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Relation Between Bronchial Responsiveness to Inhaled 902 ASTHMA Thorax: first published as 10.1136/thx.2005.041913 on 29 July 2005. Downloaded from Relation between bronchial responsiveness to inhaled leukotriene D4 and markers of leukotriene biosynthesis P Gyllfors, M Kumlin, S-E Dahle´n, F Gaber, P-O Ehrs, B Dahle´n ............................................................................................................................... Thorax 2005;60:902–908. doi: 10.1136/thx.2005.041913 Background: While clinical trials with antileukotrienes have shown overall beneficial effects in asthma, the factors that determine leukotriene dependent asthma are still unclear. A study was undertaken to determine See end of article for whether or not leukotriene responsiveness in the airways correlates with endogenous leukotriene authors’ affiliations ....................... biosynthesis. Methods: Bronchial responsiveness to leukotriene (LT) D4 was assessed as PD20FEV1 in 20 subjects with Correspondence to: mild asthma and 10 healthy controls, and compared with bronchial responsiveness to methacholine and Dr B Dahle´n, Division of two global measures of leukotriene production—urinary LTE and ex vivo production of LTB in whole Respiratory Medicine, 4 4 Department of Medicine, blood. Karolinska University Results: In patients with asthma the bronchoconstrictor activity of LTD4 was about 1300 times greater than Hospital Huddinge, methacholine (geometric mean PD20 0.69 nmol v 887 nmol). Those who were most responsive to LTD4 SE-141 46 Stockholm, Sweden; Barbro.dahlen@ were relatively less responsive to methacholine (p,0.01). There was, however, no correlation between medhs.ki.se bronchial responsiveness to LTD4 and urinary LTE4 or blood ex vivo LTB4 levels in asthmatic subjects or healthy controls. Subjects with asthma treated with inhaled corticosteroids produced higher levels of LTB4 Received 4 February 2005 (p,0.05). Accepted 13 July 2005 Published Online First Conclusions: General measures of leukotriene production cannot predict bronchial responsiveness to LTD4. 29 July 2005 The unique bronchoconstrictive potency of LTD4 on human airways may relate to the locally regulated ....................... expression of the cysteinyl LT1 receptor. he leukotrienes (LT) and, in particular, the cysteinyl However, in patients with AIA there was no correlation leukotrienes (CysLTs; LTC4, LTD4 and LTE4) mediate between U-LTE4 and the treatment response to the leuko- http://thorax.bmj.com/ Tcentral components of asthmatic airway inflammation triene antagonist montelukast.5 such as bronchospasm, mucus production, eosinophil recruit- While it is uncertain whether the production of leuko- ment, and vascular reactions leading to tissue oedema.1 Over trienes correlates with the beneficial effect of antileuko- the past decade antileukotrienes—that is, drugs which block trienes, the responsiveness to leukotrienes in the airways has the formation or actions of leukotrienes—have been intro- not been taken into account. It is not known if increased duced as new treatments for asthma. Antileukotrienes bronchial responsiveness to leukotrienes is an indicator of a therefore have a completely different mode of action from predominant leukotriene component in asthmatic inflamma- that of other asthma medications.1 tion. We have therefore embarked on a series of studies of The further clinical use of antileukotriene drugs is, factors that determine leukotriene responsiveness in the on September 30, 2021 by guest. Protected copyright. however, hampered by a lack of understanding of which airways. The aim of the first investigation in this project was patients benefit from this treatment.1 There is a distribution to assess whether or not the responsiveness of an individual of clinical responsiveness to antileukotriene drugs that to inhaled LTD4 is related to the general propensity to suggests the presence of responders and non-responders.2–5 synthesise leukotrienes. As CysLTs cause bronchoconstriction Attempts to correlate the treatment response with genetic and many other biological effects by activation of the G polymorphism in 5-lipoxygenase (the first enzyme in the protein coupled CysLT1 receptor, it was hypothesised that leukotriene pathway) or leukotriene C4 synthase (the enzyme there might be a relation between the endogenous level of initiating production of CysLTs) have produced conflicting agonist (CysLTs) and the airway responsiveness to inhaled 6–8 results. So far, no major genetic determinant of leukotriene 13 LTD4. It is common for agonist levels to influence the degree dependent asthma has been identified. of receptor expression.14 For this study, two different global Another strategy in the quest to define responsiveness to measures of leukotriene production—U-LTE4 and blood ex antileukotriene drugs has been to define more precisely the vivo LTB4 generation—were assessed. LTE4 is the end product phenotypic characteristics of such patients. The focus has of the CysLTs excreted into the urine and its level is a been on the possibility that the propensity to generate reflection of whole body biosynthesis of CysLTs.15 As leukotrienes during asthmatic inflammation is a marker of circulating levels of leukotrienes in the blood are very low leukotriene dependent asthma. This hypothesis has received and far below the detection limit of reliable assays, some support from the observations that subjects with standardised ex vivo stimulation of whole blood with aspirin intolerant asthma (AIA) respond well to antileuko- secretagogues such as a calcium ionophore has been triene treatment and have a high basal production of leukotrienes measured as urinary LTE (U-LTE ).5 9–11 It has 4 4 Abbreviations: CysLT, cysteinyl leukotriene; FEV , forced expiratory also been claimed that the degree of ex vivo release of CysLTs 1 volume in 1 second; FeNO, fractional exhaled nitric oxide; ICS, inhaled from blood leucocytes is correlated directly with the clinical corticosteroids; MCh, methacholine; PD10,PD15,PD20, provocative dose 12 response to the leukotriene receptor antagonist pranlukast. causing a 10%, 15% and 20% decrease in FEV1 www.thoraxjnl.com Markers of leukotriene biosynthesis in asthma 903 introduced as an indirect method of assessing the biosyn- Study design 16 thetic capacity of blood cells for leukotriene production. In The screening visit included subject characterisation with Thorax: first published as 10.1136/thx.2005.041913 on 29 July 2005. Downloaded from this setting LTB4 is the main leukotriene formed, and its documentation of history, a MCh challenge, and a skin prick synthesis is thought to reflect the degree of 5-lipoxygenase test. Three further visits were scheduled 2 weeks apart, and activity. the subjects always reported to the clinic at the same time in This cross sectional study of 20 subjects with asthma and the morning. At visit 1 FeNO was measured according to the 10 healthy controls therefore tested whether bronchial ATS/ERS standard,19 dynamic spirometric tests were per- responsiveness to LTD4, expressed as the PD20 value, was formed, blood samples were collected for analysis of whole correlated with leukotriene production measured as U-LTE4 blood ex vivo LTB4 production, and urinary samples were and blood ex vivo production of LTB4. Bronchial responsive- collected for analysis of baseline U-LTE4 concentrations. In ness to LTD4 was also compared with responsiveness to the subjects with asthma, quality of life was measured using methacholine (MCh), selected as a general marker of airway the Asthma Quality of Life Questionnaire (AQLQ) devised by responsiveness, and with the fraction of expired nitric oxide Juniper et al.20 The patients were asked to indicate the extent (FeNO) as a surrogate marker of airway inflammation, both to which their quality of life was limited on a 7-point scale being common asthma outcome variables in treatment where 1 indicates maximal impairment and 7 no impairment studies. Although descriptive data on LTD4 responsiveness at all. At visit 2, blood and urine samples were collected and are available in the literature, there is almost no mechanistic spirometric tests performed as the subjects underwent a information about factors that determine leukotriene respon- bronchoscopic examination as part of a separate ongoing siveness in humans.17 mechanistic investigation of the leukotriene pathway in the lung. At visit 3, inhalation challenge with LTD4 was METHODS performed in addition to blood and urine sampling. Short acting b agonists were withheld for at least 6 hours before Subjects 2 Twenty subjects with intermittent to mild asthma according visits except for visit 2. to GINA criteria18 and documented airway hyperresponsive- ness to MCh and 10 healthy individuals were included in the Inhalation challenge study. Subjects with asthma were recruited from a general Pulmonary function was measured as FEV1 on a spirometer practitioner’s clinic and the healthy volunteers through (Vitalograph MDI Compact; Fo¨rbandsmaterial, Stockholm, advertisements. All subjects were never smokers or non- Sweden) and the baseline defined as the best of three smokers for the last 2 years with a smoking history of less recordings. All bronchoprovocation tests were performed than 5 pack years who had not had a respiratory tract using a dosimeter controlled jet nebuliser (Spira Elektro 2; infection during the 4 weeks before screening. Atopic Intramedic, Ba˚lsta, Sweden). Challenges always began with subjects were not studied during seasonal allergen exposure inhalation of the respective diluent.
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