thromboxane-b2 and Asthma

Prostaglandins (PGs) are a family of lipid compounds that are derived from arachidonic acid via the cyclooxygenase pathway, and consist of PGD

Topics: Animals; Asthma; Humans; Hypersensitivity; Prostaglandins; Rhinitis, Allergic; Thromboxane B2

Topics: Asthma; Biomarkers; Cardiovascular Diseases; Humans; Immunoenzyme Techniques; Ischemia; Kidney Failure, Chronic; Radioimmunoassay; Reference Values; Specimen Handling; Thrombosis; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Asthma; Drugs, Chinese Herbal; Humans; Lipid Peroxides; Thromboxane B2

Aspirin can cause bronchoconstriction in some asthmatic patients through increased production of proinflammatory mediators, particularly leukotrienes. However, recent in vivo evidence has suggested that aspirin also triggers the production of lipoxins, which act as natural antagonists of prostaglandins and leukotrienes. Aside from patients with known aspirin-sensitive asthma, physicians have avoided the use of aspirin in asthmatic patients in general because it was believed that this agent might precipitate worsening of their condition.. We sought to establish the effect of aspirin on pulmonary inflammation and function in patients with persistent asthma.. After withdrawal of their usual anti-inflammatory medication, patients with mild-to-moderate persistent asthma undertook double-blind, randomized, crossover treatment with 75 mg/d aspirin and placebo for 3 weeks each. Treatment evaluation included histamine challenge, spirometry, impulse oscillometry, total and alveolar exhaled nitric oxide measurement, and serum thromboxane B2 and 15-epilipoxin A4 levels.. Fifteen patients completed the trial. Compared with placebo, there were no differences in histamine PC(20) values (0.17 doubling-dilution shift; 95% CI, -0.38 to 0.73; P = 1), exhaled nitric oxide levels (0.95-fold change; 95% CI, 0.45-2.00; P = 1), or any other inflammatory, spirometric, or oscillometry measurements. Aspirin led to a significant decrease in thromboxane B2 levels (17.53-fold difference; 95% CI, 5.46-56.49; P < .001). Baseline 15-epilipoxin A4 levels were increased at 4.88 ng/mL, and there was no increase with aspirin versus placebo (0.99-fold difference; 95% CI, 0.79-1.24; P = 1).. In this preliminary study of 15 patients, low-dose aspirin did not lead to increased 15-epilipoxin A4 synthesis or alter inflammatory markers in patients with mild-to-moderate persistent asthma.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Breath Tests; Bronchial Provocation Tests; Double-Blind Method; Female; Humans; Inflammation; Lipoxins; Lung; Male; Nitric Oxide; Placebos; Respiratory Function Tests; Thromboxane B2

The circadian variation in urinary leukotriene E(4) (LTE(4)) excretion with a morning acrophase has recently been reported in nocturnal asthma (NA); however, the effects of inhaled corticosteroids (ICS) on this circadian rhythmicity of leukotriene (LT) in patients with NA are controversial.. We first measured peak expiratory flow (PEF), urinary LTE(4), 11-dehydro-thromboxane B(2) (TXB(2)), and creatinine levels six times every 4 h for 24 h in two groups: patients with mild-to-moderate, steroid-naive NA (n = 10, group A), and patients with severe NA treated with high-dose ICS (n = 10, group B). Next, group A patients received 2 weeks of treatment with 800 microg/d of inhaled fluticasone propionate (FP), and we compared the measured parameters before and after treatment.. In group A, a circadian rhythm in urinary LTE(4) with peak levels at approximately 4 AM associated with reduced PEF was observed. Group B had suppression of urinary LTE(4) excretion and had no circadian rhythmicity, as seen in group A, despite a dip in PEF at 4 AM. A high dose of FP in group A significantly (p < 0.05) reduced LTE(4) levels and abolished the circadian rhythm, as well as improving PEF. We found no significant difference in the circadian rhythm of urinary 11-dehydro-TXB(2) between groups A and B, and high-dose FP partially decreased urinary 11-dehydro-TXB(2) levels but not significantly.. A high-dose of ICS reduced urinary LTE(4) levels and abolished their circadian variation in patients with asthma, suggesting that LT might contribute to the mechanism of NA.

Topics: Administration, Inhalation; Adult; Androstadienes; Asthma; Circadian Rhythm; Creatinine; Female; Fluticasone; Glucocorticoids; Humans; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Thromboxane B2

To observe the clinical effect of Chanbei Kechuanping (CBKCP) on bronchial asthma and to explore its mechanism.. Ninety-six patients of bronchial asthma were randomly divided into two groups, the CBKCP treated group and the control group (treated by Guilong Kechuanning). The changes on symptoms and signs of asthma, pulmonary function, T-lymphocyte subsets, plasma soluble interleukin-2 receptor (sIL-2R), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha(6-keto-PGF1 alpha) were observed before and after treatment.. (1) The markedly effective rate and effective rate in the CBKCP treated group were higher than those in the control group. The pulmonary function, including 1 second forced expiratory volume, maximum expiratory flow rate and forced lung expiratory vital capacity were all improved in both groups, but the effect was more obvious in the CBKCP treated group. (2) As compared with the control group, CBKCP showed more obvious effect in lowering sIL-2R, T-lymphocyte subset and raising 6-keto-PGF1 alpha. Experimental study of guinea pig with asthma model showed that CBKCP could markedly prolong the latent time of asthma attack, lower the percentage of mast cells in total cells in the alveoli lavage solution, blood acidophic cell count and degranulation rate of mast cells, and decrease IgE, IL-4 and TXB2 levels as well as increase the 6-keto-PGF1 alpha level.. CBKCP has favorable therapeutic effect on asthma attack, it might play the role partly by regulating the functional T-lymphocyte subsets, reducing the level of IgE, sIL-2R, IL-4 and TXB2, and increasing the level of 6-keto-PGF1 alpha.

Topics: Adolescent; Adult; Aged; Animals; Asthma; Drugs, Chinese Herbal; Female; Guinea Pigs; Humans; Immunoglobulin E; Interleukin-4; Male; Middle Aged; Receptors, Interleukin-2; T-Lymphocyte Subsets; Thromboxane B2

To test the hypothesis that urinary levels of arachidonic acid metabolites may be a predicting factor of the effects of pranlukast, a selective leukotriene (LT) antagonist, on chronic adult asthma, we investigated the relationship between its clinical efficacy and urinary eicosanoid levels.. An open, multicenter trial was conducted involving 38 stable moderate and severe asthmatic patients (mean percent predicted FEV1 was 71%). All patients received pranlukast (225 mg twice daily) for 4 weeks after a 2-week run-in period. Urinary levels of LTE4, 11-dehydro-thromboxane (TX) B2, 2,3-dinor-6-keto-prostaglandin (PG) F1alpha, and creatinine were measured in 3-h urine collected on day 1 of the treatment. The responder was defined by an improvement of asthma symptom scores and peak expiratory flow rate (PEFR).. One patient was excluded because of an adverse effect, nausea. Thirteen out of 37 subjects were responders and 24 were nonresponders. There were no significant differences in patients' backgrounds and urinary arachidonate levels between the two groups. The urinary LTE4 to 2,3-dinor-6-keto-PGF1alpha ratio in the responder was significantly lower (P=0.01) than that in the nonresponder. In all patients, a significant inverse correlation was revealed between the baseline urinary LTE4/2,3-dinor-6-keto-PGF1alpha ratio and the improvement of PEFR in the morning (r=-0.43, P=0.007).. These data suggested that the urinary ratio of LTE4 to 2,3-dinor-6-keto-PGF1alpha might be one of the predictive markers of the clinical efficacy of this LT-receptor antagonist in asthmatic subjects.

Topics: Adult; Aged; Anti-Asthmatic Agents; Asthma; Chromones; Female; Humans; Leukotriene Antagonists; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Prostaglandins F; Thromboxane B2

Thromboxane (TX) A2 is an important bronchoconstrictor in the pathogenesis of asthma. Seratrodast, known as AA-2414, is a new oral TXA2 receptor antagonist which is currently prescribed in asthma therapy in Japan. However its clinical effects have been very different in individual subjects. To assess whether the clinical efficacy of TXA2 antagonist is predictable on the basis of urinary arachidonic acid metabolites in urine of patients with asthma, an open and multicentre trial was conducted. Fifty adult asthmatic subjects (women/men = 28/22) were enrolled [resting mean forced expiratory volume in 1 sec (FEV1)% was 82%; range, 50-96%]. Urinary levels of 11-dehydro-TXB2, leukotriene (LT) E4, 2,3-dinor-6-keto-prostaglandin F1alpha and creatinine in 3-h urine collected in the morning at the start of seratrodast (80 mg day(-1), once a day at evening for 4 weeks) were measured. Responders were defined by improvements of asthma symptoms score and peak expiratory flow rate (PEFR). Of the 50 subjects, 45 completed this study. Eighteen patients were responders and the other 27 were nonresponders. There were no significant differences between the two groups in patients' characteristics, baseline lung functions, treatments and baseline urinary eicosanoids. The 11-dehydro-TXB2/LTE4 ratio of responders was significantly higher (P = 0.0091) than that of non-responders (mean +/- SE, 7.49+/-0.71 vs. 5.09+/-0.67). Eleven patients out of 18 responders agreed to continue this drug for 6 months, the 11-dehydro-TXB2/LTE4 ratio decreased during this period, but not significantly. Our data demonstrated that responders and non-responders to TXA2 receptor antagonist existed in patients with asthma, and it suggests that the ratio of urinary eicosanoids might be a possible predictor of the effects of TXA2 receptor antagonist.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Asthmatic Agents; Asthma; Benzoquinones; Creatinine; Eicosanoids; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Receptors, Thromboxane; Thromboxane B2

We investigated the effect of thromboxane (TX) synthetase inhibitor, OKY-046, on bronchial hypersensitivity in 16 asthmatics by a double-blind, placebo-controlled, crossover trial. Bronchial sensitivity to methacholine was measured by Astograph. Blood samples were taken to measure plasma levels of TX metabolites. No significant differences of forced expiratory volume in 1 sec (FEV1), bronchial sensitivity, or bronchial reactivity were observed after OKY-046 administration, compared to baseline or after placebo. However, responders showed a significant decrease in the plasma TXB2/6-keto-PGF1alpha ratio as compared to nonresponders. Our data failed to confirm an inhibitory effect of OKY-046 on bronchial hypersensitivity, but suggested the importance of its therapeutic dose monitoring.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Asthma; Bronchial Hyperreactivity; Double-Blind Method; Enzyme Inhibitors; Female; Forced Expiratory Volume; Humans; Male; Methacrylates; Placebos; Spirometry; Thromboxane B2; Thromboxane-A Synthase

Leukotriene (LT) and thromboxane A2 (TXA2) receptor antagonists have been used in the treatment of asthma.. We examined the effects of an LT receptor antagonist, TXA2 receptor antagonist, and TXA2 synthetase inhibitor on bronchoprovocation test (BPT) in patients with mild-to-moderate atopic asthma.. BPT was performed four times in each of six asthmatics. Development of the immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) was confirmed on the first BPT (BPT1). After a 7-day washout period, an LT receptor antagonist (pranlukast, 450 mg/d), TXA2 receptor antagonist (seratrodast, 80 mg/d), or TXA2 synthetase inhibitor (ozagrel, 800 mg/d) was administered orally over 7 days at random using a cross-over method (BPT2-4). Blood levels of LTB4, LTC4, LTD4, 11-dehydrothromboxane B2, eosinophil cationic protein, and histamine were measured at reaction phases of pre-BPT, IAR, and LAR.. Administration of pranlukast suppressed IAR by 80.5% (p < 0.0001) and LAR by 54.6% (p = 0.0391). Ozagrel significantly suppressed IAR by 39.5% (p = 0.0413), but the fall in FEV1 was >20% (21.56+/-4.173%). Seratrodast did not suppress IAR or LAR. Blood levels of chemical mediators did not correlate with the suppressive effects of the tested drugs.. The LT receptor antagonist was considered to be the most effective. LT might play a more important role in the pathogenesis of asthma than TXA2. Our data showed that measurement of blood levels of chemical mediators is not useful in identifying the pathogenic mechanisms of asthma.

Topics: Administration, Oral; Adult; Anti-Asthmatic Agents; Antigens; Asthma; Benzoquinones; Blood Proteins; Bronchial Provocation Tests; Bronchoconstriction; Chromones; Cross-Over Studies; Eosinophil Granule Proteins; Female; Follow-Up Studies; Heptanoic Acids; Histamine; Humans; Leukotriene Antagonists; Male; Membrane Proteins; Methacrylates; Receptors, Leukotriene; Receptors, Thromboxane; Ribonucleases; Thromboxane B2; Thromboxane-A Synthase; Treatment Outcome

Inhaled frusemide inhibits airway narrowing and causes a transient increase in forced expiratory volume in one second (FEV1) during hypertonic saline challenge. This inhibitory effect could be secondary to prostaglandin release during challenge. The involvement of prostaglandins in the inhibitory action of frusemide during challenge with 4.5% NaCl was investigated by premedicating with indomethacin, a prostaglandin synthetase inhibitor.. Fourteen asthmatic subjects (eight women) aged 26.6 (range 18-56) years participated in a double blind, placebo controlled, crossover study. The subjects attended five times and inhaled 4.5% NaCl for 0.5, 0.75, 1, 1.5, 2, 4, 8, 8, and 8 minutes, or part thereof, or until a provocative dose causing a 20% fall in FEV1 (PD20 FEV1) was recorded. Indomethacin (100 mg/day) or placebo were taken three days before all visits, except control day. The FEV1 was measured and frusemide (38.0 (6.4) mg, pH = 9) or vehicle (0.9% NaCl, pH = 9) were inhaled 10 minutes before the challenge. Bronchodilation was calculated as the percentage rise in FEV1 from the prechallenge FEV1 to the highest FEV1 recorded during the challenge.. Frusemide caused a fold increase in PD20 FEV1 compared with the vehicle which was similar in the presence of both indomethacin and placebo (3.7 (95% CI 2.0 to 7.3) versus 3.3 (2.0 to 5.4)). Frusemide, but not vehicle, also caused a transient percentage rise in FEV1 during challenge with 4.5% NaCl which was not blocked by indomethacin (3.6% (1.2 to 6.0)) or placebo (3.1% (1.0 to 5.2)).. Inhaled frusemide inhibited airway narrowing and caused a transient increase in FEV1 during challenge with 4.5% NaCl. These effects were not blocked by indomethacin, which suggests that the inhibitory action of frusemide is not secondary to prostaglandin release.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bronchial Provocation Tests; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Forced Expiratory Volume; Furosemide; Humans; Indomethacin; Male; Middle Aged; Thromboxane B2

To determine the efficacy of salmeterol alone in a group of patients with moderate asthma with nocturnal worsening of symptoms.. Double-blind, randomized, placebo-controlled crossover study.. Tertiary care hospital specializing in respiratory diseases.. Ten patients with nocturnal asthma.. Subjects were randomized to salmeterol, 100 micrograms twice daily, or placebo for 6 weeks with a 1-week washout between treatment periods. Symptoms, nocturnal awakenings, and beta 2-agonist use were recorded daily. Spirometry was performed at weeks 1 and 6 of each period at bedtime and at 4 AM, and methacholine challenge was performed at 4 AM followed by bronchoscopy with BAL. BAL fluid analysis included cell count and differential count, eosinophil cationic protein, Charcot-Leyden crystal protein, leukotriene B4, and thromboxane B2.. The percentage of nights with awakenings decreased significantly with salmeterol (69.8 +/- 8.7% vs 30.6 +/- 10.8% for placebo and salmeterol, respectively; p = 0.02). The percentage of 24-h days with supplemental inhaled beta 2-agonist use significantly decreased with salmeterol (85.9 +/- 9.4% vs 70.4 +/- 10.1% for placebo and salmeterol, respectively; p = 0.04). There were no significant differences in bronchial reactivity, 4 AM FEV1, overnight percentage change in FEV1, or indexes of airway inflammation.. Salmeterol alone improves the number of nocturnal awakenings and supplemental 24-h beta 2-agonist use in nocturnal asthma without significantly altering lung function and airway inflammation.

Topics: Adrenergic beta-Agonists; Adult; Albuterol; Asthma; Blood Proteins; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Bronchodilator Agents; Bronchoscopy; Cell Count; Circadian Rhythm; Cross-Over Studies; Double-Blind Method; Eosinophil Granule Proteins; Eosinophils; Female; Follow-Up Studies; Forced Expiratory Volume; Glycoproteins; Humans; Inflammation; Inflammation Mediators; Leukotriene B4; Lung; Lysophospholipase; Male; Methacholine Chloride; Placebos; Ribonucleases; Salmeterol Xinafoate; Sleep; Spirometry; Thromboxane B2

To investigate the significance of Ligusticum wallichii Mixture (LWM) and its possible therapeutical mechanism in bronchial asthma, clinical and experimental studies were carried out.. LWM inhibited bronchospasm induced by histamine and acetylcholine in guinea pigs; the plasma level of TXB2 was decreased remarkably and the incubation period from antigen inhalation to asthma attack could be delayed by LWM; the incidence of asthma and its mortality were reduced in guinea pigs, compared with control, P < 0.01. In addition, the prolonged period of induced asthma attack was negatively correlated to the plasma level of TXB2 in guinea pigs (P < 0.01). It was observed that the plasma level of TXB2 was decreased, the forced expiratory volume in 1 sec (FEV1%) was elevated significantly in asthmatic patients after they were treated by LWM. Moreover, the total effective rate was significantly better than that in the control (92% : 62%). It indicated that: (1) The effects of airway allergic inflammation (AAI) might be the important pathological basis for the bronchial asthma, (2) TXA2 might be an important inflammatory mediator in asthma which could be taken as an useful biochemical parameter for evaluating clinical effects, (3) LWM could relax tracheal smooth muscle, improve pulmonary function, inhibit the synthesis and release of TXA2 with no side effects.

Topics: Adult; Animals; Asthma; Bronchi; Cricetinae; Drugs, Chinese Herbal; Female; Forced Expiratory Volume; Humans; Male; Muscle Contraction; Muscle, Smooth; Thromboxane B2

In this study we evaluated the role of thromboxane in causing allergen-induced early and late asthmatic responses and airway hyperresponsiveness in asthmatic subjects. Twelve atopic subjects with stable asthma and documented early and late asthmatic responses to an inhaled allergen were treated with placebo or CGS 13080, a specific thromboxane synthetase inhibitor, given orally (200 mg four times daily) for two days before, the day of, and the day after allergen inhalation. Treatments were administered in a double-blind, placebo-controlled, crossover fashion. The effect of pretreatment with CGS 13080 was examined on serum TxB2 levels and the magnitude of the asthmatic responses after inhaled allergen. Serum TxB2 levels increased significantly from 96 ng.ml-1 (SEM 29) 3 h after diluent to 151 ng.ml-1 (SEM 27) 3 h after allergen (p = 0.008). CGS 13080 pretreatment markedly inhibited the levels of TxB2 at all time points before and after inhaled allergen (p = 0.0001) and had a small but significant effect on the magnitude of the early asthmatic responses after allergen (p = 0.0009). CGS 13080 did not alter either late asthmatic responses, baseline airway responsiveness, or the increase in histamine airway responsiveness after allergen. These results suggest that allergen-induced early asthmatic responses, but not late responses or allergen-induced airway hyperresponsiveness, are partly caused by thromboxane release.

Topics: Adult; Allergens; Asthma; Bronchial Provocation Tests; Bronchoconstriction; Double-Blind Method; Female; Humans; Imidazoles; Male; Pyridines; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Time Factors

Bradykinin is a naturally occurring nonapeptide which may contribute to the pathogenesis of bronchial asthma. When inhaled by asthmatic subjects it is a potent bronchoconstrictor, but with repeated challenge airways responsiveness to the peptide decreases markedly. In vitro studies suggest that loss of bradykinin responsiveness may be due to the secondary generation of relaxant prostanoids. We have used the potent cyclooxygenase inhibitor flurbiprofen to investigate the potential role of prostanoid generation in bradykinin tachyphylaxis in eight asthmatic patients. The effects of oral flurbiprofen (150 mg) and matched placebo were observed on two consecutive dose response studies with inhaled bradykinin and histamine in a double-blind, randomized study. Venous blood was taken to measure the serum concentration of thromboxane B2 (TxB2) as a check on the extent of cyclooxygenase blockade achieved by flurbiprofen. Following recovery from the first challenge with bradykinin, the asthmatic airways showed a reduced response to a second challenge with this nonapeptide, the provocative concentration producing a 20% fall from baseline (PC20) increasing from 0.07 to 0.42 mg.ml-1 (p less than 0.01). The airway response to inhaled histamine after the second bradykinin challenge was not significantly changed. In the presence of demonstrable cyclooxygenase inhibition, flurbiprofen failed to prevent the development of reduced responsiveness to bradykinin observed on the second challenge, the PC20 increasing from 0.10 to 0.48 mg.ml-1 (p less than 0.01). This study demonstrates that repeated exposure to inhaled bradykinin results in loss of the bronchoconstrictor response which appears specific for this agonist and not secondary to the increased generation of protective prostanoids.

Topics: Adolescent; Adult; Airway Resistance; Asthma; Bradykinin; Bronchial Provocation Tests; Bronchoconstriction; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Flurbiprofen; Forced Expiratory Volume; Humans; Male; Random Allocation; Thromboxane B2

Plasma prostaglandin (PG) and thromboxane (Tx) levels from bronchial asthmatic patients were assayed by 9-anthryldiazomethane reversed-phase high-performance liquid chromatography method. TxB2 levels from stable bronchial asthmatic patients were significantly higher than those from normal healthy subjects. PGF2 alpha levels were significantly elevated in atopic patients compared with nonatopic ones. PG patterns differed between asthmatic and nonasthmatic conditions in the same patients. PGF2 alpha levels were significantly elevated in the patients with spontaneous attacks compared with those without attacks and 6-keto PGF1 alpha levels were significantly lower in bronchial asthmatic patients having attacks than in the patients without attacks. There were no significant differences of PG levels between mild and moderate asthmatic subjects. Aminophylline injection in patients with mild spontaneous attacks had no significant effects on PG levels which were compared before and after injection.

Topics: Adult; Aminophylline; Anthracenes; Asthma; Chromatography, High Pressure Liquid; Female; Fluorescent Dyes; Humans; Male; Middle Aged; Prostaglandins; Thromboxane B2

The calcium-dependent constriction of bronchial smooth muscle cells and release of mediators derived from mast cells is important in the pathophysiology of asthma. We hypothesized that nifedipine, a slow calcium channel blocker, would inhibit or attenuate acetylcholine-induced bronchoconstriction in asthmatics. Because one consequence of mast cell activation is the release of platelet-activating factor, we wondered whether thromboxane levels would be increased during acute bronchial constriction in asthmatics. Bronchoconstriction was induced in 8 asthmatics (6 men, 2 women) by acetylcholine; each subject was pretreated either with placebo or nifedipine (20 mg sublingually) on 2 separate days. Vital capacity, forced expiratory volume in 1 s, peak expiratory flow rates and oscillatory resistance were measured prior to and after the intake of placebo or nifedipine as well as after an acetylcholine challenge. Pretreatment with nifedipine significantly attenuated acetylcholine-induced changes in all four lung function parameters studied, but did not significantly influence the increase in thromboxane B2 plasma concentrations observed after the acetylcholine challenge. From these data we conclude that nifedipine inhibits the acetylcholine-induced bronchoconstriction in asthmatics. This effect may be either a direct action on bronchial smooth muscle or may be due to the inhibition of mediators other than thromboxane.

Topics: Acetylcholine; Adult; Airway Resistance; Asthma; Bronchial Provocation Tests; Double-Blind Method; Female; Humans; Male; Nifedipine; Random Allocation; Thromboxane B2

The effect of specific antigen challenge on the lung function of eight allergic asthmatic patients after placebo and indomethacin pretreatment has been investigated. Plasma levels of thromboxane B2(TxB2), metabolite of thromboxane A2, 6-keto-PGF1 alpha, metabolite of epoprostenol, (prostacyclin, PGI2) and beta-thromboglobulin (beta TBG) following antigen challenge in these eight patients have also been measured after placebo and indomethacin pretreatment. Each patient underwent two antigen inhalations 1 week apart. One challenge took place after 4 days pretreatment with indomethacin capsules 25 mg four times daily, and the other took place following 4 days placebo pretreatment, one matched capsule four times daily. The order of administration was random but balanced and blind with respect to the patient. Following placebo pretreatment two patients presented with an early antigen response only, four presented with a biphasic antigen response and two presented with a delayed antigen response only. The asthmatic response for each patient was consistent on re-exposure. Indomethacin pretreatment suppressed the delayed antigen induced asthmatic response. This suppression was reproducible. There was a rise in plasma TxB2 levels on antigen challenge following placebo pretreatment but not following indomethacin pretreatment, whereas there was a rise in 6-keto-PGF1 alpha after antigen challenge following indomethacin but not placebo pretreatment. No significant change in plasma beta TBG or platelet counts from control values was observed following antigen challenge with either placebo or indomethacin pretreatment. It is suggested that the production of PGI2 and suppression of TxA2 by indomethacin pretreatment contribute to the suppression of the delayed antigen induced asthmatic response and that platelets play a minimal role in this process.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Asthma; Beta-Globulins; beta-Thromboglobulin; Humans; Immunization; Indomethacin; Lung; Maximal Expiratory Flow Rate; Respiratory Function Tests; Thromboxane B2; Thromboxanes; Time Factors

Various inflammatory eicosanoid levels in biomaterials from airways of asthma and their associations with clinical parameters remain uncertain. We hypothesized that prostaglandin and leukotriene levels differ between in exhaled breath condensates (EBCs) and in sputum in mild, moderate, and severe levels of asthma and that EBC and sputum eicosanoid levels are associated with indexes of pulmonary function and inflammation.. To determine the differences between EBC and sputum eicosanoid levels in healthy participants and patients with asthma with different asthma severity levels.. Collected EBC and sputum, as well as pulmonary function, were examined in adult patients with asthma and healthy participants. Exhaled breath condensate prostaglandin D2-methoxime (PGD2-MOX), cysteinyl leukotrienes (CysLTs), leukotriene B4 (LTB4), and thromboxane B2 levels, and some sputum eicosanoid and tryptase levels were measured. Differences in eicosanoid levels among participants and their associations with pulmonary function and tryptase and granulocyte levels in sputum were then evaluated.. Analysis of 94 EBCs and 43 sputa revealed that EBC and sputum PGD2-MOX and CysLT levels were significantly higher in patients with asthma than in healthy participants. Exhaled breath condensate PGD2-MOX, CysLT, and LTB4 levels were significantly higher in patients with severe asthma. Exhaled breath condensate PGD2-MOX level was also significantly correlated with sputum tryptase levels and lower pulmonary function in patients with asthma. Sputum PGD2-MOX and CysLT levels were significantly correlated with the proportion of eosinophils among all cells in sputum in patients with asthma.. The results suggest that EBC PGD2 levels are associated with impairment of pulmonary function in adults with asthma who have undergone guideline treatment. Exhaled breath condensate or sputum PGD2 and CysLTs may represent severity or airway inflammation in asthma.

Topics: Adult; Asthma; Breath Tests; Cysteine; Eicosanoids; Female; Granulocytes; Humans; Inflammation; Leukotriene B4; Leukotrienes; Lung; Male; Middle Aged; Prostaglandin D2; Sputum; Thromboxane B2; Tryptases

Nowadays, bronchial asthma is still a severe disease threatening human health, and it is incumbent upon us to seek effective therapeutic drugs. Mahuang decoction (MHD), a classic famous Chinese prescription, has been used for thousands of years to prevent phlegm from forming, stop coughing and relieve asthma, but the relevant mechanism has not been thoroughly clarified. This study aims to investigate the anti-airway inflammation effect of MHD and the possible molecular mechanism underlying IL21/STAT3 signaling pathway, so as to provide guidance for the treatment of MHD on bronchial asthma.. Specific pathogen free SD rats were randomly divided into 6 groups: normal control group, model group, positive group (Compound methoxyphenamine), MHD-treated groups at doses of 10 ml/kg, 5 ml/kg and 2.5 ml/kg, 10 rats in each group. Except for the normal control group, rats in other groups were sensitized with ovalbumin via introperitoneal injection and challenged with ovalbumin inhalation to trigger asthma model. At 24 h after the last excitation, bronchoalveolar lavage fluid (BALF) of every rat was drawn and the number of inflammatory cells was analyzed using cell counting method. ELISA method was performed to determine the concentrations of TXB. MHD intervention demonstrated a strong inhibitory action on the secretion of inflammatory mediators as well as the inflammatory cell infiltration in pulmonary tissues of asthmatic rats, and also depressed the protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in pulmonary tissues. MHD effectively mitigates airway inflammation and regulates the IL-21/STAT3 signaling pathway in rat asthma model.

Topics: 6-Ketoprostaglandin F1 alpha; Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Ephedra sinica; Leukocyte Count; Lung; Matrix Metalloproteinase 9; Ovalbumin; Phytotherapy; Plant Preparations; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Thromboxane B2; Tissue Inhibitor of Metalloproteinase-1

Asthma is a chronic inflammatory disorder of the airway and is characterized by airway remodeling, hyperresponsiveness, and shortness of breath. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicines (TCM), has been demonstrated to have good therapeutic effects on experimental allergic asthma. However, its anti-asthma mechanism remains currently unknown. In the present work, metabolomics studies of biochemical changes in the lung tissue and plasma of ovalbumin (OVA)-induced allergic asthma mice with mKG treatment were performed using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Partial least squares-discriminate analysis (PLS-DA) indicated that the metabolic perturbation induced by OVA was reduced after mKG treatment. A total of twenty-four metabolites involved in seven metabolic pathways were identified as potential biomarkers in the development of allergic asthma. Among them, myristic acid (

Topics: Acetylcarnitine; Animals; Asthma; Biomarkers; Drugs, Chinese Herbal; Female; Hypersensitivity; Lung; Metabolome; Mice; Mice, Inbred BALB C; Myristic Acid; Sphingosine; Thromboxane B2

We examined composition of plasma non-esterified fatty acids (NFAs), erythrocyte fatty acids, levels of eicosanoids in patients with asthma and chronic obstructive pulmonary disease (COPD) with different type of the inflammatory response. The results of our study show that asthma and COPD in remission are associated with changes in the composition NFAs of plasma, FA of erythrocytes, level eicosanoid despite the difference in the regulation of immunological mechanisms of systemic inflammation. These changes are characterized by excessive production of arachidonic acid (20:4n-6) and cyclooxygenase and lipoxygenase metabolites (thromboxane B2, leukotriene B4) and deficiency of their functional antagonist, eicosapentaenoic acid (20:5n-3). The recognized association between altered fatty acid composition and disorders of the immune mechanisms of regulation of systemic inflammation in COPD and asthma demonstrated the important role of fatty acids and their metabolites in persistence of inflammatory processes in diseases of the respiratory system in the condition of remission.. Izuchen sostav zhirnykh kislot (ZhK) plazmy krovi i membran éritrotsitov, uroven' éĭkozanoidov u bol'nykh bronkhial'noĭ astmoĭ (BA) i khronicheskoĭ obstruktivnoĭ bolezn'iu legkikh (KhOBL) pri raznom tipe vospalitel'noĭ reaktsii. Ustanovleno, chto techenie BA i KhOBL v period remissii, nesmotria na razlichie immunologicheskikh mekhanizmov reguliatsii sistemnogo vospaleniia, soprovozhdaetsia odnonapravlennymi izmeneniiami sostava neéterifitsirovannykh zhirnykh kislot plazmy krovi i ZhK membran éritrotsitov, urovnia éĭkozanoidov, kharakterizuiushchimisia povyshennoĭ produktsieĭ arakhidonovoĭ kisloty (20:4n-6) i ee tsiklooksigenaznykh i lipoksigenaznykh metabolitov (tromboksan V2, leĭkotrien V4) na fone defitsita funktsional'nogo antagonista – éĭkozapentaenovoĭ kisloty (20:5n-3). Obnaruzhennaia assotsiatsiia mezhdu modifikatsieĭ sostava zhirnykh kislot krovi i narusheniem immunnykh mekhanizmov reguliatsii sistemnogo vospaleniia pri KhOBL i BA svidetel'stvuet o vazhnom znachenii zhirnykh kislot i ikh metabolitov v persistentsii vospalitel'nogo protsessa pri zabolevaniiakh bronkholegochnoĭ sistemy v period remissii.

Topics: Adult; Arachidonic Acid; Asthma; Case-Control Studies; Eicosapentaenoic Acid; Female; Humans; Inflammation; Leukotriene B4; Lipoxygenases; Male; Prostaglandin-Endoperoxide Synthases; Pulmonary Disease, Chronic Obstructive; Thromboxane B2

When the window of an Asbestos-contaminated room from a broken ceiling was opened wide, A 73 year-old male physician of Oriental origin, who was sitting in the next room, suddenly developed a severe asthma attack, which did not stop by the use of a hand-held Albuterol inhaler. Temporary relief was obtained only by using a Compressor-Nebulizer (Inspiration 626 with Albuterol Sulfate Inhalation Solution 0.083%). During the attack, abnormal areas were discovered at the upper lobes of both lungs, where Thromboxane B2 (TXB2) was markedly increased to 500 ng (BDORT units) (the rest of the lung had about 2.5 ng), 2 types of Asbestos (Chrysotile and Crocidolite) were abnormally increased to 0.120-0.135 mg, (BDORT units) Acetylcholine was markedly reduced to 0.5 ng (the rest of the lung was low, about 100 ng), DHEA was extremely reduced to 1 ng (the rest of the lung had about 52 ng), and telomere was less than 1 yg (= 10(-24) g). Bacterial & viral infections were also present in these abnormal areas, but no antibiotics entered the abnormal parts of the lungs. Therefore, one optimal dose of Astragalus was given once, which resulted in a rapid continuous excretion of large amounts of the above 2 types of Asbestos & TXB2 in urine & sputum, and Asthma symptoms reduced slightly in severity. Additional acupuncture & shiatsu given on all the known acupuncture points for lung disease only created slight, temporary improvement. Then, the respiratory & cardiac center of the Medulla Oblongata was found to have similar abnormalities as the lungs. Therefore, 100 mW output of Light Emitting Diode of red spectra (650 nm center spectrum) was projected on the abnormal area of the medulla oblongata on the back of the head. This resulted drug uptake of on and off and significantly reduced difficulty of breathing. Additional application of the EMF Neutralizer on the abnormal area of the Medulla Oblongata for 3 hours resulted in continuous drug uptake and complete disappearance of asthma. As a result of one optimal dose of Astragalus, the remaining Asbestos in the lungs & medulla oblongata was completely excreted in the urine and Sputum in 2 weeks. Then, even when the patient entered the Asbestos-contaminated room and slept there every day without opening the window, no asthma attack occurred even as late as 5 months later.

Topics: Acetylcholine; Acupuncture Therapy; Aged; Asbestos; Asthma; Astragalus Plant; Dehydroepiandrosterone; Humans; Lung; Male; Medulla Oblongata; Nebulizers and Vaporizers; Phototherapy; Plant Extracts; Thromboxane B2; Treatment Outcome

Exercise-induced bronchospasm (EIB) occurs in athletes with and without asthma. Studies have suggested an inflammatory basis for EIB in asthmatics; however whether inflammation plays a similar role in EIB in athletes without asthma remains unclear. Our objective was to determine whether there is evidence of an inflammatory basis for exercise-induced bronchospasm occurring in non-asthmatic athletes. Ninety-six athletes without asthma from varsity college teams underwent eucapnic voluntary hyperventilation testing. Sputum was induced from subjects with hypertonic saline inhalation post-eucapnic voluntary hyperventilation testing and was analyzed with enzyme-linked immunosorbent assays for IL-5, IL-8, IL-13, cysteinyl-leukotrienes, prostaglandin E2, histamine, leukotriene B4, and thromboxane B2. In addition, inflammatory (neutrophils, lymphocytes, eosinophils, and macrophages) and epithelial cell counts in sputum were recorded. Multivariate regression modeling showed a significant correlation between concentrations of select inflammatory mediators after eucapnic voluntary hyperventilation testing and severity of EIB. Means of the log-transformed concentrations of inflammatory mediators in EIB-positive athletes were significantly higher post-eucapnic voluntary hyperventilation than in EIB-negative athletes. Similar findings were not demonstrated with inflammatory cells. Concentrations of inflammatory mediators are higher in EIB-positive athletes than in EIB-negative athletes without asthma after eucapnic voluntary hyperventilation testing. The severity of EIB in our cohort also is significantly correlated with increased concentrations of select inflammatory mediators suggesting a potential inflammatory basis for EIB in athletes without asthma.

Topics: Adult; Age Factors; Asthma; Asthma, Exercise-Induced; Bronchial Hyperreactivity; Cohort Studies; Dinoprostone; Female; Histamine; Humans; Incidence; Inflammation; Inflammation Mediators; Leukotriene B4; Male; Multivariate Analysis; Probability; Respiratory Function Tests; Risk Assessment; Sensitivity and Specificity; Sex Factors; Sports; Sputum; Thromboxane B2

High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)2. This binding could interfere with the role of C3a and C5a in inflammation.

Topics: Animals; Asthma; Blood Pressure; Calcium; Cell Line; Cell Migration Inhibition; Complement C3a; Complement C5a; Dose-Response Relationship, Drug; gamma-Globulins; Histamine Release; Humans; Immunoglobulins, Intravenous; Mast Cells; Mice; Respiratory Distress Syndrome; Swine; Thromboxane B2

Leukotrienes, generated from arachidonic acid via the lipoxygenase pathway, play an important role in the pathophysiology of asthma. Therefore, leukotriene inhibitors, such as Zileuton, are used in the treatment of asthma. However, thromboxanes, generated from arachidonic acid via the cyclooxygenase pathway, play an important role in platelet aggregation and thrombosis. Therefore, we studied whether Zileuton, by shifting arachidonic acid to the cyclooxygenase pathway, enhances thromboxane production and, hence, platelet aggregation. Blood samples were collected from 10 asthmatic patients before and 2 weeks after standard Zileuton treatment. Spontaneous platelet aggregation was measured in platelet-rich plasma. Platelet-rich plasma was also used to determine thromboxane B(2), a stable metabolite of thromboxane A(2), as the indirect measure of thromboxane A(2) because thromboxane A(2) is too unstable for assay. Baseline thromboxane B(2) and platelet aggregation values in the 10 asthmatic patients were normal. Treatment with Zileuton for 2 weeks significantly increased thromboxane B(2) levels from baseline levels of 267 +/- 54 microg/l to 389 +/- 62 microg/l after 2 weeks of treatment (P < 0.0002). Spontaneous platelet aggregation also increased significantly from baseline values of 4.2 +/- 2.4% to 6.8 +/- 2.8% after 2 weeks of treatment (P < 0.0001). These results establish that Zileuton, an effective drug for asthma, adversely affects in vitro platelet function. The findings suggest that this drug, and perhaps related agents also, may pose a thrombotic risk; clinical attention will be needed to address this possibility.

Topics: Adult; Aged; Asthma; Female; Humans; Hydroxyurea; Lipoxygenase Inhibitors; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2

1. Cyclo-oxygenase (COX) and lipoxygenase (LO) share a common substrate, arachidonic acid. Aspirin and related drugs inhibit COX activity. In a subset of patients with asthma aspirin induces clinical symptoms associated with increased levels of certain LO products, a phenomenon known as aspirin-sensitive asthma. The pharmacological pathways regulating such responses are not known. 2. Here COX-1 and LO activity were measured respectively by the formation of thromboxane B(2) (TXB(2)) or leukotrienes (LT) C(4), D(4) and E(4) in whole blood stimulated with A23187. COX-2 activity was measured by the formation of prostaglandin E(2) (PGE(2)) in blood stimulated with lipopolysaccharide (LPS) for 18 h. 3. No differences in the levels of COX-1, COX-2 or LO products or the potency of drugs were found in blood from aspirin sensitive vs aspirin tolerant patients. Aspirin, indomethacin and nimesulide inhibited COX-1 activity, without altering LO activity. Indomethacin, nimesulide and the COX-2 selective inhibitor DFP [5,5-dimethyl-3-(2-isopropoxy)-4-(4-methanesulfonylphenyl)-2(5H)-furanone] inhibited COX-2 activity. NO-aspirin, like aspirin inhibited COX-1 activity in blood from both groups. However, NO-aspirin also reduced LO activity in the blood from both patient groups. Sodium salicylate was an ineffective inhibitor of COX-1, COX-2 or LO activity in blood from both aspirin-sensitive and tolerant patients. 4. Thus, when COX activity in the blood of aspirin-sensitive asthmatics is blocked there is no associated increase in LO products. Moreover, NO-aspirin, unlike other NSAIDs tested, inhibited LO activity in the blood from both aspirin sensitive and aspirin tolerant individuals. This suggests that NO-aspirin may be better tolerated than aspirin by aspirin-sensitive asthmatics.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Benzene Derivatives; Calcimycin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Furans; Humans; Indomethacin; Ionophores; Isoenzymes; Leukotrienes; Lipopolysaccharides; Lipoxygenase; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thromboxane B2

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).. 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.. 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.. 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.

Topics: Adult; Anti-Asthmatic Agents; Aspirin; Asthma; Blood Proteins; Bronchial Provocation Tests; Chromones; Drug Hypersensitivity; Eosinophil Granule Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Leukocyte Count; Leukotriene D4; Leukotriene E4; Male; Middle Aged; Ribonucleases; Thromboxane B2

Seratrodast, an antagonist to thromboxane A2 (TXA2) receptors, is not always effective in patients with bronchial asthma. In fact, some respond definitely to this drug while others not. In the present study, to clarify the predictability of the clinical effects of Seratrodast, we investigated whether there is a correlation between the levels of TXB2 and 11-DHTXB2, both of which are metabolites of TXA2, in urine and sputum taken before the administration and the clinical effects seen after initiation of the treatment. Baseline concentrations of TXA2 metabolites in urine/sputum were not significantly different between responders and non-responders. However, 4 cases who had remarkably responded to Seratrodast had significantly higher baseline 11-DHTXB2 levels than the rest of the patients. These results suggested that bronchial asthma patients with high urinary 11-DHTXB2 levels could markedly respond to Seratrodast treatment.

Topics: Adult; Aged; Anti-Asthmatic Agents; Asthma; Benzoquinones; Female; Heptanoic Acids; Humans; Male; Middle Aged; Prostaglandin Antagonists; Sputum; Thromboxane A2; Thromboxane B2

Although there is increasing evidence of the importance of cysteinyl leukotrienes (LT) as mediators of aspirin-induced bronchoconstriction in aspirin-sensitive asthma, the cellular origin of the LT is not yet clear.. Urinary concentrations of leukotriene E4 (LTE4), 11-dehydrothromboxane B2, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine were measured during the 24 h following cumulative intravenous administration of increasing doses of lysine aspirin to asthmatic patients. In addition, the urinary concentrations of these metabolites were measured on 5 consecutive days in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs.. In aspirin-induced asthma patients (AIA, n=10), the basal concentration of urinary LTE4, but not the other metabolites, was significantly higher than that in aspirin-tolerant asthma patients (ATA, n=10). After intravenous aspirin provocation, the AIA group showed a 13.1-fold (geometric mean) increase in excretion of LTE4 during the first 3 h, and 9alpha,11beta-prostaglandin F2 also increased in the AIA group during the first 0-3 h and the 3-6 h collection period. Ntau-methylhistamine excretion was also increased, but to a lesser degree. Administration of aspirin caused significant suppression of 11-dehydrothromboxane B2 excretion in both the AIA and ATA groups. When the percentage of maximum increase of each metabolite from the baseline concentrations was compared between the AIA group and the ATA group, a significantly higher increase in excretion of LTE4, 9alpha,11beta-prostaglandin F2, and Ntau-methylhistamine was observed in the AIA group than the ATA group. An increased excretion of LTE4 and 9alpha,11beta-prostaglandin F2 has been detected in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti-inflammatory drugs.. Considering that human lung mast cells are capable of producing LTC4, prostaglandin D2, and histamine, our present results support the concept that mast cells, at least, may participate in the development of aspirin-induced asthma.

Topics: Adult; Aged; Aspirin; Asthma; Bronchial Provocation Tests; Cyclooxygenase Inhibitors; Dinoprost; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Mast Cells; Methylhistamines; Middle Aged; Sensitivity and Specificity; Thromboxane A2; Thromboxane B2; Time Factors

Circadian rhythmicity of cysteinyl leukotrienes (LTs) and thromboxane (TX)-A(2) in healthy subjects and nocturnal asthmatic patients remains a subject of controversy. The aim of this study was to investigate the contribution of these mediators to the pathogenesis of nocturnal asthma.. We measured peak expiratory flow rate, urinary concentration of LTE(4), 11-dehydro-TXB(2), and creatinine eight times every 3 h in three groups: healthy control subjects (n = 5, group A), nocturnal asthmatic patients (n = 9, group B), and nonnocturnal asthmatic subjects (n = 9, group C). To evaluate the reproducibility of the measurement of urinary LTE(4), we measured urinary LTE(4) in group A for 3 separate days.. The urinary LTE(4) concentrations from 3 to 6 AM were significantly (p < 0.05) higher than from 3 to 6 PM in both group A and group B, but not in group C. The mean levels of LTE(4) in group B and group C were significantly higher (p < 0.05) than those in group A. In group B, another small peak was observed from 6 to 9 PM. No significant day-to-day variation was observed in group A. Urinary 11-dehydro-TXB(2) values from 3 to 6 AM were significantly (p < 0.001) higher than those levels from 3 to 6 PM in all groups, and the mean levels in group B and group C were significantly higher than those in group A (p < 0.05).. Circadian rhythmicity of urinary LTE(4) with a morning peak was found in healthy control subjects and nocturnal asthmatic subjects, but not in nonnocturnal asthmatic patients. It was suggested that cysteinyl LTs rather than TXA(2) might contribute to the nocturnal worsening of asthma.

Topics: Adult; Aged; Asthma; Circadian Rhythm; Creatinine; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Middle Aged; Peak Expiratory Flow Rate; Reference Values; Thromboxane A2; Thromboxane B2

The effects of YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl )propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene D(4) and thromboxane A(2) receptors, on antigen-induced increases in airway resistance were investigated in mediator-controlled novel asthmatic models using actively sensitized guinea pigs. While the predominant mediator was thromboxane A(2), complete inhibition of cyclooxygenase induced mediation by cysteinyl-leukotrienes. About 1-mg/kg indomethacin induced a state where both mediators participated equally. YM158 inhibited increases in resistance whether only one or both mediators were involved. When leukotriene D(4) and thromboxane A(2) equally participated, ED(50) values for 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzo pyran hemihydrate (pranlukast; 3.9 mg/kg) and 7-(3,5,6-trimethyl-1, 4-benzoquinon-2-yl)-7-phenylheptanoic acid (seratrodast; 2.1 mg/kg) were similar to that for YM158 (8.3 mg/kg), although those effects on the corresponding mediator-induced reaction were 10 times stronger than those of YM158. Additionally, the maximum inhibition of YM158 was stronger than those of either single receptor antagonist. In conclusion, YM158 has a potentially greater efficacy in wider types of experimental asthmatic models than single receptor antagonists.

Topics: Administration, Oral; Airway Resistance; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Asthma; Benzoquinones; Chromones; Dose-Response Relationship, Drug; Guinea Pigs; Heptanoic Acids; Indomethacin; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotriene E4; Lipid Metabolism; Lung; Male; Membrane Proteins; Ovalbumin; Receptors, Leukotriene; Receptors, Thromboxane; Tetrazoles; Thiazoles; Thromboxane B2; Time Factors

Bronchoconstrictor cysteinyl leukotrienes (LT) and thromboxane (TX) A2 have been implicated in the pathogenesis of asthma. Determination of urinary leukotriene E4 (LTE4) and 11-dehydro-TXB2 levels are often used to assess cysteinyl LT and TXA2 production in humans. To define the potential role in the pathogenesis of asthma, we investigated the urinary LTE4 and 11-dehydro-TXB2 levels. LTE4 and 11-dehydro-TXB2 levels were determined using liquid chromatography/tandem mass spectrometry (LC/MS) and gas chromatography/mass spectrometry (GC/MS), respectively. Urinary LTE4 levels in asthmatic patients (192 +/- 122 pg/mg creatinine, n = 14) were significantly higher (P < 0.005) than those in healthy volunteers (55 +/- 16 pg/mg creatinine, n = 13), but no significant difference in 11-dehydro-TXB2 levels was observed. A significant inverse correlation (r = -0.821, P < 0.005) was found between urinary LTE4 levels and the forced expiratory volume in 1 s (FEV1) but no significant correlation was observed between urinary 11-dehydro-TXB2 levels and FEV1. The present findings suggest that cysteinyl LTs play a more important role in the pathogenesis of asthma than TXA2.

Topics: Adult; Aged; Asthma; Chromatography, Liquid; Female; Forced Expiratory Volume; Gas Chromatography-Mass Spectrometry; Humans; Leukotriene E4; Male; Mass Spectrometry; Middle Aged; Reference Values; Thromboxane B2

To investigate whether platelets are activated during an asthmatic attack and to detect the correlation between platelet activation and severity of bronchial asthma.. Plasma concentration of thromboxane B2(TXB2) and 11-dehydro-TXB2(11-DH-TXB2) and P-selectin (CD 62P) on platelet surface were measured in 44 patients with asthma and in 18 normal individuals using ELISA and FCP. The serum ECP level and pulmonary function were also analysed.. The plasma level of 11-DH-TXB2 and TXB2 and the positive percentage of CD 62P on platelets were significantly increased in patients with acute asthma (n = 28) as compared with the control (n = 18, P < 0.01). The plasma concentration of 11-DH-TXB2 and TXB2 were decreased significanty after the control of asthma. The level of platelet activation was correlated with ECP (r = 0.785, P < 0.05), FEV1% (r = -0.867, P < 0.01) and PEF(r = -0.745, P < 0.05).. These results suggest that there is an abnormal platelet activation in asthmatics, which can reflect the severity of bronchial asthma to a certain extent, although its exact, mechanism is unknown. The platelets secret a wide range of biologically active substances capable of inducing or augmenting the airway inflammatory responses in asthma.

Topics: Adolescent; Adult; Aged; Asthma; Blood Platelets; Blood Proteins; Eosinophil Granule Proteins; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; P-Selectin; Peak Expiratory Flow Rate; Platelet Activation; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Ribonucleases; Thromboxane B2

To observe the clinical effect of Pingchuan oral liquid, including Hanchuan oral liquid (HCOL) and Rechuan oral liquid (RCOL), and to explore its mechanism.. HCOL and RCOL were prepared based on the therapeutic principles of eliminate phlegm, remove blood stasis, lower reversed Qi flow and relieve asthma. HCOL was used to treat 50 patients of bronchial asthma in Group A and RCOL for 55 patients in Group B, and they were compared with 52 patients treated with Guilong Kechuanning capsule in the control group. The relevant animal experiment was also conducted.. The total effective rate of HCOL was 88.0%, that of RCOL was 90.9%, they were significantly higher than that of the control (73.1%, P < 0.05). Moreover, the two new preparations showed the effects in easing main symptoms and signs of asthma, decreasing peripheral eosinophilic granulocyte count and immunoglobulin level, and improving pulmonary function superior to those of Guilong Kechuanning capsule (P < 0.05, P < 0.01). Experimental study showed that they could lower blood thromboxane B2 and endothelin, raise blood nitric oxide and 6-keto-prostaglandin F1 alpha.. Pingchuan oral liquid is obviously effective in treating bronchial asthma, the mechanism possibly lays on adjusting immune function, anti-allergy and antagonizing inflammatory media.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Animals; Anti-Asthmatic Agents; Asthma; Child; Child, Preschool; Drugs, Chinese Herbal; Female; Guinea Pigs; Humans; Male; Middle Aged; Phytotherapy; Thromboxane B2

The airway of asthmatic patients is hyperresponsive to various stimuli in vivo. There are, however, only a few reports that compared the in vivo responsiveness of asthmatic patients and non-asthmatic subjects to those of lung parenchyma in vitro.. To compare the contractile response, release of various chemical mediators, and responsiveness to drugs in samples of lung parenchyma excised from asthma patients with those of non-asthmatic subjects.. Human lung parenchymal strips were subjected to passive sensitization with sera of 5+ RAST titer to mites. The strip was suspended in a magnus bath containing a buffer solution. Parenchymal contraction was induced by PGF2 alpha. After washing, the baseline concentrations of thromboxane B2 (TXB2), leukotriene (LT), and histamine were measured in each bath and then contraction was induced by the addition of a mite antigen. The concentrations of TXB2, LT, and histamine were measured after contraction. The inhibitory effects of TXA2 synthetase inhibitor (DP-1904) and TXA2 receptor antagonist (AA-2414) were also evaluated in both tissue samples.. There were no significant differences between lung parenchymal tissues of asthmatic and non-asthmatic patients with regard to PGF2 alpha-induced contraction, antigen-induced contraction, release of chemical mediators, and the response to drugs.. Unlike the response in vivo, there are no differences in the response to stimuli in vitro between lung parenchymal tissues of asthmatic and non-asthmatic patients.

Topics: Aged; Airway Resistance; Animals; Antigens; Ascaris; Asthma; Benzoquinones; Dinoprost; Dogs; Female; Heptanoic Acids; Histamine Release; Humans; Immune Sera; Immunization, Passive; Leukotrienes; Lung; Male; Middle Aged; Mites; Muscle Contraction; Muscle, Smooth; Radioallergosorbent Test; Smoking; Thromboxane B2; Thromboxane-A Synthase

Alcohol-induced bronchoconstriction is due to high blood concentrations of acetaldehyde, a metabolic product of ethanol, which lead to the release of histamine from basophils and mast cells.. We examined the inhibitory effects of azelastine hydrochloride, which inhibits histamine release and blocks H1 receptors, in alcohol-induced asthma.. Subjects were 13 Japanese asthmatic patients. We measured the change in FEV1 after ingestion of 30 g of pure ethanol. Blood ethanol, acetaldehyde, histamine, leukotriene C4 (LTC4), and thromboxane B2 (TXB2) concentrations were also measured. Alcohol challenge test was repeated in responders after administration of azelastine for 1 week at 4 mg/day.. Of 13 asthmatic patients, five (38.5%) tested positive during an ethanol challenge test, represented by a fall more than 20% in FEV1. The responders had a high blood ethanol, and showed a rise in blood acetaldehyde and histamine concentrations, but not in LTC4 or TXB2. After azelastine treatment, there was no significant fall in FEV1 among responders. Neither the rise in blood ethanol nor blood acetaldehyde levels were blunted by treatment with azelastine, but the rise in blood histamine was blunted by this treatment.. Our results suggest that antihistamine agents may be effective against alcohol-induced asthma by both blocking H1 receptors and inhibiting histamine release.

Topics: Acetaldehyde; Adult; Aged; Asthma; Bronchoconstrictor Agents; Bronchodilator Agents; Ethanol; Female; Histamine; Humans; Leukotriene C4; Male; Middle Aged; Phthalazines; Respiratory Function Tests; Thromboxane B2

The role of cysteinyl leukotrienes (cys-LTs) and thromboxane A(2) (TXA(2)) in guinea pig models of aspects of bronchial asthma was investigated. In a novel antigen (BSA)-induced asthmatic model using passively sensitized guinea pigs, pretreatment with varying doses of indomethacin controlled the ratio of followed lipid mediators, LTC(4)/D(4)/E(4) and TXB(2), in lungs of challenged guinea pigs. The predominant mediator in indomethacin-untreated asthma was TXA(2), and complete inhibition of cyclooxygenase by i.v. injection of 5-mg/kg indomethacin-induced cys-LTs mainly mediated asthmatic response. Furthermore, a 1-mg/kg indomethacin dose induced an asthmatic state where both cys-LTs and TXA(2) equally participated. Either LTD(4) or TXA(2) receptor antagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD(4) and TXA(2) receptor antagonists exhibited significant effects irrespective of the condition used. Under conditions where both mediators equally participate, a combination of both receptor antagonists showed additive inhibition. YM158, a newly synthesized and orally active dual antagonist for LTD(4) and TXA(2) receptors, showed the same antiasthmatic effect as a combinated LTD(4) receptor antagonist and a TXA(2) receptor antagonist mixture. Therefore, broad-acting compounds such as YM158 are expected to have antiasthmatic efficacies in a broader class of asthmatic patients than single-acting drugs.

Topics: Administration, Oral; Animals; Asthma; Chromones; Disease Models, Animal; Guinea Pigs; Immunization, Passive; Leukotriene Antagonists; Leukotrienes; Male; Membrane Proteins; Phenylacetates; Receptors, Leukotriene; Receptors, Thromboxane; Serum Albumin, Bovine; Sulfonamides; Tetrazoles; Thiazoles; Thromboxane A2; Thromboxane B2

Further definition of the role of leukotrienes (LT) and prostaglandins (PG) in asthma would be helped by a noninvasive method for assessing airway production. The supernatant from sputum induced with hypertonic saline and dispersed using dithiotrietol has been successfully used to measure other molecular markers of airway inflammation and might be a useful method. We have measured induced sputum supernatant LTC(4)/D(4)/E(4) concentrations using enzyme immunoassay and PGE(2), PGD(2), TXB(2), and PGF(2alpha) using gas chromatography-negative ion chemical ionization-mass spectroscopy in 10 normal subjects and in 26 subjects with asthma of variable severity. Sputum cysteinyl-leukotrienes concentrations were significantly greater in subjects with asthma (median, 9.5 ng/ml) than in normal control subjects (6.4 ng/ml; p < 0.02) and greater in subjects with persistent asthma requiring inhaled corticosteroids (median, 11.4 ng/ml) or studied within 48 h of an acute severe exacerbation of asthma (13 ng/ml) than in subjects with episodic asthma treated with inhaled beta(2)-agonists only (7.2 ng/ml). There were no significant differences in the concentrations of other eicosanoids between groups, although there was a negative correlation between the percentage sputum eosinophil count and sputum PGE(2) concentration (r = -0.48; p < 0.01) in subjects with asthma. We conclude that induced sputum contains high concentrations of eicosanoids and that sputum LTC(4)/D(4)/E(4) concentrations are significantly greater in subjects with asthma than in normal subjects. The inverse relationship between eosinophilic airway inflammation and sputum PGE(2) concentration would be consistent, with the latter having an anti-inflammatory role.

Topics: Adult; Asthma; Cysteine; Eicosanoids; Eosinophils; Female; Humans; Inflammation Mediators; Leukocyte Count; Leukotrienes; Male; Middle Aged; Prostaglandins; Sputum; Thromboxane B2

A marked and sustained bronchoconstriction after antigen challenge was produced in actively sensitised guinea pigs, and correlated with increments of thromboxane (TX) A2 level in both the plasma and bronchoalveolar lavage fluid. DP-1904 given orally relieved the bronchoconstriction and increase in TXA2 in a dose-dependent manner. In platelet-depleted animals, antigen-induced bronchoconstriction and TXA2 release in the plasma were significantly reduced compared to those of non-platelet-depleted animals, indicating that platelets are a major cell source of TXA2 production, the remainder originating from the other cells excluding platelets. In the platelet-deprived animal, DP-1904 showed further significant inhibition of the constriction and plasma TXA2 level, and therefore likely inhibits TXA2 synthesis of various cells, including platelets, in the bloodstream. The results suggested that TXA2 is an important mediator responsible for producing antigen-induced bronchoconstriction, and endogenously originated from various cells including platelets in guinea pigs.

Topics: Animals; Anti-Asthmatic Agents; Antigens; Asthma; Blood Platelets; Enzyme Inhibitors; Guinea Pigs; Imidazoles; Male; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Various kinds of cells and their mediators are thought to be involved in the pathogenesis of bronchial asthma. However, changes in each mediator or relationship among mediators during an asthmatic attack have not been well documented. In this study, to clarify whether eosinophil protein X (EPX) is a marker which is distinct from leukotriene E4 (LTE4), or 11-dehydrothromboxane B2 (11DTXB2), we measured the urinary excretion of EPX, LTE4, and 11DTXB2 in 14 asthmatics who were admitted to the hospital with either an acute asthmatic attack or status asthmaticus. These patients included eight atopic and six non-atopic types of bronchial asthma, with a median age of 34.0 years. Urinary excretion of EPX was significantly high on admission with the asthmatic attack, and returned to control levels 175 [122 -384] microg/day when the patients were in the improved state (1036-317 microg/day, P < 0.01). Similar findings were observed in LTE4 (155-59 ng/day, P < 0.01) and 11DTXB2 (991-442ng/day, P<0.01). No significant differences in values were observed between atopic and non-atopic types of asthma in all three substances. When the individual data during the attack state were analysed, a significant correlation was observed between changes (%) in urinary EPX and those in urinary LTE4, but no such relationship was observed between changes (%) in urinary EPX and those in urinary 11DTXB2. These results suggest that measuring urinary EPX levels may be a useful marker for the understanding and management of the disease.

Topics: Acute Disease; Adolescent; Adult; Aged; Allergens; Asthma; Blood Proteins; Chromatography, High Pressure Liquid; Eosinophil-Derived Neurotoxin; Eosinophils; Female; Forced Expiratory Volume; Humans; Immunoglobulin E; Leukotriene E4; Male; Middle Aged; Ribonucleases; Thromboxane B2

Cineole (eucalyptol) is the isolated active agent of eucalyptus oil. Traditionally, it is recommended for treating the symptoms of airway diseases exacerbated by infection. We have examined the inhibitory effect of 1.8-cineole on LPS-and IL1beta-stimulated mediator production by human monocytes in vitro. For the first time, we report on a dose-dependent and highly significant inhibition of production of tumor necrosis factor-alpha, interleukin-1beta, leukotriene B4 and thromboxane B2 by 1.8-cineole. In summary, this is the first report on a new mechanism of action of monoterpenes suggesting 1.8-cineole as a strong inhibitor of cytokines that might be suitable for longterm treatment of airway inflammation in bronchial asthma and other steroid-sensitive disorders.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Asthma; Cyclohexanols; Cytokines; Eucalyptol; Female; Humans; In Vitro Techniques; Inflammation; Inflammation Mediators; Interleukin-1; Leukotriene B4; Lipopolysaccharides; Male; Menthol; Monocytes; Monoterpenes; Respiratory Tract Diseases; Terpenes; Thromboxane B2; Tumor Necrosis Factor-alpha

The objective of this study was to define the participation of cysteinyl leukotrienes (LTs) or thromboxane A2 in the pathogenesis of aspirin-sensitive asthma (ASA). Leukotriene E4 (LTE4) and 11-dehydrothromboxane B2 (11DTXB2) values in spot urine were measured in 22 asthmatics with a history of aspirin sensitivity and in 17 without such a history (non-aspirin-sensitive asthma [NASA]) in the outpatient clinic. The urinary LTE4 value was significantly higher in ASA patients than in NASA (340 +/- 47 vs 65 +/- 15 pg/mg.cr, P < 0.001), but there was no significant difference in urinary 11DTXB2 between the two groups (891 +/- 77 vs 657 +/- 90 pg/mg.cr). A high value of LTE4 was not associated with type of asthma, severity of disease, oral prednisolone treatment, sex, or age. A higher value of 11DTXB2 was observed in the atopic type than the nonatopic type in ASA (1086 +/- 111 vs 697 +/- 147 pg/mg.cr, P < 0.05). No correlation was observed between urinary LTE4 and 11DTXB2 in either ASA or NASA. In conclusion, LTs may play an important role in the pathogenesis of ASA, and TXA2 in the pathogenesis of the atopic type in ASA.

Topics: Aspirin; Asthma; Case-Control Studies; Drug Hypersensitivity; Female; Humans; Leukotriene E4; Male; Middle Aged; Severity of Illness Index; Thromboxane B2

Cysteinyl leukotrienes (LTs) and thromboxane A2 (TXA2) are known to play an essential role in the pathogenesis of atopic asthma. However, their role in nonatopic asthma has not as yet been clarified. The objectives of this study were to define (1) the participation of LTs and TXA2 in nonatopic asthma and (2) the relationship between LTs and TXA2 in asthma attacks.. Urinary excretion of leukotriene E4 (LTE4) and 11-dehydrothromboxane B2 (11DTXB2) was measured in 10 atopic and 10 nonatopic asthmatics who were admitted to hospital with either an acute asthma attack or status asthmaticus.. In atopic asthmatics, urinary excretion of LTE4 and 11DTXB2 was significantly higher on admission with an asthma attack, and returned to control levels when the patients were in the improved state (179+/-29 to 65+/-16 ng/day in LTE4, 1,085+/-250 to 440+/-90 ng/day in 11DTXB2). Similar findings were observed in nonatopic asthmatics (148+/-13 to 61+/-11 ng/day in LTE4, 1,089+/-206 to 457+/-60 ng/day in 11DTXB2). However, when the individual data during the attack were analyzed, there was no correlation between urinary excretion of LTE4 and that of 11DTXB2 in both types of asthma.. Both LTs and TXA2 may be implicated in the pathogenesis of the nonatopic as well as the atopic type of asthma, but no correlation between these two metabolites was observed in the individuals.

Topics: Adolescent; Adult; Aged; Asthma; Female; Humans; Hypersensitivity, Immediate; Leukotriene E4; Male; Middle Aged; Status Asthmaticus; Thromboxane B2

A role of prostaglandins (PGs) and leukotrienes (LTs) in the pathogenesis of nasal polyps has been recently suggested. Cyclooxygenase (CO) products (thromboxane B2, PGE2 and 6-keto PGF1 alpha) and lipoxygenase (LO) products (LTB4 and LTC4) were investigated by radioimmunoassay in polyps, hypertrophic turbinates and nasal mucosa from 14 patients with non-allergic (n = 6), allergic chronic rhinitis (n = 6) and aspirin-sensitive asthma (ASA) (n = 2), who underwent polypectomy. In all tissues CO metabolite levels were found higher than LO products (P < 0.01). Nasal polyps showed a significantly lower (P < 0.05) arachidonic acid (AA) metabolism in comparison to nasal mucosa. In polyps of allergic patients significantly higher LTB4 levels (P < 0.001) and a tendency to produce higher amounts of CO products in comparison to non-allergic subjects were observed, whereas in turbinates of non-allergic patients LT levels were significantly higher in comparison to those of allergic ones (P < 0.01). In ASA patients a decreased CO/LO ratio was found supporting the hypothesis of an imbalance of AA metabolism in this syndrome. These findings seem to indicate that the occurrence of nasal polyps may represent the result of different chronic inflammatory stimuli, regulated in part by AA metabolites.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Asthma; Dinoprostone; Humans; Leukotriene B4; Leukotriene C4; Lipoxygenase; Middle Aged; Nasal Mucosa; Nasal Polyps; Prostaglandin-Endoperoxide Synthases; Rhinitis; Thromboxane B2; Turbinates

To investigate the mechanisms of airway hyperresponsiveness (AHR), we examined the time course for asthmatic responses (including immediate asthmatic response (IAR), late asthmatic response (LAR), and AHR), airway inflammation (including edema in the airway, accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF), and mediator release including histamine and thromboxane A2 (TXA2) in BALF after the repeated provocation of aeroantigen in sensitized guinea pigs. Furthermore, we examined the effect of S-1452, a TXA2 receptor antagonist, on the antigen-induced airway obstruction and AHR in guinea pigs. We found that IAR occurred 1 min after every antigen inhalations. LAR was observed every 4 h after the inhalation of antigen without 1st or 2nd challenge. AHR was initially observed 4 h after the 5th inhalation of antigen, and then AHR was observed at every time measured even after the 6th provocation. The water content of the airway increased after the 2nd antigen inhalation. A number of leukocytes, especially eosinophils in BALF, was observed 30 min after the 2nd antigen inhalation. Desquamation of epithelia was observed 30 min after the 5th antigen inhalation. TXB2 and histamine in BALF were detected after the first antigen inhalation. These results suggest that LAR is caused by repeated airway inflammation such as eosinophilia and mediator release including TXA2. AHR may appear with the damages of lung tissue such as desquamation of epithelia. Oral administration of S-1452 (1 and 10 mg/kg) significantly inhibited LAR and AHR, assessed after the 6th antigen challenge. The present findings suggest that repeated antigen challenge causes airway inflammation and leads to the onset of LAR and AHR when became chronic. Furthermore, persistent generated TXA2 plays an important role in the pathogenesis of antigen-induced late-phase obstruction and AHR.

Topics: Airway Obstruction; Airway Resistance; Animals; Antigens; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchitis; Bronchoalveolar Lavage Fluid; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Male; Prostaglandin Antagonists; Pulmonary Edema; Thromboxane B2; Time Factors

To explore the effect of the Xingbei Granule (XBG) in treating bronchial asthma and its mechanism.. Systematic clinical observation and animal experimental study on the XBG were carried out.. The XBG not only could reduce the symptom of asthma, improve the ventilatory function effectively, but also has the effect of antagonizing the change of asthmatic inflammatory medium, alleviating the air-way's inflammatory reaction and lowering the air-way's hyperreactivity.. XBG do attain the dual goal of controlling the asthmatic symptoms and reducing the asthmatic attack.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Anti-Asthmatic Agents; Asthma; Drugs, Chinese Herbal; Female; Guinea Pigs; Humans; Male; Middle Aged; Respiratory Function Tests; Thromboxane B2

To elucidate the mechanism of development of asthma, we tried to develop a model which elicited a late asthmatic response by a combination of systemic and inhaled sensitization with ovalbumin in guinea pigs. Eighty-seven percent of animals elicited both an immediate and late asthmatic response after the third antigen inhalation. Airway eosinophilia and airway hyperresponsiveness (AHR) induced after the third challenge were more severe than those after the first challenge. There was a good correlation between airway eosinophilia and AHR in this model under experimental modulation of the number of eosinophils, such as by interleukin 5 or antieosinophil antibody injection. These results demonstrate that eosinophils play an important role in the development of late asthmatic response and AHR.

Topics: Animals; Antibodies; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Disease Models, Animal; Eosinophils; Guinea Pigs; Histamine; Interleukin-5; Leukocyte Count; Leukotriene C4; Male; Methacholine Chloride; Ovalbumin; Passive Cutaneous Anaphylaxis; Pulmonary Eosinophilia; Thromboxane B2; Time Factors

To determine the role of neutrophil elastase in asthmatic responses, we studied the effect of ONO-5046, a specific neutrophil elastase inhibitor, on antigen-induced asthmatic responses in allergic sheep. Pulmonary resistance (RL) was measured for 8 h after antigen challenge. Measurements of airway responsiveness to methacholine and bronchoalveolar lavage fluid (BALF) were obtained 8 h after challenge. Antigen challenge caused early and late increases in RL, airway hyperresponsiveness (AHR), and recruitment of neutrophils and eosinophils along with increases in TXB2 and LTB4 in BALF. ONO-5046 treatment significantly reduced both early and late bronchoconstriction, neutrophil recruitment, increases in LTB4 in BALF, and AHR. ONO-5046 post-treatment significantly reduced the increase in RL 8 h after antigen challenge. Another neutrophil elastase inhibitor, FR 134043, significantly reduced both early and late bronchoconstriction. ONO-5046 had little effect on calcium ionophore-induced LTB4 release from isolated neutrophils and whole blood obtained from drug-treated sheep. These findings suggest that neutrophil elastase is involved in antigen-induced bronchoconstriction and AHR mediated by neutrophil accumulation and 5-lipoxygenase products in allergic sheep.

Topics: Airway Resistance; Animals; Antigens; Asthma; Benzoquinones; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Calcimycin; Glycine; Heterocyclic Compounds; Leukocyte Elastase; Leukocytes; Leukotriene B4; Masoprocol; Methacholine Chloride; Pancreatic Elastase; Polycyclic Compounds; Sheep; Sulfonamides; Thromboxane B2

Aspirin-sensitive patients may be desensitized through a graded series of exposures to aspirin. We investigated the underlying mechanism of aspirin desensitization by measuring the release of leukotrienes B4 and C4 from calcium ionophore-stimulated peripheral blood monocytes. Compared with monocytes from normal volunteers (n = 5), monocytes from patients with aspirin-sensitive asthma (n = 10) released increased amounts of thromboxane B2 (1060 +/- 245 pg/ml vs 456 +/- 62 pg/ml), leukotriene B4 (861 +/- 139 pg/ml vs 341 +/- 44 pg/ml), and leukotriene C4 (147 +/- 31 pg/ml vs 56 +/- 6 pg/ml) at baseline. After aspirin desensitization, thromboxane B2 release was almost completely suppressed in both groups. Leukotriene B4 release was significantly decreased in the aspirin-sensitive group (484 +/- 85 pg/ml) but not in the normal subject group (466 +/- 55 pg/ml). The need for prednisone decreased significantly after patients were desensitized to aspirin (10.4 +/- 2.2 mg/day to 1.6 +/- 2.8 mg/day). These results demonstrate that desensitization to aspirin results in decreased monocyte leukotriene B4 release. On the basis of the bronchospastic and inflammatory potential of leukotrienes, the decrease in leukotriene release may contribute to the clinical improvement seen after aspirin desensitization.

Topics: Adult; Aspirin; Asthma; Desensitization, Immunologic; Female; Humans; Leukotriene B4; Leukotriene C4; Male; Middle Aged; Monocytes; Thromboxane B2

Toluene diisocyanate (TDI) is a volatile, highly reactive chemical widely used as a polymerizing agent in the production of polyurethane foams, lacquers, adhesives, and other items. Repeated airway exposures in the workplace to TDI may cause a concentration-dependent risk of developing chronic airway disorders. Different pathomechanisms are involved. IgE-mediated sensitization and irritative effects were clearly demonstrated in exposed subjects as well as in animals. In this study we examined the cellular and mediator composition in bronchoalveolar lavage fluid (BALF) of guinea pigs (eight in each group) exposed to TDI (10, 20, or 30 ppb) on 5 consecutive days for 2 hours each. Increased numbers of eosinophils and significantly elevated levels of LTB4 and LTC4/LTD4/LTE4 were obtained in BALF of all exposed animals when compared to nonexposed control animals. PGD2 and TXB2 remained unaltered in BALF. Stimulation of BALF cells of exposed and control animals with Ca-ionophore A23187 and arachidonic acid induced an increased generation of LTB4. Furthermore, BALF cells of the exposed animal groups generated immunoreactive LTC4/LTD4/LTE4, whereas controls did not show peptido-leukotriene formation in the presence and absence of stimuli. Our data clearly demonstrate an influx of eosinophils into the airways associated with mediator release and higher cellular responsiveness after TDI exposure.

Topics: Animals; Arachidonic Acid; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Calcimycin; Dose-Response Relationship, Drug; Eosinophils; Female; Guinea Pigs; Inflammation Mediators; Leukocyte Count; Leukotrienes; Prostaglandin D2; Thromboxane B2; Toluene 2,4-Diisocyanate

In order to find the relationship between endothelin and asthma, we investigated the level of plasma endothelin of guinea pigs with asthma, and the bronchoconstriction of endothelin to the guinea pigs. We also measured the plasma concentration of PGE2 TXB2 PGF2 alpha LTC4 after using ET intravenously. The results showed that the level of plasma endothelin elevated significantly in guinea pigs with asthma. The bronchoconstriction was positively related to the dosage of endothelin intravenously. PLA2 antagonist and cyclooxygenase inhibitor can reduce the bronchoconstriction caused by endothelin. All these indicated that endothelin may contribute to the cause of asthma.

Topics: Albumins; Animals; Asthma; Bronchoconstriction; Dinoprostone; Endothelins; Guinea Pigs; Male; Thromboxane B2

1. IgG1-mediated anaphylactic bronchoconstriction was elicited by intravenous administration of antigen to guinea-pig 2 days after passive sensitization with IgG1-rich serum, and this response was not affected by heating the serum (at 56 degrees C, for 4 h). IgE-mediated bronchoconstriction, provoked 14 days after passive sensitization with IgE-rich serum, was completely abolished by the heating of the serum. 2. S-1452 (10 mg kg-1, p.o.), a selective thromboxane (Tx) A2 antagonist, significantly but incompletely suppressed the IgG1-mediated bronchoconstriction, but did not affect the IgE-mediated one, while diphenhydramine (5 mg kg-1, i.v.), a histamine antagonist, almost completely inhibited both IgG1- and IgE-mediated bronchoconstriction. 3. Pretreatment with propranolol (1 mg kg-1, i.v.), a beta-adrenergic blocker, in addition to diphenhydramine, caused a long-lasting bronchoconstriction following antigen challenge in both animal models. This histamine-independent bronchoconstriction was markedly suppressed by S-1452 at a low dose of 0.1 mg kg-1. 4. A significant increase in bronchial responsiveness to i.v. acetylcholine (ACh), compared to the prechallenge value, occurred as early as 3 min and persisted for 24 h after antigen challenge in the IgG1 model, but was not observed in the IgE model. S-1452 (10 mg kg-1, p.o.) inhibited the IgG1-mediated bronchial hyperresponsiveness, as assessed 60 min after antigen challenge. 5. A marked elevation of TxB2 levels was observed in bronchoalveolar lavage fluid (BALF) 3 min after antigen challenge in the IgG1 model, while levels were not changed in the IgE model. In contrast, the plasma TxB2 level assessed 1 min after antigen challenge was increased in both the IgGI and IgE models.6. The results indicate that the inhibition of IgGl- but not IgE-mediated bronchoconstriction by higher doses of S-1452 may result from the suppression of increased bronchial responsiveness to allergic mediators such as histamine, which is probably due to TxA2 generated in the airway lumen rather than in plasma. In both the IgGI and IgE models, plasma TxA2 appeared to contribute directly to the bronchoconstriction, its action being almost completely masked by histamine-mediated bronchoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic beta-Antagonists; Animals; Antibodies, Monoclonal; Antigens; Asthma; Bridged Bicyclo Compounds; Bronchial Hyperreactivity; Bronchoconstriction; Diphenhydramine; Fatty Acids, Monounsaturated; Guinea Pigs; Immunoglobulin E; Immunoglobulin G; Male; Receptors, Prostaglandin; Thromboxane A2; Thromboxane B2

Nedocromil sodium, a disodium salt of a pyroquinolinedicarboxylic acid, raises the bronchial hyperresponsiveness threshold, because it inhibits the mediators released by the various cells, and reduces the involvement and activation of inflammatory cells. The aim of this study was to evaluate the state of activation of the immunocompetent cells and the main chemical mediators present in the bronchoalveolar lavage (BAL) fluid from 10 atopic asthmatic patients, before and after treatment with nedocromil sodium. The following examinations were performed before treatment and after 120 days of therapy with nedocromil sodium at 16 mg/day (two 2-mg puffs x 4): the level of chemical mediators and the state of activation of immunocompetent cells in BAL fluid; immunological analytes in activation of immunocompetent cells in BAL fluid; immunological analytes in peripheral blood; aspecific bronchial challenge test with ultrasonicated bidistilled H2O fog to evaluate variations in the hyperreactivity threshold; questionnaire to determine any adverse effects of treatment (cough, breathlessness, sleep disorders). Our findings demonstrate that nedocromil sodium prevents the release of chemotactic and inflammatory mediators by the effector cells and thus stabilizes microvascular permeability and epithelial damage, so raising the threshold of response to bronchoconstriction stimuli. Lastly, nedocromil sodium is associated with a better preventive therapeutic efficacy and good tolerance and can therefore be suggested as a valid drug to be used in the long-term treatment of bronchial asthma.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albumins; Asthma; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Dinoprostone; Eosinophil Granule Proteins; Humans; Hypersensitivity; Immunoglobulins; Immunologic Factors; Leukocytes; Leukotriene B4; Lymphocytes; Macrophages; Male; Nedocromil; Peptide Hydrolases; Ribonucleases; Thromboxane B2

We investigated the acute airway response to nitrogen dioxide (NO2) and ozone in healthy and asthmatic subjects. A) 12 subjects with mild bronchial asthma and 8 healthy subjects were studied to determine the effects of shortterm exposure to NO2 on lung function, bronchoalveolar lavage cells and mediators, and bronchial mucosal biopsy specimens. The asthmatic subjects exhibited changes in prostanoid and leukotriene mediators but no changes in differential cell numbers after NO2 exposure, whereas the normal subjects showed no consistent effects. These results indicate that changes in mediator profile induced by NO2 may be found without concomitant alterations in differential cell numbers. B) Ozone has been demonstrated to induce deterioration of lung function and bronchial responsiveness but it is not clear whether subjects with asthma or rhinitis are more susceptible than normals. We studied the effect of a short-term exposure to ozone on lung function and airway responsiveness to methacholine in 12 subjects with atopic asthma, 18 subjects with allergic rhinitis, and 38 healthy subjects. There was a large interindividual variability in the airway response to ozone but no statistically significant difference between study groups with respect to changes of lung function and airway responsiveness. Our data indicate that an intrinsic variability in ozone sensitivity is of higher relevance than a pre-existing airway disease such as asthma or rhinitis. By comparing both studies we suggest that the relationship between airway disease and airway responsiveness to oxidant pollutants is not homogeneous over substances.

Topics: Adult; Air Pollutants; Airway Resistance; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Exercise Test; Female; Forced Expiratory Volume; Humans; Male; Nitrogen Dioxide; Ozone; Prostaglandin D2; Thromboxane B2

A simple method for purification of basophils from a relatively small volume of blood has been developed, which enables us to collect basophils with a purity of over 80%. Basophils were partially purified from 10-20 ml of citrated whole blood using the discontinuous Percoll density gradient centrifugation technique and then contaminant cells were removed using monoclonal antibodies against CD2, CD19, CD14 and CD16. At the end of the procedure, basophils were > 80% pure with lymphocytes accounting for most of the contaminating cells. When stimulated with anti-IgE or fMLP, histamine release from purified basophils was similar to that from mixed leukocytes. When highly purified basophils were challenged with calcium ionophore A23187, generation of leukotriene C4 (LTC4) was not significantly different between asthmatic patients and normal subjects (45.6 +/- 22.6 vs 52.7 +/- 25.6 ng/10(6) cells). Basophils were capable of generating LTC4 in approximately the same quantities as eosinophils (46.5 +/- 11.7 ng/10(6) cells, n = 3). Furthermore, it has been shown that incubation of basophils and eosinophils with calcium ionophore generates only small quantities of thromboxane B2 (TXB2).

Topics: Antibodies, Anti-Idiotypic; Asthma; Basophils; Blood Cells; Calcimycin; Cell Separation; Centrifugation, Density Gradient; Histamine Release; Humans; Leukotriene C4; N-Formylmethionine Leucyl-Phenylalanine; Thromboxane B2

The aim of this study was to evaluate by cytofluorimetry, the phenotype and the activation of alveolar macrophages (CD14; CD33; CD44; CD54; CD23; HLA-DR) and, by radioimmunoassay, the "in vivo and in vitro" macrophage secretory pattern (IL-1 alpha; IL-1 beta; IL6; IL8; PGE2; PGD-1 alpha; TXB2; LTB4) in atopic patients with mild asthma in intercritical phase and with bronchial hyperreactivity (PD20 FEV1 = 377 +/- 262.8 micrograms). In asthmatic patients we have demonstrated that the number of cells recovered in BALF expressing the phenotypic features (CD14; CD33; HLA-DR; CD23; CD44; CD54) was larger than in control subjects. By analysing the culture medium of unstimulated and LPS-stimulated alveolar macrophages from asthmatic and normals we have demonstrated a greater production of IL-1 beta (p = 0.005) and IL-8 (p = 0.005) in the first group than in one second, as confirmed by a Wilcoxon test. Concerning the secretory pattern in BALF of asthmatic patients we obtained similar results, showing a significant IL-1 beta (p = 0.005) and IL-8 (p = 0.002) increase suggesting a persistent cellular activation. On the contrary we could not show any significant increase of IL-1 alpha (p = 0.31) and IL-6 (p = 0.22). The cellular activation was confirmed by increased levels of different chemical mediators such as TXB2 (p = 0.005); LTB4 (p = 0.004); PGE2 (p = 0.007); PGF-1 alpha (p = 0.008) which were recovered from BALF of asthmatic patients compared to normal subjects. In conclusion alveolar macrophages play an important role in the pathogenesis of asthma because of the presence of cytokines and mediators in BALF and in the supernatant of alveolar macrophage cultures.

Topics: Adult; Asthma; Biopsy; Bronchi; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cytokines; Flow Cytometry; Humans; Interleukins; Leukotriene B4; Macrophage Activation; Macrophages, Alveolar; Phenotype; Prostaglandins; Radioimmunoassay; Thromboxane B2

In order to examine the hypothesis that in aspirin-induced asthma (AIA) cyclooxygenase inhibition is associated with enhanced release of leukotrienes (LTs), we measured urinary leukotriene E4 (LTE4) and 11-dehydro-thromboxane B2 (TXB2) (as a measure of cyclooxygenase production) following challenge with oral aspirin or inhaled methacholine, in 10 AIA patients. We also determined serum tryptase and eosinophilic catonic protein (ECP) levels, in order to evaluate mast cell and eosinophil activation. Urinary LTE4 excretion was increased sevenfold 4-6 h after aspirin challenge, while 11-dehydro-TXB2 decreased gradually reaching 50% baseline levels 24 h after challenge (p < 0.05). This was accompanied by a significant fall in blood eosinophil count at 6 h, and a tendency to a rise in ECP. The intensity of both LTE4 and 11-dehydro-TXB2 responses depended on the dose of aspirin used (p < 0.001, analysis of variance (ANOVA)). The accompanying maximum fall in forced expiratory volume in one second (FEV1) was not correlated with peak LTE4 levels. In contrast to aspirin, methacholine challenge producing comparable bronchial obstruction, did not alter eicosanoid excretion or serum tryptase or ECP levels. In a separate study, lysine-aspirin inhalation challenge was performed in seven AIA patients, four of whom had responded with a rise in serum tryptase to oral aspirin challenge. Challenge with inhaled aspirin led to similar bronchoconstriction as with oral challenge, but non-respiratory symptoms such as scarlet flush or rhinorrhea were absent, and serum tryptase levels remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aspirin; Asthma; Blood Proteins; Bronchial Provocation Tests; Bronchoconstriction; Chymases; Eosinophil Granule Proteins; Eosinophils; Female; Humans; Leukotriene E4; Male; Mast Cells; Methacholine Chloride; Middle Aged; Ribonucleases; Serine Endopeptidases; SRS-A; Thromboxane B2; Tryptases

Plasma and lung homogenate lyso-PAF were measured by using the method of bioassay in guinea pigs with allergic asthma and asthmatic patients. The results showed that Lyso-PAF levels were increased significantly in asthmatics, and it was positively correlated with TXB2 levels. It is suggested that PAF plays an important role in bronchial asthma, which may be correlated with TXA2. The method of bioassay of Lyso-PAF is stable, reliable and special instruments are not needed.

Topics: Adolescent; Adult; Animals; Asthma; Biological Assay; Female; Guinea Pigs; Humans; Lung; Male; Middle Aged; Ovalbumin; Platelet Activating Factor; Thromboxane B2

The spontaneous and stimulated generation of fatty acid cyclo-oxygenase pathway-derived products of arachidonic acid from highly purified (91.6 +/- 1.3%, n = 23) human blood eosinophils obtained from asthmatics were examined using combined gas chromatography/mass spectrometry. Under resting conditions, eosinophils spontaneously generated 0.24 +/- 0.10 pg prostaglandin E2 (PGE2), 0.51 +/- 0.20 prostaglandin D2 (PGD2), 0.35 +/- 0.10 pg prostaglandin F2 alpha (PGF2 alpha) and 8.5 +/- 2.2 pg thromboxane B2 (TXB2), the stable metabolite of TXA2 per 10(6) cells. In contrast, 6-keto-prostaglandin F1 alpha and 9 alpha,11 beta-prostaglandin F2 were not detectable. Stimulation of eosinophils with platelet-activating factor (PAF) for 5 min induced a two- to sixfold increase in the biosynthesis of prostanoids. More than 95% of the generated prostanoids were released into the surrounding medium. The response to PAF was inhibited by the PAF receptor antagonist WEB 2086 (1 microM). The fatty acid cyclo-oxygenase inhibitor, ibuprofen, abolished both the spontaneous and PAF-stimulated generation of prostanoids by eosinophils. LTB4, PMA and calcimycin also produced an increase in prostanoid production, whereas lyso-PAF, the PAF precursor and metabolite, failed to induce prostanoid generation over basal production. In conclusion, the results demonstrate that PAF potently activates human eosinophils to generate and release several fatty acid cyclo-oxygenase metabolites of the arachidonic acid pathway, with TXB2 being the most abundant. These data are in agreement with previous observations suggesting that PAF may be an important stimulus for prostanoid release by the eosinophil in allergic diseases such as asthma.

Topics: Asthma; Cells, Cultured; Dose-Response Relationship, Drug; Eosinophils; Humans; Ibuprofen; Leukocytes; Platelet Activating Factor; Prostaglandins; Thromboxane B2

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)

Topics: Adult; Allergens; Aspirin; Asthma; Bronchial Provocation Tests; Female; Histamine; Humans; Leukotriene E4; Male; Middle Aged; SRS-A; Thromboxane B2

Aspirin and nonsteroidal antiinflammatory drugs induce bronchospastic reactions in patients with aspirin-sensitive respiratory disease. Although the mechanism of this reaction is unknown, all drugs that induce the respiratory reaction also inhibit the cyclooxygenase enzyme. The ensuing changes in arachidonate metabolism are presumed to play a role in the pathogenesis of the reaction. We measured generation of leukotrienes and thromboxane by calcium ionophore stimulated blood monocytes. Before aspirin challenge, monocytes released significantly more thromboxane B2 in patients with aspirin sensitivity than in patients without aspirin sensitivity or in healthy control subjects (p < 0.02). During aspirin-induced bronchospasm, release of leukotriene B4 increased significantly (45.5%, p = 0.018), whereas release of thromboxane B2 decreased (-46.9%, p = 0.028). Two hours after ingestion of 60 mg aspirin, normal monocyte release of thromboxane B2 did not drop, whereas leukotriene B4 release increased. Monocytes formed only minimal amounts of leukotriene C4. We conclude that the profile of released eicosanoids from aspirin-sensitive monocytes is distinct from non-aspirin-sensitive subjects, and that these differences could contribute to the development of bronchospasm after aspirin ingestion.

Topics: Administration, Oral; Adult; Arachidonic Acid; Aspirin; Asthma; Bronchial Spasm; Calcimycin; Eicosanoids; Female; Humans; Leukotriene B4; Male; Middle Aged; Monocytes; Thromboxane B2

1. The capacity of various drugs (acetylsalicylic acid (ASA), ketoprofen, diclofenac, piroxicam, BW 755C, BW A4C, nedocromil sodium and azelastine) to inhibit human polymorphonuclear neutrophil (PMN)-mediated platelet activation was investigated. In this model, stimulated PMN release cathepsin G (Cat G), a serine proteinase which, in turn, induces platelet activation. 2. Among the different tested drugs, azelastine (100 microM for 1 min) was the only one able to prevent platelet aggregation. The cyclo-oxygenase inhibitors were all inactive, although used at effective concentrations as judged by inhibition of thromboxane B2 (TxB2) formation. Inhibition of platelet aggregation by azelastine was concentration-dependent, the range of active concentrations being of 20-70 microM. Release from platelets of 5-hydroxytryptamine was also inhibited at 30 microM and above, but never reached 100%. 3. The inhibition by azelastine is due to an effect on both cells. Indeed, beta-glucuronidase release from activated PMN and platelet activation by purified Cat G were both affected. 4. However, used at high concentrations (greater than 100 microM) azelastine was toxic since it released significant amounts of lactate dehydrogenase (LDH) from PMN and platelets. 5. These results show the capacity of azelastine, an anti-allergic and anti-asthmatic compound, to inhibit the cell-to-cell communication between PMN and platelets, an effect which may be relevant for its therapeutic efficacy or for a new application in diseases in which PMN and platelets are involved.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Asthma; Glucuronidase; Humans; In Vitro Techniques; L-Lactate Dehydrogenase; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Phthalazines; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Serotonin; Thromboxane B2; Vasodilator Agents

Alveolar macrophages (AM) are among the cells involved in the bronchial inflammation of asthma. It has been shown that AM are a heterogeneous cell population in normal subjects. The heterogeneity of AM from 36 asthmatic patients and 23 normal subjects was studied using Percoll density fractionation. AM recovered from asthmatic patients are mainly in the lower density fractions (1.03 and 1.04 g/ml), whereas AM from normal subjects are in the higher density fractions (1.05 and 1.07 g/ml). Electron microscopic studies showed that low density AM of both asthmatic and normal subjects appear to have morphologic characteristics of activated cells by comparison with high density AM that present characteristics of quiescent cells in both asthmatic and normal subjects. The functional activity of AM fractions of asthmatic and control subjects was assessed using the release of the oxygen free radicals induced by opsonized zymosan and TxB2 generation by A23187. There was no difference between the five fractions of asthmatic or control subjects with regard to oxygen species release. The TxB2 generation was increased in the low density AM from asthmatics when compared with the same fractions of normal subjects. The hypodense cells produced less TxB2 than did cells of higher density in both asthmatic and normal subjects. The density of AM was correlated with the recent instability of the asthma but not with the severity of it. This study shows that AM from asthmatic subjects, when compared with those from control subjects, are heterogeneous, hypodense cells and that they predominate. Hypodense AM did not appear to be hyperresponsive in vitro and may have been already committed into the airways.

Topics: Adolescent; Adult; Aged; Asthma; Bronchoalveolar Lavage Fluid; Calcimycin; Cell Count; Cell Separation; Humans; Macrophages; Microscopy, Electron; Middle Aged; Pulmonary Alveoli; Superoxides; Thromboxane B2; Zymosan

In order to investigate the role of platelets in allergic asthma, the time related changes in plasma levels of beta-TG, PF4 and TXB2 were evaluated following BPT with HD in 19 patients with bronchial asthma who were positive in skin test and RAST to HD. The results obtained were as follows. 1) Plasma beta-TG and PF4 levels tended to increase following BPT with HD at the time of immediate asthmatic response (IAR) in patients showing IAR alone. 2) Plasma beta-TG and PF4 levels increased significantly (p less than 0.05) at IAR and tended to increase at the time of late asthmatic response (LAR) in patients showing a dual asthmatic response (DAR). 3) The levels of plasma TXB2 in patients showing IAR alone significantly increased at IAR (p less than 0.05) and gradually decreased and the levels of plasma TXB2 in patients showing a DAR increased in each period of IAR, 3 hr after BPT and LAR, and the peak of TXB2 was observed in 3 hours after BPT. 4) These results suggest that platelets are activated at IAR and there was also a possible activation in platelets at LAR.

Topics: Adult; Allergens; Asthma; beta-Thromboglobulin; Bronchial Provocation Tests; Dust; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Factor 4; Thromboxane B2

We examined the effect of AH 21-132, which has been reported to relax airway smooth muscle and inhibit platelet activating factor (PAF)-induced airway hyperreactivity, on ozone-induced airway hyperresponsiveness (AHR) with airway inflammation in dogs. Airway responsiveness (AR) to methacholine was measured by modified Astograph (7 Hz oscillation method) before and after ozone exposure, and the numbers of neutrophils in the peripheral blood and total cell counts, differential cell counts and TXB2 in BALF were measured before and after ozone exposure. Ozone exposure was carried out for 2 hr at an ozone level of 3.46 +/- 0.10 ppm (mean +/- SE). There was a significant increase in AR to methacholine after ozone exposure (p less than 0.01), and the numbers of neutrophils in the peripheral blood and the total cell and neutrophil counts in BALF increased significantly (p less than 0.05). Pretreatment with AH 21-132 at an oral dose of 20 mg/kg significantly prevented the ozone-induced AHR to methacholine (p less than 0.01), and also inhibited the increase of neutrophil counts in the peripheral blood, and the total cell counts and the neutrophil counts in BALF after ozone exposure. There was no significant change in the levels of TXB2 in BALF before and after ozone exposure. In dogs not exposed to ozone, AR to methacholine and respiratory resistance to methacholine significantly decreased after administration of AH 21-132 at an oral dose of 20 mg/kg (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Airway Resistance; Animals; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Cell Count; Dogs; Female; Leukocyte Count; Naphthyridines; Neutrophils; Ozone; Platelet Aggregation Inhibitors; Thromboxane B2

Alterations in cell numbers, vascular permeability, and concentrations of various inflammatory mediators in the lung were measured in a guinea pig model of the late asthmatic reaction. Animals sensitized by inhalation of ovalbumin were challenged with an aerosol of ovalbumin or saline, and bronchoalveolar lavage fluid (BALF) and peripheral blood were collected after periods ranging from 5 min to 72 h. Increased vascular leakage within the lungs was indicated by elevated BALF/plasma albumin ratios at all time points, and was maximal 6 h after challenge. There were increased numbers of eosinophils in BALF by 6 h after challenge and they remained elevated at least until 72 h. A corresponding increase in the proportion of blood leukocytes represented by eosinophils was observed at 6 and 17 h, which suggests that these cells may be drawn to the lung following their release into the circulation, but by 72 h the proportion in blood had returned to normal. A transitory neutrophilia was evident in BALF and blood 6 h after allergen exposure, but there were no allergen-induced changes in BALF numbers of macrophages, lymphocytes, epithelial cells, or mast cells (as assessed by concentrations of cell-associated histamine). beta-Glucuronidase activity was significantly increased in BALF of guinea pigs at 2 h and 17 h following challenge. The degree to which eicosanoids can be recovered in BALF was investigated by instilling a range of tritiated compounds into the lungs of normal guinea pigs at the time of lavage. Ratio high-performance liquid chromatography revealed that there had been little metabolism of the eicosanoids recovered in BALF. However, there was evidence for a rapid removal of these mediators from the lung, a process which will militate against their accurate quantitation in BALF. Histamine, prostaglandin D2, and thromboxane B2 were detected in BALF but did not differ between treatment groups, and levels showed no simple relationship with the other inflammatory changes measured.

Topics: Albumins; Animals; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Glucuronidase; Guinea Pigs; Histamine; Inflammation; Male; Ovalbumin; Prostaglandin D2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antigens; Asthma; Bronchoconstriction; Guinea Pigs; Imidazoles; In Vitro Techniques; Lung; Ovalbumin; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Inflammatory mediators have been implicated in the pathogenesis of human asthma and have been demonstrated to increase in bronchoalveolar lavage fluid during the time of the immediate asthmatic response (IAR) after allergen instillation in the lungs. However, the relationship of these mediators, measured early to the late asthmatic response (LAR), airway reactivity, and clinical asthma, is unknown. In the present study, we evaluated mediator levels in bronchoalveolar lavage fluid before and 5 minutes after allergen challenge from three subject groups: atopic subjects without asthma (N = 7), atopic subjects with asthma and without LAR [-) LAR) (N = 6), and atopic subjects with asthma and with LAR [+) LAR) (N = 6). Subjects with asthma were differentiated into subjects with and without LARs based on at least a 15% decrease in FEV1 between 3 to 8 hours postallergen inhalation. The mediators, prostaglandin D2 thromboxane B2 leukotriene C4 (LTC4), and histamine, were measured both before and after allergen instillation. Baseline prechallenge levels were similar, except in the case of LTC4. LTC4 was detectable at baseline significantly more frequently in the atopic subjects with asthma with and without LAR when these subjects were compared to the atopic subjects without asthma (nine of 12 detectable versus one of seven detectable). In all groups, significant increases in mediator levels were observed in the groups with asthma postallergen challenge, compared to the atopic subjects without asthma. Atopic subjects with asthma and without LAR had significantly higher levels of all four mediators after challenge than atopic subjects with asthma and with LAR and atopic subjects without asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Allergens; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Forced Expiratory Volume; Histamine; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Methacholine Chloride; Middle Aged; Prostaglandin D2; Skin Tests; SRS-A; Thromboxane B2; Time Factors

We studied the effects of OKY-046 on type I allergic reactions. OKY-046 (100 mg/kg) given orally suppressed antigen-induced bronchoconstriction and TXB2 generation in broncho alveolar lavage fluid in rats passively sensitized with anti-DNP-As monoclonal IgE. At the dose of 30 mg/kg given intraduodenally, it also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti DNP-As serum and actively sensitized with ovalbumin. However, aspirin (30 mg/kg) didn't suppressed them significantly. Azelastine (10 mg/kg) inhibited bronchoconstriction in passively sensitized rats and actively sensitized guinea pigs. In 48 hour homologous PCA reactions of rats and mice, oral administration of OKY-046 (300 mg/kg) and tranilast (100 mg/kg) suppressed the extravasated dye in the skin. OKY-046 decreased histamine release from passively sensitized rat peritoneal exudate cells. There was no effect of OKY-046 on SRS-A and leukotriene release from actively sensitized guinea pig lungs and passively sensitized rats. In conclusion, we think that OKY-046 should be an useful asthmatic drug or anti-allergic drug by oral administration.

Topics: Acrylates; Administration, Oral; Animals; Asthma; Bronchi; Depression, Chemical; Guinea Pigs; Histamine Release; Lung; Male; Methacrylates; Mice; Muscle Contraction; Muscle, Smooth; Passive Cutaneous Anaphylaxis; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2; Thromboxane-A Synthase

Clinical observations indicate that beta-adrenergic drugs may increase bronchial reactivity in asthmatics. To find out possible reasons for this phenomenon the beta-adrenergic receptor function of isolated lymphocytes of asthmatic patients treated with clenbuterol alone or with ketotifen and clenbuterol together were studied. The cAMP levels of lymphocytes stimulated by different doses of isoproterenol were measured by radioimmunoassay and have been compared in the groups of healthies, and asthmatic patients after 3-months running of clenbuterol (Spiropent, Sandoz), as well as in the same asthmatics after one-week running of parallel administration of ketotifen and clenbuterol. There was no difference between the beta-adrenergic receptor function in asthmatic patients treated with clenbuterol alone vs. untreated healthies. Applying ketotifen and clenbuterol together the beta-adrenergic receptor function increased compared to the values obtained after application of clenbuterol alone (intraindividual-control) as well as vs. the group of healthies (control). Data presented support the view that therapeutic doses of selective beta 2-agonists do not lead to damage of the beta-adrenoceptor function. The improvement of receptor function after parallel administration of clenbuterol and ketotifen may be a consequence of the participation of ketotifen in the control of beta-adrenergic receptor system. Thus it seems unlikely that down-regulation of beta-adrenergic receptors is responsible for the beta-agonist induced bronchial hyperreactivity. That's why TXB-2 levels in the plasma of the same asthmatic patients and healthy volunteers were determined by RIA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Asthma; Clenbuterol; Cyclic AMP; Drug Therapy, Combination; Humans; Ketotifen; Lymphocytes; Receptors, Adrenergic, beta; Thromboxane B2

The purpose of this study was to test the hypothesis that mediators and cells associated with bronchoconstriction or inflammation are locally synthesized and/or released in the airways of asthmatic subjects in response to isocapnic hyperpnea (ISH). Seven atopic, mildly asthmatic subjects were studied. Baseline measurements were reported previously and included forced expiratory volumes, flow rates, bronchoalveolar lavage (BAL), and methacholine reactivity. Approximately 1 yr later, spirometry and BAL were repeated, but BAL was performed immediately after ISH challenge. As indices of inflammation, BAL measurements were made of eosinophils, neutrophils, epithelial cells, leukotrienes B4, C4, D4, and E4, prostaglandins D2, E2, and F2 alpha, thromboxane B2, histamine, and total protein. Compared with baseline, ISH was associated with higher BAL concentrations of the following: leukotriene B4 (10 versus 121 pg/ml, p = 0.02), leukotrienes C4/D4/E4 (46 versus 251 pg/ml, p = 0.02), eosinophils (0.8 versus 2.2%, p = 0.04), and epithelial cells (2.1 versus 6.1%, p = 0.05). Trends toward significant increases were seen in BAL concentrations of neutrophils and prostaglandin D2. No statistically significant increases were found in BAL measurements of total protein, histamine, prostaglandins E2 or F2 alpha, thromboxane B2, lymphocytes, or macrophages. The magnitude of the response to ISH, as measured by change in FEV1, did not correlate with BAL levels of cells or mediators. This study indicates that ISH, even in mildly asthmatic subjects, is associated with airway increases in a spectrum of bronchoactive mediators and inflammatory cells, supporting the observations of others that antagonists of a single mediator are unlikely to have major clinical effectiveness in ISH or exercise-induced asthma.

Topics: Adult; Asthma; Bronchoalveolar Lavage Fluid; Carbon Dioxide; Chromatography, High Pressure Liquid; Female; Humans; Leukotrienes; Male; Prostaglandins; Radioimmunoassay; Spirometry; Thromboxane B2

We studied the effect of AA-2414, a TXA2 receptor antagonist, on platelet function in 12 asthmatic patients, 6 males and 6 females, whose mean age was 43.6 years. AA-2414 was orally administered to each patient at 20 mg/day for two weeks and then at 40 mg/day for the following two weeks. Platelet aggregation, plasma concentration of TXB2, and serum concentrations of AA-2414 and its metabolites were measured before and after the administration of each dose. Platelet aggregation induced by U-46619 (an analogue of PGH2), STA2 (a stable analogue of TXA2) and arachidonic acid with the administration of AA-2414 was significantly inhibited. The degree of this inhibition was proportional to the serum level of the drug. Plasma concentration of TXA2 tended to be lowered by administration of AA-2414, but it was not statistically significant. Eight (75.0%) of the 12 patients showed clinical improvement. In the cases where the drug was ineffective, the inhibition of platelet aggregation after administration of AA-2414 was less than in those cases where it was effective. We conclude that AA-2414 might exert its antiplatelet and antiasthmatic effects through antagonism of the TXA2 receptor. Investigation of the response to AA-2414 may be useful in assessing the clinical effect of this compound.

Topics: Administration, Oral; Adolescent; Adult; Aged; Asthma; Benzoquinones; Heptanoic Acids; Humans; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinones; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane B2

In order to determine the mechanism of bronchoconstriction induced by the inhalation of adenosine in asthmatics, we measured, by the astograph method, cyclic nucleotides, leukotrienes and thromboxane B2 before and after the inhalation, and we studied the relationship between serum theophylline concentration and Rrs cont, Dmin and S Grs/Grs cont of the astogram obtained by inhaled adenosine. Plasma TXB2 level was significantly raised (p less than 0.05) after inhalation, but cAMP, cGMP, LTB4 and LTC4 did not change. In the astogram, Dmin was significantly elevated (p less than 0.01) when plasma theophylline concentration was raised to the therapeutic level, but Rrs cont and S Grs/Grs cont showed no remarkable change. We confirmed that inhaled adenosine caused bronchoconstriction in asthmatic patients, and that Dmin was elevated after the administration of theophylline. These results suggest that TXB2, a metabolic product of arachidonic acid, may be one of the most important mediators in the bronchoconstriction mechanism of inhaled adenosine.

Topics: Adenosine; Administration, Inhalation; Adult; Aged; Asthma; Bronchi; Cyclic AMP; Female; Humans; Leukotrienes; Male; Middle Aged; Thromboxane B2

To assess the role of arachidonic acid metabolites in pathogenesis of bronchial asthma, we measured thromboxane B2 (TxB2), 6-keto PGF1 alpha, leukotriene (LT) C4, and LTB4 in venous blood plasma in patients with bronchial asthma and in controls. The level of TxB2 was significantly higher in 18 asthmatics with attacks than that in 11 controls (77.3 +/- 48.8 pg/ml vs 48.8 +/- 9.4 pgml). The levels of 6-keto PGF1 alpha in both asthmatics with attacks (17.8 +/- 6.7 pg/ml) and without an attack (16.4 +/- 9.7) were significantly higher than that in controls (11.6 +/- 3.9 pg/ml). The levels of LTC4 in asthmatics with attacks (0.84 +/- 0.11 ng/ml, n = 11) were significantly higher than that in controls, furthermore the level of LTC4 in asthmatics without an attack. The level of LTB4 was significantly higher in asthmatics with attacks (295.0 +/- 160.7 pg/ml, n = 26) than that in controls (161.7 +/- 25.3 pg/ml, n = 12) and asthmatics without an attack (182.4 +/- 97.9 pg/ml, n = 22). These findings suggest that the arachidonic acid metabolites are related to the asthma attack and are associated with the pathogenesis of bronchial asthma.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Asthma; Female; Humans; Leukotriene B4; Male; Middle Aged; SRS-A; Thromboxane B2

There is a relationship between severity of bacterial bronchial asthma clinical symptoms and plasma 6-keto-PGF1 alpha, TxB2: in moderate disease against grave one as well as in clinical versus subclinical forms (remission) relevant indices are reduced. On the one hand elevated content of blood 6-keto-PGF1 alpha seems compensatory rising in response to TxB2 bronchoconstriction. On the other hand, it impairs microcirculation and enhances mediators of inflammation, promotes exudation and edema of bronchoalveolar mucosa, thus contributing to obstruction.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Asthma; Bronchi; Constriction, Pathologic; Female; Humans; Male; Microcirculation; Middle Aged; Thromboxane B2

We report here an efficient method for simultaneous and quantitative determinations of plasma prostaglandins (PGs) from asthmatic patients using 9-anthryldiazomethane-reversed-phase high performance liquid chromatography (HPLC). Detection and simultaneous quantitation of 20 pg PGE1, PGE2, PGF2 alpha and 100 pg 6-keto PGF1 alpha, thromboxane B2 (TXB2) was possible by the present method. Preliminary studies showed that plasma TXB2 levels from stable asthmatic patients were elevated compared with normal healthy subjects, suggesting pathophysiologic implications regarding PGs and TXB2 in asthma may be elicited by the present HPLC method.

Topics: Anthracenes; Asthma; Chromatography, High Pressure Liquid; Dinoprost; Dinoprostone; Fluorometry; Humans; Microchemistry; Prostaglandins; Radioimmunoassay; Thromboxane B2; Time Factors

Recently identified Ascaris suum sensitive cynomolgus monkeys were further characterized to determine if a chronologic relationship existed between mediator release and onset of bronchoconstriction. In these anesthetized Ascaris-sensitive monkeys, aerosol antigen challenge of each animal produced rapid and severe bronchoconstriction, as determined by decreases in dynamic lung compliance (-80.2 +/- 4.1%) and airway conductance (-64.5 +/- 13.8%). Maximum changes were achieved within 5 min following exposure and remained substantially altered throughout the 30 min observation period. However, changes in pulmonary function related to duration of onset and maximum change seemed to have some correlation with each animals' sensitivity to the antigen. Comparison of pre- and post-challenge blood gas profiles, showed a progressive formation of respiratory acidosis through decreases in arterial blood pH, partial pressure of O2 (pO2), O2 saturation (sO2) and an increase in partial pressure of CO2 (pCO2). When arterial blood plasma was assayed by RIA for mediators of anaphylaxis, large increases in 5-hydroxyeicostetraenoi acid (5-HETE), leukotriene B4 (LTB4) and histamine were observed. No amount of prostaglandin F2-alpha (PGF2 alpha) or thromboxane A2 were detected. Two of the three monkeys also produced detectable amounts of leukotriene C4 (LTC4). Therefore, in Ascaris-sensitive monkeys, histamine is the predominate mediator released and is probably responsible for at least the early part (5-10 min) of the observed bronchoconstriction. However, mediators from the lipoxygenase pathway may also be playing a role in the antigen-induced bronchoconstriction, especially beyond the 10 min period following anaphylaxis.

Topics: Animals; Antigens, Helminth; Ascaris; Asthma; Dinoprost; Histamine; Histamine Release; Hydroxyeicosatetraenoic Acids; Leukotrienes; Macaca fascicularis; Male; Radioimmunoassay; Respiratory Function Tests; Thromboxane B2; Time Factors

The role of substance P in the pathogenesis of asthma is unclear. Animal studies suggest that it may be important, whereas human studies do not confirm this. Alveolar macrophages can be recovered easily by bronchoalveolar lavage (BAL) and stimulated in vitro. To assess the role of substance P in humans, we tested its ability to stimulate alveolar macrophages from six normal subjects and seven asthmatic patients. BAL cells were separated by adherence and alveolar macrophages constituted 95% of the adherent cell population. Four concentrations of substance P were used (10(-7), 10(-6), 10(-5), 10(-4) M). To assess the non-specific activation of alveolar macrophages we used three concentrations of lipopolysaccharides (LPS) (5, 10, 20 micrograms/ml). The stimulation of alveolar macrophages was assessed by the release of thromboxane B2 by radioimmunoassay. This study indicates that alveolar macrophages are stimulated by LPS but are poorly activated or not at all by substance P.

Topics: Adolescent; Adult; Aged; Asthma; Bronchoalveolar Lavage Fluid; Child; Female; Humans; In Vitro Techniques; Macrophage Activation; Macrophages; Male; Middle Aged; Substance P; Thromboxane B2

The purpose of this study was to investigate whether procaterol (beta 2 agonist) inhibits the release of cyclooxygenase products in bronchoalveolar lavage fluid (BALF) during in vivo allergic bronchoconstriction in passively sensitized guinea pigs. Antigen-induced bronchoconstriction was significantly inhibited by pretreatment with procaterol. The concentrations of 6-keto-PGF1 alpha, PGF2 alpha and TXB2 in BALF significantly decreased in guinea pigs pretreated with inhaled procaterol. The concentration of TXB2, which is the stable metabolite of TXA2, a strong bronchoconstrictor, was especially markedly decreased compared with that in the control animals. These data indicate that procaterol (beta 2 agonist) may inhibit the release of chemical mediators during allergic reactions as well as directly decrease the contractility of airway smooth muscle. Consequently, regular inhalation of procaterol may be clinically useful for prophylaxis of bronchial asthma.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Animals; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Ethanolamines; Guinea Pigs; Male; Premedication; Procaterol; Prostaglandins; Thromboxane B2

Plasma levels of arachidonic acid metabolites, such as thromboxane A2 (TXA2), prostacyclin (PGI2) and leukotrienes (LTS) were measured in patients with exercise-induced asthma (EIA). Asthmatic patients were exercised by treadmill. Before, immediately after and at 5, 15 and 30 minutes after exercise, pulmonary function tests were performed and peripheral venous blood was collected at the indicated times. Plasma TXB2 levels rose after exercise, and this tendency was stronger in EIA negative patients than in EIA positive patients. Plasma 6-keto-PGF1 alpha levels rose slightly after exercise in both EIA positive and negative patients. Plasma LTC4 levels were almost unchanged after exercise in EIA positive patients. Plasma LTC4 levels rose after exercise in EIA negative patients, though the value was always higher in EIA positive patients than in EIA negative patients. Plasma LTB4 levels in both EIA positive and negative patients increased slightly till 5 minutes after exercise, then decreased, and then tended to rise again. Plasma LTB4 levels were higher in EIA positive patients than in EIA negative patients at all times. The ratio of TXB2 to 6-keto-PGF1 alpha after exercise rose more remarkably in EIA negative patients than in EIA positive patients. From these results, we suspected that the metabolites of arachidonic acid may contribute less to chemical mediators of EIA, but the arachidonic acid products of EIA positive patients activated rather towards lipoxygenase cascade than EIA negative patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Arachidonic Acids; Asthma; Asthma, Exercise-Induced; Female; Humans; Leukotrienes; Male; Thromboxane B2

Wy-45,911 (4-[hydroxy-[3-(2-quinolinylmethoxy)phenyl] amino]-4-oxabutanoic acid, methyl ester) was found to inhibit competitively leukotriene D4 (LTD4)-induced contractions of the isolated guinea pig trachea but not those of leukotriene C4 (LTC4), even in the presence of a gamma-glutamyltranspeptidase inhibitor, reduced glutathione (GSH). Tracheal contractions induced by histamine or pilocarpine were also not significantly altered by Wy-45,911. The drug inhibited the tracheal contractions induced by antigen, even in the presence of GSH. This latter effect resulted from inhibition of 5-lipoxygenase (5-LO), as the synthesis of 5-LO products by rat polymorphonuclear leukocytes and by mouse macrophages was markedly reduced by Wy-45,911. The drug inhibited both LTD4-induced and antigen-induced bronchoconstriction when injected intraduodenally or intragastrically into intact guinea pigs though it was more potent against LTD4-induced bronchoconstriction. We conclude that Wy-45,911 is a novel, orally active LTD4 antagonist in the guinea pig, with some 5-LO inhibitory activity.

Topics: Animals; Antigens; Arachidonic Acid; Arachidonic Acids; Asthma; Cyclooxygenase Inhibitors; Guinea Pigs; Lipoxygenase Inhibitors; Macrophages; Male; Muscle Contraction; Peritoneal Cavity; Quinolines; Receptors, Leukotriene; Receptors, Prostaglandin; SRS-A; Thromboxane B2; Trachea

1. The chemically novel acetohydroxamic acids, BW A4C, BW A137C and BW A797C, are potent inhibitors of the synthesis of leukotriene B4 (LTB4) from arachidonic acid by human leucocyte homogenates: the concentrations required for 50% inhibition (IC50) were 0.1 microM, 0.8 microM and 0.5 microM respectively. Inhibition was less at higher concentrations of arachidonic acid. 2. These compounds also inhibited the synthesis of [14C]-5-HETE from [14C]-arachidonic acid and the calcium-dependent synthesis of LTB4 from 5-HPETE. This, therefore, suggests that they inhibit 5-lipoxygenase and LTA4 synthase. 3. Concentrations of acetohydroxamic acids required to inhibit metabolism of arachidonic acid by cyclo-oxygenase, 12-lipoxygenase and 15-lipoxygenase were 10 to 100 times higher than those required to inhibit 5-lipoxygenase. 4. The compounds were potent inhibitors of LTB4 synthesis induced by the ionophore, A23187, in human intact leucocytes. This inhibition was reversed by washing the cells. They were also potent, selective inhibitors of LTB4 synthesis induced by A23187 in whole rat blood: binding to rat plasma proteins did not greatly reduce the effectiveness of the compounds. 5. The effects of the acetohydroxamic acids, administered either intravenously or orally to rats, on the synthesis of LTB4, and thromboxane B2 (TXB2) in A23187-stimulated blood ex vivo was studied. The three compounds caused dose-dependent inhibition of the synthesis of LTB4 but not TXB2. Inhibition of LTB4 synthesis persisted for up to 6 h after a single oral dose of 50 mg kg-1. 6. The plasma concentrations of unchanged compound determined by h.p.l.c. correlated with the inhibition of LTB4 synthesis ex vivo.

Topics: Animals; Arachidonate 5-Lipoxygenase; Arachidonate Lipoxygenases; Asthma; Blood Platelets; Carrier Proteins; Chromatography, High Pressure Liquid; Humans; Hydroxamic Acids; In Vitro Techniques; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Rats; Thromboxane B2

In order to test the hypothesis that alveolar macrophages (AM) from asthmatics might manifest abnormalities in the amounts, spectrum, or glucocorticoid regulation of eicosanoid synthesis, we compared arachidonic acid (AA) metabolism under resting and ionophore A23187-stimulated conditions in cultured AM obtained by bronchoalveolar lavage from 10 asthmatic, nine atopic, and 10 nonatopic normal subjects. [14C]AA-prelabeled AM constitutively released free [14C]AA and release increased significantly with A23187 incubation. Under resting conditions, unlabeled cells produced small amounts of immunoreactive thromboxane B2 (TxB2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4). With A23187 stimulation there were significant increases in the synthesis of all immunoreactive metabolites, which were produced in the following relative amounts: LTB4 much greater than TxB2 greater than PGD2 greater than leukotriene C4 greater than PGE2. High performance liquid chromatographic separation of radiolabeled eicosanoids produced by prelabeled cells confirmed the radioimmunoassay results and further indicated the production of relatively large amounts of 5-hydroxyeicosatetraenoic acid and 12-hydroxyheptadecatrienoic acid. Pretreatment (16 h) with 1 microM methylprednisolone inhibited A23187-induced synthesis of immunoreactive cyclooxygenase products to a greater extent than immunoreactive leukotrienes. We identified no significant differences among the three study groups in the quantities or profiles of eicosanoids synthesized either constitutively or with A23187 stimulation, nor in their regulation by methylprednisolone.

Topics: Adolescent; Adult; Arachidonic Acid; Arachidonic Acids; Asthma; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cells, Cultured; Chromatography, High Pressure Liquid; Humans; Hypersensitivity; Leukotrienes; Macrophages; Methylprednisolone; Prostaglandins; Pulmonary Alveoli; Reference Values; Thromboxane B2

The aim of this study was to investigate circadian variation in concentrations of arachidonic acid (AA) metabolites in relation to the circadian pattern in bronchial patency. Blood samples were obtained at 4-hr intervals from 2000 of 1 day until 1400 of the next from 12 diurnally active asthmatic and six diurnally active non-asthmatic patients. Bloods were analyzed for the prostanoids thromboxane A2 (measured as stable metabolite 6-keto-PGF1a), PGE2 and PGF2a. Airways patency was assessed by self-measurement of peak expiratory flow (PEF). In asthmatics, circadian variation was detected in PEF as well as PGE2 and TXB2. The circadian trough of the PEF rhythm closely coincided with the circadian peak of the PGE2 and TXB2 rhythms. In the controls, the PEF was not circadian rhythmic. Of the AA metabolites only 6-keto-PGF1a exhibited 24-hr bioperiodicity in the controls. The controls exhibited a significantly higher circadian mean of PEF (P less than 0.001), while the asthmatics had a lower 24-hr average PGE2 but greater mean TXB2/PGE2 ratio. The obstructive effect caused by the overall 24-hr deficiency of PGE2 in asthmatics is possibly amplified by the increased of TXB2 during the early morning hours. This dissociation of the temporal patterns in TXB2 and PGE2 levels over the 24 hr is discussed as a characteristic finding for asthmatics.

Topics: Adult; Arachidonic Acids; Asthma; Circadian Rhythm; Dinoprost; Dinoprostone; Female; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Prostaglandins F; Reference Values; Thromboxane B2

The effect of a fish oil enriched diet containing about 3 g of eicosapentaenoic acid was studied in 10 patients with aspirin intolerant asthma. Subjects were studied during six weeks on a control diet followed by six weeks on the fish oil diet in a single blind study design. They were asked to record their peak expiratory flow (PEF) twice daily, bronchodilator and steroid doses, and subjective ratings of pulmonary symptoms on diary cards. There were no significant changes in symptom scores over the six weeks of either the control diet or the fish oil diet. PEF values, however, were significantly lower during the fifth and sixth week of the fish oil diet than during the control diet (308 v 262 l/min week 5 and 306 v 256 l/min week 6). Bronchodilator usage was also greater during the fifth and sixth week of the fish oil diet than during the control period (12.0 v 7.4 and 13.0 v 7.4 puffs a day in weeks 5 and 6). This pilot study suggests that fish diets may have a deleterious effect on patients with aspirin intolerant asthma.

Topics: Adult; Aged; Albuterol; Aspirin; Asthma; Dietary Fats, Unsaturated; Docosahexaenoic Acids; Drug Combinations; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Unsaturated; Female; Fish Oils; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Thromboxane B2

Methods for the profiling of prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), 15(S),9 alpha,11 beta-trihydroxyprosta-5Z,13E-dien-1-oic acid (9 alpha,11 beta-PGF2), 6-keto-prostaglandin F1 alpha (6kPGF1 alpha), and thromboxane B2 (TxB2) in bronchoalveolar lavage (BAL) fluids from human subjects by combined capillary gas chromatography-mass spectrometry are described. Aliquots (5 ml) of BAL fluid obtained using a standardized lavage protocol were extracted on octadecylsilyl silica cartridges after addition of 0.8 to 2.0 nanograms of tetradeuterated analogs of PGE2, PGF2 alpha, and 6kPGF1 alpha as internal standards. Eluted analytes and internal standards were prepared for vapor phase analysis by sequential reactions resulting in the formation of methyloxime-pentafluorobenzyl ester-trimethylsilyl ether derivatives. The derivatized analytes were detected by simultaneous monitoring of ions at six different masses characteristic for each of the derivatized prostanoids. The samples were of adequate purity for identification and quantitation of each of the prostanoids with detection limits of 0.1 to 0.2 picograms of each analyte per milliliter of BAL fluid. The time required for analysis of each sample was approximately 30 minutes. Standard curves of unlabeled species of the six prostanoids extracted after addition to BAL fluid were linear over a range from subpicogram to nanogram quantities. The differences between the amounts of prostanoid added and the amounts of prostanoid measured were typically less than 19%, and the intra-assay coefficients of variation for repeated measurements of a single sample were less than 20%. PGE2, PGD2, PGF2 alpha, and TxB2 were detectable in BAL fluids from normal subjects with levels of each of these compounds being less than 2.6 picograms/ml. BAL fluids from patients with lung disease presented qualitative and quantitative profiles of prostanoids markedly different than those from normal subjects. These analytical methods provide a basis for in vivo comparisons of prostanoid profiles in the lower respiratory tract of man and should be readily adaptable for use in a variety of clinical studies.

Topics: Alveolitis, Extrinsic Allergic; Asthma; Body Fluids; Gas Chromatography-Mass Spectrometry; Humans; Prostaglandins; Pulmonary Alveoli; Reference Values; Thromboxane B2

Lyophilized onion extract and ether extracts of onions were separated by chromatographic methods into several subfractions and tested for their effects on asthmatic reactions of guinea pigs to allergen, histamine, acetylcholine and platelet-activating factor (PAF) inhalation as well as on thromboxane biosynthesis of human platelets and lung fibroblasts. Onion oils are counteracting the bronchial obstruction due to PAF inhalation.

Topics: Allium; Animals; Asthma; Blood Platelets; Bronchial Provocation Tests; Cells, Cultured; Fibroblasts; Guinea Pigs; Humans; Plant Oils; Platelet Activating Factor; Thromboxane B2

Amoxanox has potent antiallergic activity because it inhibits the release of chemical mediators such as histamine and leukotrienes. We studied the in vitro effect of amoxanox on arachidonic acid metabolism, including the lipoxygenase and cyclooxygenase pathways. Amoxanox inhibited calcium ionophore A23187-induced formation of 5-HETE, LTB4, SRS-A (LTC4, LTD4 and LTE4), and 12-HETE in rat peritoneal resident monocytes. These results indicate that amoxanox inhibits 5- and 12-lipoxygenases. The compound, however, did not affect the formation of TXB2 or 6-keto-PGF1 alpha in guinea pig lung fragments and PGE2 or PGF2 alpha in bovine seminal vesicles, suggesting that it did not inhibit cyclooxygenase. These results show that the antiallergic action of amoxanox is associated, at least in part, with the reduction of leukotrienes due to the inhibition of lipoxygenases.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 5,8,11,14-Eicosatetraynoic Acid; Aminopyridines; Animals; Asthma; Calcimycin; Cattle; Guinea Pigs; Histamine H1 Antagonists; Hydroxyeicosatetraenoic Acids; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Male; Monocytes; Prostaglandins; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Human alveolar macrophages were obtained during diagnostic bronchoalveolar lavage. Cells were cultured, and morphological examination (including electron microscopy) revealed that not more than 5% of the cultured cells were identifiable as cells other than alveolar macrophages. The cells were sensitized with human myeloma immunoglobulin E. and then challenged with anti-immunoglobulin E anti-sera. The experiments employed a highly specific monoclonal antibody and three affinity purified reagents. The formation of immunoglobulin E/anti-immunoglobulin E complexes facilitated release from alveolar macrophages of leukotriene B4, prostaglandin F2 alpha, thromboxane B2 and the lysosomal hydrolase N-acetyl-beta-D-glucosaminidase. There was no release of active oxygen species, with this stimulus, as measured by lucigenin chemiluminescence. Immunoglobulin E receptors were identified histochemically on the surface of human alveolar macrophages, and were visualized as conjugates with colloidal gold by electron microscopy. These results support the view that human alveolar macrophages may contribute to type 1 hypersensitivity reactions in the lung.

Topics: Asthma; Humans; Macrophage Activation; Macrophages; Oxygen; Pulmonary Alveoli; Receptors, Fc; Receptors, IgE; Receptors, Immunologic; Thromboxane B2

Arachidonic acid metabolites may play a role in the pathophysiology of bronchial asthma, influencing bronchial tone, airways inflammation and bronchial hyperreactivity. This study was designed to investigate the effect of nedocromil sodium, at a range of concentrations, on the metabolism of arachidonic acid released from alveolar macrophages (AMs) obtained by bronchoalveolar lavage in healthy and asthmatic subjects. The only effect of nedocromil sodium observed in this study was a slight decrease in LTD4 synthesis by AMs from asthmatic patients. This possible effect of nedocromil sodium on LTD4 metabolism deserves further investigation.

Topics: Asthma; Calcimycin; Chromatography, Thin Layer; Humans; Leukotriene B4; Nedocromil; Pulmonary Alveoli; Quinolines; SRS-A; Thromboxane B2

In a case control study 31 asymptomatic patients with asthma and/or hay fever and 31 normal controls had their bleeding time measured using the Simplate II device and venostasis. Mean bleeding time in the atopic group (527 s) was significantly prolonged compared to the controls (393 s) (p less than 0.0005). Platelet aggregation to collagen and ADP (but not to PAF-acether) was significantly depressed in the atopics. Mean circulating platelet mass was significantly greater in atopics than in the controls (p = 0.006). Stepwise multiple regression analysis showed that within the control group bleeding time was best predicted by platelet mass (p = 0.007). No such relationship was found in the atopics. However stepwise multiple regression analysis showed that bleeding time in the atopics (but not in the controls) was best predicted by PAF-acether induced platelet aggregability (p less than 0.05). In neither group was bleeding time related to collagen induced platelet thromboxane B2 production. It is hypothesised that in respiratory atopy the depressed aggregatory function of platelets is not compensated for sufficiently by an increase in platelet mass, leading to prolongation of the bleeding time. This haemostatic imbalance, whose cause remains to be established, appears to constitute a trait of atopy.

Topics: Adenosine Diphosphate; Adult; Asthma; Bleeding Time; Collagen; Female; Humans; Male; Platelet Activating Factor; Platelet Aggregation; Platelet Count; Platelet Function Tests; Rhinitis, Allergic, Seasonal; Thromboxane B2

Topics: Adenosine Triphosphate; Asthma; beta-Thromboglobulin; Blood Platelets; Collagen; Dust; Histamine; Humans; Platelet Aggregation; Thromboxane B2

Topics: Adolescent; Adult; Asthma; Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Female; Humans; Male; Prostaglandins; Thromboxane B2; Thromboxanes

Topics: Adolescent; Age Factors; Asthma; Asthma, Exercise-Induced; Blood Platelets; Child; Cyclic AMP; Exercise Test; Female; Histamine; Humans; Leukocytes; Lipoxygenase; Male; Thromboxane B2

Skin blister fluid (SBF) samples obtained after allergen skin testing in a total of 26 patients with late cutaneous reactions (LCRs) were examined for the presence of various vasoactive mediators. Histamine was predominant during the early phase of the wheal and flare reaction(206 +/- 40 ng/ml) and decreased with the development of the LCR toward normal SBF levels (around 20 ng/ml). Kallikrein activity was measurable in low amounts (around 5 ng/ml) in three out of 13 SBF samples taken 30 min after skin testing and in five of 13 SBF samples taken 6 hr after allergen testing. The thromboxane B2 content of SBF showed an increase with the development of LCR (control skin 976 +/- 483 ng/ml; allergen-tested skin 30 min after allergen injection, 1465 +/- 1566 ng/ml; allergen-tested skin 6 hr after antigen injection, 1775 +/- 731 ng/ml). SBF obtained from normal skin as well as from allergen-tested skin showed significant platelet-activating property as measured in an in vitro serotonin-release assay from washed human platelets. It is concluded that during the development of late-phase reactions a complex interaction of various mediator systems takes place.

Topics: Adolescent; Adult; Allergens; Animals; Asthma; Blister; Child; Female; Histamine Release; Humans; Hypersensitivity, Immediate; Intradermal Tests; Kallikreins; Male; Rats; Rhinitis, Allergic, Seasonal; Serotonin; Skin; Skin Tests; Thromboxane B2

Topics: Adolescent; Adult; Asthma; Dinoprost; Dinoprostone; Humans; Macrophage Activation; Macrophages; Middle Aged; Prostaglandins E; Prostaglandins F; Thromboxane B2

Topics: Asthma; Dinoprost; Humans; Lung; Physical Exertion; Prostaglandins F; Radioimmunoassay; Respiration; Thromboxane B2; Thromboxanes

Topics: Asthma; Epinephrine; Humans; Prostaglandins; Prostaglandins E; Prostaglandins F; Radioimmunoassay; Thromboxane B2