PubMed Health⌕ Search

Biomedical subjects

S E Dahlén

Publications and source records attributed to S E Dahlén.

At least 19 recordsLinked to original sources
PubMed2001

Pulmonary gas exchange and sputum cellular responses to inhaled leukotriene D(4) in asthma.

Inhalational challenges with inflammatory mediators may provoke lung function disturbances similar to those shown in spontaneous acute asthma. Cysteinyl leukotrienes (CysLTs) have recently been established as mediators of bronchoconstriction in asthma but their effects on pulmonary gas exchange in asthma have not been assessed. We therefore investigated the effects of leukotriene D(4) (LTD(4)) challenge resulting in a significant decrease in FEV(1) (mean +/- SE, by 32 +/- 3%) in 13 nonsmoking, mild asthmatics. Respiratory system resistance (Rrs), and respiratory and inert gases were measured before and immediately after, and at 15 and 45 min after challenge. After bronchoprovocation, Rrs increased (by 106 +/- 12%), Pa(O(2)) decreased (by 25 +/- 4 mm Hg), and ventilation-perfusion distributions moderately to severely deteriorated, as shown by increases in the dispersions of pulmonary blood flow (Log SDQ, by 59 +/- 12%) and alveolar ventilation (Log SDV, by 65 +/- 20%) (p < 0.05 each). Sputum eosinophils (p < 0.05) and urinary LTE(4) (p < 0.005) increased after challenge. Despite the lack of mathematical correlations between spirometric and Rrs changes and gas exchange indices, the pattern of improvement of the functional variables after challenge ran in parallel. These findings support the evidence that CysLTs, in addition to being potent bronchoconstrictors, also provoke profound disturbances of pulmonary gas exchange in asthma.

Administration, Inhalation↗
PubMed2001

An alternative pathway for metabolism of leukotriene D(4): effects on contractions to cysteinyl-leukotrienes in the guinea-pig trachea.

Contractions of guinea-pig tracheal preparations to cysteinyl-leukotrienes (LTC(4), LTD(4) and LTE(4)) were characterized in organ baths, and cysteinyl-leukotriene metabolism was studied using radiolabelled agonists and RP-HPLC separation. In the presence of S-hexyl GSH (100 microM) the metabolism of [(3)H]-LTC(4) into [(3)H]-LTD(4) was inhibited and the LTC(4)-induced contractions were resistant to CysLT(1) receptor antagonism but inhibited by the dual CysLT(1)/CysLT(2) receptor antagonist BAY u9773 (0.3 - 3 microM) with a pA(2)-value of 6.8+/-0.2. In the presence of L-cysteine (5 mM), the metabolism of [(3)H]-LTD(4) into [(3)H]-LTE(4) was inhibited and the LTD(4)-induced contractions were inhibited by the CysLT(1) receptor antagonist ICI 198,615 (1 - 10 nM) with a pA(2)-value of 9.3+/-0.2. However, at higher concentrations of ICI 198,615 (30 - 300 nM) a residual contraction to LTD(4) was unmasked, and this response was inhibited by BAY u9773 (1 - 3 microM). In the presence of the combination of S-hexyl GSH with L-cysteine, the LTD(4)-induced contractions displayed the characteristics of the LTC(4) contractile responses, i.e. resistant to CysLT(1) receptor antagonism, increased maximal contractions and slower time-course. This qualitative change of the LTD(4)-induced contraction was also observed in the presence of S-decyl GSH (100 microM), GSH (10 mM) and GSSG (10 mM). S-hexyl GSH, S-decyl GSH, GSH and GSSG all stimulated a formation of [(3)H]-LTC(4) from [(3)H]-LTD(4). In conclusion, GSH and GSH-related compounds changed the pharmacology of the LTD(4)-induced contractions by stimulating the conversion of LTD(4) into LTC(4). Moreover, the results indicate that, in addition to the metabolism of LTC(4) into LTD(4) and LTE(4), also the formation of LTC(4) from LTD(4) may regulate cysteinyl-leukotriene function.

Animals↗
PubMed2001

Benefits of high altitude allergen avoidance in atopic adolescents with moderate to severe asthma, over and above treatment with high dose inhaled steroids.

Some patients with severe asthma cannot be controlled with high doses of inhaled steroids (ICS), which may be related to ongoing environmental allergen exposure. We investigated whether 10 weeks of high altitude allergen avoidance leads to sustained benefits regarding clinical and inflammatory markers of disease control in adolescents with persistent asthma despite treatment with high dose ICS. Eighteen atopic asthmatic adolescents (12-18 yr, 500-2000 microg ICS daily) with established house dust mite allergy, participated in a parallel-group study. Quality of life (PAQL), lung function, bronchial hyperresponsiveness (BHR) to adenosine and histamine, induced sputum and urine samples were collected repeatedly from 10 patients during a 10-week admission period to the Swiss Alps (alt. 1560 m) and at 6 weeks after return to sea level. Results were compared with those in eight patients, studied in their home environment at sea level for a similar time period. Throughout the study, asthma medication remained unchanged in both groups. During admission to high altitude, PAQL, lung function, BHR to adenosine and histamine, and urinary levels of eosinophil protein X (U-EPX), leukotriene E4 (U-LTE4) and 9alpha11beta prostaglandin F2 (U-9alpha11beta PGF2) improved significantly (P < 0.05), with a similar tendency for sputum eosinophils (P < 0.07). Furthermore, the changes in PAQL and BHR to adenosine and histamine were greater in the altitude than in the control group (P < 0.05). At 6 weeks after renewed allergen exposure at sea level, the improvements in PAQL (P < 0.05), BHR to adenosine (P < 0.07) and histamine (P < 0.05), as well as U-EPX (P < 0.05) and U-LTE4 (P < 0.05) were maintained. A short period of high altitude allergen avoidance, on top of regular treatment with ICS and long-acting beta2-agonists, results in improvement of asthma, as assessed by clinical and inflammatory markers of disease severity. These findings indicate that short-term, rigorous allergen avoidance can improve the long-term control of severe asthma over and above what can be achieved even by high doses of inhaled steroids.

Administration, Inhalation↗
PubMed2001

Health effects of diesel exhaust emissions.

Epidemiological studies have demonstrated an association between different levels of air pollution and various health outcomes including mortality, exacerbation of asthma, chronic bronchitis, respiratory tract infections, ischaemic heart disease and stroke. Of the motor vehicle generated air pollutants, diesel exhaust particles account for a highly significant percentage of the particles emitted in many towns and cities. This review is therefore focused on the health effects of diesel exhaust, and especially the particular matter components. Acute effects of diesel exhaust exposure include irritation of the nose and eyes, lung function changes, respiratory changes, headache, fatigue and nausea. Chronic exposures are associated with cough, sputum production and lung function decrements. In addition to symptoms, exposure studies in healthy humans have documented a number of profound inflammatory changes in the airways, notably, before changes in pulmonary function can be detected. It is likely that such effects may be even more detrimental in asthmatics and other subjects with compromised pulmonary function. There are also observations supporting the hypothesis that diesel exhaust is one important factor contributing to the allergy pandemic. For example, in many experimental systems, diesel exhaust particles can be shown to act as adjuvants to allergen and hence increase the sensitization response. Much of the research on adverse effects of diesel exhaust, both in vivo and in vitro, has however been conducted in animals. Questions remain concerning the relevance of exposure levels and whether findings in such models can be extrapolated into humans. It is therefore imperative to further assess acute and chronic effects of diesel exhaust in mechanistic studies with careful consideration of exposure levels. Whenever possible and ethically justified, studies should be carried out in humans.

Animals↗
PubMed1999

Leukotriene C4 is a tight-binding inhibitor of microsomal glutathione transferase-1. Effects of leukotriene pathway modifiers.

Microsomal glutathione transferase-1 (MGST-1) is an abundant protein that catalyzes the conjugation of electrophilic compounds with glutathione, as well as the reduction of lipid hydroperoxides. Here we report that leukotriene C4 is a potent inhibitor of MGST-1. Leukotriene C4 was found to be a tight-binding inhibitor, with a Ki of 5.4 nM for the unactivated enzyme, and 9.2 nM for the N-ethylmaleimide activated enzyme. This is the first tight-binding inhibitor characterized for this enzyme. Leukotriene C4 was competitive with respect to glutathione and non-competitive toward the second substrate, CDNB. Analysis of stoichiometry supports binding of one molecule of inhibitor per homotrimer. Leukotrienes A4, D4, and E4 were much weaker inhibitors of the purified enzyme (by at least 3 orders of magnitude). Leukotriene C4 analogues, which have been developed as antagonists of leukotriene receptors, were found to display varying degrees of inhibition of MGST-1. In particular, the cysteinyl-leukotriene analogues SKF 104,353, ONO-1078, and BAYu9773 were strong inhibitors (IC50 values: 0.13, 3. 7, and 7.6 microM, respectively). In view of the partial structural similarity between MGST-1, leukotriene C4 synthase, and 5-lipoxygenase activating protein (FLAP), it was of interest that leukotriene C4 synthesis inhibitors (which antagonize FLAP) also displayed significant inhibition (e.g. IC50 for BAYx1005 was 58 microM). In contrast, selective 5-lipoxygenase inhibitors such as zileuton only marginally inhibited activity at high concentrations (500 microM). Our discovery that leukotriene C4 and drugs developed based on its structure are potent inhibitors of MGST-1 raises the possibility that MGST-1 influences the cellular processing of leukotrienes. These findings may also have implications for the effects and side-effects of drugs developed to manipulate leukotrienes.

Animals↗
PubMed1999

Analyses of prostaglandin D2 metabolites in urine: comparison between enzyme immunoassay and negative ion chemical ionisation gas chromatography-mass spectrometry.

Measurements of the prostaglandin (PGD2) metabolite 9 alpha, 11 beta-PGF2 in unextracted urine performed by enzyme immunoassay (EIA) were compared with values obtained by negative chemical ionisation gas chromatography-mass spectrometry (NCI GC-MS). Values determined by NCI GC-MS were in the same range but consistently lower than those obtained by EIA, suggesting that other endogenous compounds could be contributing to the immunoreactivity. Isoprostanes were generated by autoxidation of arachidonic acid and the 9 alpha, 11 beta-PGF2 antibody demonstrated less than 0.7% crossreactivity to the mix, making it unlikely that isoprostanes in urine interfere with quantification of 9 alpha, 11 beta-PGF2 by EIA. This was further supported by the 70% reduction in immunoreactive material measured in urine after three days treatment in a healthy volunteer with the cyclooxygenase inhibitor ibuprofen. Purification of urine samples by reverse phase high-performance liquid chromatography (HPLC) revealed the presence of two immunoreactive compounds in addition to 9 alpha, 11 beta-PGF2. The compounds were identified as dinor compounds by NCI GC-MS. One of the compounds was identical to 9 alpha, 11 beta-2,3-dinor-PGF2 which was generated by beta-oxidation of 9 alpha, 11 beta-PGF2 and identified by electron impact (EI)-GC-MS. In conclusion, urinary 9 alpha, 11 beta-PGF2 concentrations measured by EIA represent the sum of 9 alpha, 11 beta-PGF2 and two isomers of its dinor metabolite. Thus, the direct EIA is fast, sensitive and sufficiently specific to monitor activation of the PGD2 pathway, thereby providing a valuable clinical tool to assess the status of mast cell activation in vivo.

Adult↗
PubMed1999

Markers of inflammation and bronchial reactivity in children with asthma, exposed to animal dander in school dust.

Several studies have confirmed the presence of animal dander allergens in school dust but the effect of this indirect animal exposure on health has not been evaluated. In this study we investigated bronchial reactivity and markers of eosinophil activity and inflammation during two separate weeks of school in 10 children with mild asthma and a positive skin prick test to cat and dog. At the beginning and the end of the first week the children underwent bronchial challenges with methacholine, and at the beginning and the end of the second week they underwent nasal lavages (NAL) and induced sputum samplings. Blood and urine samples for analysis of inflammatory markers were obtained before and after both school weeks. Peak expiratory flow (PEF) and symptoms of asthma and allergy were recorded daily, and spirometry was performed on each visit. The exposure to animal dander allergens was estimated from dust samples obtained in the subjects' schools and homes. Bronchial sensitivity to methacholine increased in the week when this was measured. The proportion of eosinophils in peripheral blood, and urinary eosinophil protein X (EPX), decreased in both weeks. There was a trend towards an increase of eosinophil peroxidase (EPO) and myeloperoxidase (MPO) in sputum in the week when these proteins were measured. The concentrations of cat (Fel d1) and dog (Can f1) allergens were higher in dust collected in schools than in homes. Our results show that in children with mild asthma and animal dander allergy, there is a significantly increased bronchial sensitivity to methacholine after one school week. There is also a significant decrease in the number of circulating eosinophils and a trend towards an increase of sputum EPO, which could correlate with the early phase of eosinophil recruitment to the lungs. These effects may be related to the continuous exposure to animal allergens in school dust.

Adolescent↗
PubMed1999

Asthma and leukotrienes: antileukotrienes as novel anti-asthmatic drugs.

Antileukotriene drugs inhibit the formation or action of leukotrienes, which are potent lipid mediators generated from arachidonic acid in lung tissue and inflammatory cells. The leukotrienes were discovered in basic studies of arachidonic acid metabolism in leucocytes 20 years ago and were found to display a number of biological activities which may contribute to airway obstruction. Clinical studies with antileukotriene drugs have indeed demonstrated that leukotrienes are significant mediators of airway obstruction evoked by many common trigger factors in asthma. Moreover, treatment trials have established that this new class of drugs has beneficial anti-asthmatic properties, and several antileukotrienes have recently been introduced as new therapy of asthma. This communication presents an overview of the biosynthesis of leukotrienes, their biological effects and clinical effects of antileukotrienes in the treatment of asthama.

Anti-Asthmatic Agents↗
PubMed1998

Agonist and antagonist activities of the leukotriene analogue BAY u9773 in guinea pig lung parenchyma.

BAY u9773(6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E),11( Z),14(Z)-eicosatetraenoic acid) is a leukotriene E4 analogue used to define 'atypical' receptors for cysteinyl-leukotrienes. The aims of this study were first to characterise the intrinsic properties of BAY u9773 in guinea-pig lung parenchyma in vitro and second to study the influence of BAY u9773 on the concentration-response relation for leukotriene D4 in the same preparation. BAY u9773 in itself caused a concentration-dependent contraction, which was not inhibited by the cyclooxygenase inhibitor indomethacin nor by the 5-lipoxygenase inhibitor zileuton (N-(1-benzo-(12)-thien-2-ylethyl)-N-hydroxyurea). The CysLT1 receptor antagonist ICI 198,615 [(1-((2-methoxy-4-(((phenylsulfonyl)amino) carbonyl)phenyl)methyl)-1H-indazol-6-yl)carbamic acid cyclopentyl ester] alone blocked the contractile response to BAY u9773 1 microM, whereas a combination of the TP receptor antagonist BAY u3405 ((3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbaz olepropanoic acid) and ICI 198,615 was required to block the contraction induced by BAY u9773 10 microM. Together the findings suggest that BAY u9773 acted as a CysLT1 receptor agonist and in the higher concentration also as a TP receptor agonist. The CysLT1 receptor antagonist ICI 198,615 partly inhibited the contractile response to leukotriene D4. Pretreatment with BAY u9773 or leukotriene D4, caused concentration-dependent rightward displacement of the concentration-response curve for leukotriene D4. The inhibition by BAY u9773 was partial, and not greater than that produced by ICI 198,615. Combination of BAY u9773 and ICI 198,615 did not produce additive inhibition, suggesting that the major part of the leukotriene D4 induced contraction in guinea pig lung parenchyma is mediated by a CysLT receptor with properties distinct from those of previously described CysLT1 and CysLT2 receptors.

Animals↗
PubMed1998

Lipid mediator pathways in the lung: leukotrienes as a new target for the treatment of asthma.

This article summarizes recent evidence supporting that antileukotriene drugs represent a new treatment of asthma which may be particularly effective when combined with drugs that have complementary effects on airway obstruction and inflammation. Firstly, it has been documented that glucocorticosteroids do not inhibit in vivo production of leukotrienes in asthmatics. In line with such findings, addition of antileukotriene drugs to a group of aspirin-intolerant asthmatics maintained on conventional therapy was found to result in an improvement of the asthma over and above the effect of the baseline treatment with inhaled and/or oral glucocorticosteroids. Likewise, in a 6-week trial in a group of severe asthmatics, the asthma deterioration caused by a reduction of the dose of inhaled steroids by half, was prevented by addition of a leukotriene antagonist to the lowered dose of glucocorticosteroids. Current evidence therefore supports that antileukotriene drugs treat components of the pathophysiology which are left unaffected by treatment with glucocorticosteroid. Secondly, in experimental studies as well as in a recent allergen bronchoprovocation study in asthmatics, it has been found that the combination of antihistaminics with antileukotriene drugs will result in a profound inhibition of both the early and the late phase of allergen-induced airway obstruction. It is hypothesized that such a combination may be useful against bronchoconstriction induced by other asthma trigger factors as well as in the treatment of asthma and rhinitits.

Anti-Asthmatic Agents↗
PubMed1998

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

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

Adrenergic beta-Agonists↗
PubMed1998

Evidence for mast cell activation during exercise-induced bronchoconstriction.

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

Adult↗