% inhibition). DPA also inhibited the XO induced increase in 6-keto-PGF1 alpha, however, not as efficient as with TXB2 (40% inhibition). Plasma cysteinyl leukotrienes increased after XO infusion reaching a peak at 20 minutes. DPA completely abolished this effect (100% inhibition). The study demonstrates that DPA attenuates or even abolishes the hemodynamic effects of XO on the pulmonary circulation in pigs. It seems that DPA inhibits the production of both lipoxygenase and cyclooxygenase products per se, and it is tempting to speculate that the observed DPA effect is caused by its action as an oxygen radical scavenger. It is further speculated that the vasoconstricting effect of XO is due to the fact that oxygen radicals may inactivate nitric oxide (NO), and that DPA stabilizes NO so it more efficiently possess its vasorelaxant activity. We conclude that DPA is an extremely potent inhibitor of XO induced pulmonary vascular effects. The mechanism of action is not fully understood, although its action as an oxygen radical scavenger may explain part of it.

Animals↗
PubMed1993

The leukotriene-receptor antagonist MK-0679 blocks airway obstruction induced by inhaled lysine-aspirin in aspirin-sensitive asthmatics.

Drugs which block the action or formation of the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) inhibit asthmatic responses evoked by allergen, exercise and cold dry air. The purpose of this study was to determine whether the specific leukotriene-receptor antagonist MK-0679 could block the airway obstruction induced by aspirin (acetylsalicylic acid (ASA)) in aspirin-intolerant asthmatics. Eight asthmatics (mean age 45 yrs), with an average history of asthma and ASA-sensitivity of about 10 yrs duration, were subjected to bronchial provocation with lysine-ASA. Baseline ASA-sensitivity was first determined in an open prestudy session by inhalation of cumulative doses of lysine-ASA to establish the dose of ASA decreasing forced expiratory volume in one second (FEV1) by 20% (PD20). Rechallenge with lysine-ASA was performed on two different occasions, 1 h after oral administration of placebo, or 750 mg of MK-0679, under double-blind conditions, in a randomized, cross-over design. Leukotriene formation was estimated by the measurement of urinary LTE4. The lysine-ASA challenge was highly reproducible (geometric mean for group PD20 being identical for the open prestudy and the placebo session), and was associated with a post-challenge increase in urinary LTE4. In contrast, after MK-0679, there was a rightward shift in the dose response relationship for all eight subjects (median shift being 4.4 fold), with three of the subjects failing to produce a 20% decrease in FEV1 despite inhalation of the highest dose of lysine-ASA feasible to deliver.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗
PubMed1992

Urinary excretion of leukotriene E4 and 11-dehydro-thromboxane B2 in response to bronchial provocations with allergen, aspirin, leukotriene D4, and histamine in asthmatics.

In vivo production of thromboxane (TX) A2 and the cysteinyl-containing leukotrienes (LT) C4, D4, and E4 in correlation to airway responses was studied. Bronchial provocation with specific allergen in atopic asthmatics was followed by a significant increase in urinary concentration of immunoreactive LTE4 (34 +/- 6 before versus 56 +/- 7 ng/mmol creatinine after allergen challenge; n = 5) and 11-dehydro-TXB2 (164 +/- 29 versus 238 +/- 25 ng/mmol creatinine). In the presence of the leukotriene-antagonist ICI-204,219, which significantly increased the PD20 for allergen, the increment in urinary excretion of LTE4 was even higher (60 +/- 8 versus 288 +/- 128 ng/mmol creatinine; n = 5). In contrast, provocation with histamine (n = 5) did not provoke release of leukotrienes or thromboxane, nor was inhalation of LTD4 (n = 7) associated with increased urinary concentration of 11-dehydro-TXB2. Furthermore, bronchoconstriction induced by inhalation of lysine-aspirin in aspirin-sensitive asthmatics (n = 4) was followed by increased levels of LTE4 in the urine, whereas the levels of 11-dehydro-TXB2 remained the same. Finally, the basal levels of LTE4 in the urine of nine aspirin-sensitive asthmatics were elevated as compared with 15 other asthmatics (112 +/- 54 versus 38 +/- 20 ng/mmol creatinine; p less than 0.001). The findings support that the cysteinyl-leukotrienes are potential mediators of allergen-induced asthma and that the release of LTE4 and 11-dehydro-TXB2 into the urine appeared to be a direct and dose-dependent effect of the antigen-antibody reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Mechanisms of hydroperoxide-induced broncho- and vasoconstriction in isolated and perfused rat lung.

The mechanisms of hydroperoxide-induced broncho- and vasoconstriction were investigated in the perfused and ventilated rat lung. Hydrogen peroxide (500 microM), tertiary butylhydroperoxide (500 microM) and arachidonic acid (100 microM) induced similar profiles of broncho- and vasoconstriction which could be prevented by the inhibitor of cyclooxygenase, diclofenac (100 microM) but not by nordihydroguaiaretic acid (5 and 25 microM), an inhibitor of lipoxygenase. The hydroperoxides also caused a time-dependent increase in the levels of thromboxane and prostacycline, products of cyclooxygenase. Furthermore, the thromboxane agonist, U44069 (100 pmoles), caused a very rapid broncho- and vasoconstriction that was preventable by the thromboxane antagonist L655.240 (1 microM). L655.240 also inhibited hydrogen peroxide-induced broncho- and vasoconstriction. The phospholipase A2 inhibitors, quinacrine (100 microM) and dibucaine (100 microM), did not prevent hydroperoxide-induced broncho- and vasoconstriction. The Ca2+ chelator, EGTA, prevented hydroperoxide and arachidonic acid-induced lung constriction, although it did not inhibit the release of thromboxane. The infusion of arachidonic acid and hydroperoxides resulted in edema in the lung which was prevented by prior administration of diclofenac, indomethacin or L655.240. These results indicate that hydroperoxide-induced broncho- and vasoconstriction and lung edema are mediated by thromboxane, a product of cyclooxygenase. The mechanism of hydroperoxide-induced release of arachidonic acid is not clear but does not seem to involve Ca2+ nor the activation of phospholipase A2.

Animals↗