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Airway Endothelin Levels in Asthma: Influence of Endobronchial Allergen Challenge and Maintenance Corticosteroid Therapy

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Airway Endothelin Levels in Asthma: Influence of Endobronchial Allergen Challenge and Maintenance Corticosteroid Therapy Eur Respir J 1997; 10: 1026–1032 Copyright ERS Journals Ltd 1997 DOI: 10.1183/09031936.97.10051026 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 Airway endothelin levels in asthma: influence of endobronchial allergen challenge and maintenance corticosteroid therapy A.E. Redington*, D.R. Springall**, M.A. Ghatei+, J. Madden*, S.R. Bloom+, A.J. Frew*, J.M. Polak**, S.T. Holgate* P.H. Howarth* Airway endothelin levels in asthma: influence of endobronchial allergen challenge and *University Medicine, Southampton General maintenance corticosteroid therapy. A.E. Redington, D.R. Springall, M.A. Ghatei, J. Hospital, UK. Depts of **Histochemistry Madden, S.R. Bloom, A.J. Frew, J.M. Polak, S.T. Holgate, P.H. Howarth. ©ERS Journals and +Medicine, Royal Postgraduate Medical Ltd 1997. School, Hammersmith Hospital, London, ABSTRACT: Endothelins (ETs) are 21 amino acid peptides which, in addition to UK. their other properties, are potent bronchoconstrictors. Whilst there is evidence of Correspondence: A.E. Redington the involvement of ET in the pathophysiology of chronic asthma, its contribution Room 4H17-21 to the acute allergic response is undefined. Health Sciences Centre To examine this, we have undertaken segmental bronchoprovocation with aller- Dept of Pathology gen and saline at separate sites in six atopic asthmatics receiving treatment with McMaster University 1200 Main Street West bronchodilators only and six atopic asthmatics additionally receiving treatment with Hamilton inhaled corticosteroids. Each challenged segment was lavaged 10 min after bron- Ontario choprovocation and concentrations of immunoreactive ET were measured in bron- Canada L8N 3Z5 choalveolar lavage fluid. In the non-steroid-treated subjects, there were significantly lower ET levels at the Keywords: Allergen challenge allergen-challenged sites compared to the saline-challenged sites (p<0.05). In the asthma bronchoalveolar lavage steroid-treated subjects, on the other hand, there was no significant difference bronchoscopy between the two sites. Levels of ET at the saline-challenged sites were significantly corticosteroids lower in the steroid-treated subjects compared to the non-steroid-treated subjects endothelin (p<0.04). These findings do not support the hypothesis that allergen exposure in asthma Received: June 17 1996 results in immediate release of endothelin. However, release at later time-points and Accepted after revision January 26 1997 a role for endothelin in late-phase bronchoconstriction are not excluded. This work was supported by the Medical Eur Respir J 1997; 10: 1026–1032. Research Council (UK). The human endothelin (ET) family comprises three 21 for the three members. Contraction of human bronchi is amino acid peptides termed ET-1, ET-2 and ET-3 [1]. believed to be principally ETB-mediated [13], whereas Endothelin-1 was originally characterized as a potent other properties of ETs relevant to asthma, such as secre- vasoconstrictor [2], but ETs are now recognized to have tion of mucus and mitogenic responses, are likely to in- many other biological properties. Of particular relevance volve ETA receptors. to asthma, all three isopeptides are potent contractile There are a number of potential sources of ET within agonists of isolated human airways [3], while ET-1 caus- the airway wall, including bronchial epithelial cells [14], es bronchoconstriction in vivo in guinea-pigs when admi- vascular endothelial cells [2] and inflammatory cells, nistered either intravenously [4] or by inhalation [5]. In such as macrophages [15] and possibly also mast cells addition, ET-1 has been shown to stimulate secretion of [16], although a mast cell origin has not yet been demon- mucus in isolated tracheal preparations [6], to activate strated in humans. In bronchial biopsies, a major site of inflammatory cells including macrophages [7] and mast immunoreactivity for ET is the airway epithelium [17, cells [8] in vitro, and to exert pulmonary proinflamma- 18]. Expression at this site is increased in asthma [19] tory effects in vivo in guinea-pigs [9]. Finally, ET-1 is and, consistent with this, ET levels in bronchoalveolar mitogenic both for fibroblasts [10] and airway smooth lavage (BAL) fluid from non-corticosteroid-treated asth- muscle [11], suggesting a possible role in airway wall matics are increased in comparison with those in BAL remodelling in asthma. fluid from healthy control subjects [20, 21]. As these Members of the ET family exert their effects via an levels correlate with the degree of airflow obstruction in interaction with specific membrane receptors. In a vari- asthma [21], it has been proposed that ET contributes to ety of systems, two receptors have been characterized, the resting bronchomotor tone in this disease. which are denoted ETA and ETB [12]. The ETA recep- We hypothesized that ET may be released during tor has a higher affinity for ET-1 or ET-2 as compared acute allergen exposure and, thereby, contribute to the with ET-3, whereas the ETB receptor has equal affinity immdiate bronchoconstrictor response. To investigate the AIRWAY ENDOTHELIN LEVELS IN ASTHMA 1027 relationship between allergen exposure and ET release The technique used to determine airway reactivity was in vivo, we have used a segmental bronchoprovocation adapted from the five breath procedure described by CHAI model. Twelve atopic asthmatic subjects, six of whom et al. [22]. All solutions were administered from an were receiving regular maintenance therapy with inhaled Inspiron nebulizer (CR Bard, Sunderland, UK) driven by corticosteroids, underwent fibreoptic bronchoscopy with compressed air at a flow rate of 8 L·min-1. After resting endobronchial allergen and sham saline challenges into for 15 min, the baseline FEV1 was recorded using a separate bronchopulmonary segments. BAL was then wedge bellows spirometer (Vitalograph Ltd, Buckingham, performed in each segment during the immediate phase UK). Subjects then inhaled five breaths of 0.9% saline of bronchoconstriction, and concentrations of immuno- via a mouthpiece, each breath taken from functional resid- reactive ET in BAL fluid were determined by radio- ual capacity (FRC) to total lung capacity (TLC), and fur- immunoassay. ther measurements of FEV1 were made after 1 and 3 min. Subjects proceeded to inhale increasing doubling concentrations (0.03–16 mg·mL-1 saline) of histamine Materials and methods (BDH, Lutterworth, Leicestershire, UK), with FEV1 mea- surements made at 1 and 3 min after each inhalation. Subjects These stepwise inhalations continued until either the FEV1 had fallen by at least 20% of the postsaline value Six atopic asthmatics (2 males and 4 females; aged or until the maximum concentration had been reached. β The log10 concentration of agonist was plotted against 23±1 yr), treated only with inhaled short-acting 2-ago- nists as required, and a further six atopic asthmatics (1 the percentage change in FEV1 from the postsaline value, male and 5 females; aged 27±2 yrs), additionally receiv- and the cumulative provocative concentration causing a ing regular therapy with inhaled corticosteroids, took 20% fall in FEV1 (PC20) was derived by linear interpo- part in the study. Their clinical and physiological para- lation between the last two data-points. meters are summarized in table 1. One subject in the Atopic status was determined by skin-prick testing us- steroid-treated group was also receiving treatment with ing the following allergen extracts: Dermatophagoides β pteronyssinus, cat allergen, mixed feathers, mixed grass the long-acting 2-agonist salmeterol. All subjects were nonsmokers, had mildly symptomatic clinically stable pollens and dog allergen (Miles Inc, Hollister Stier, asthma, and none had experienced recent symptoms of Elkhart, IN, USA). A drop of each allergen solution was upper respiratory tract infection. The study was approv- placed on the skin of the volar surface of the forearm ed by the Southampton Joint University and Hospitals and a small volume of solution introduced into the epi- Ethics Committee, and all subjects gave written informed dermis using sterile 1 mm lancets (Entaco Ltd, Studley, consent. Warwickshire, UK). A positive response was defined as a wheal diameter ≥3 mm measured at 15 min to one or more allergen extract, in the presence of negative (0.9% Physiological measurements saline) and positive (histamine acid phosphate) controls. A skin-prick test wheal dose-response series was then Subjects attended, 1–2 weeks prior to bronchoscopy, performed using serial 10 fold dilutions of the allergen for measurement of forced expiratory volume in one sec- that produced the largest response, in order to determine ond (FEV1) and airway reactivity and determination of the concentration to be used for segmental broncho- atopic status. On this occasion, those subjects receiving provocation. The lowest concentration which produced a β ≥ inhaled short-acting 2-agonists had been asked to discon- 3 mm diameter wheal response was chosen for the endo- tinue this medication for a minimum of 6 h beforehand. bronchial challenge. Table 1. – Clinical and physiological characteristics of the subjects studied Ss Age Sex FEV1 PC20 Treatment Allergen and No. yrs % pred mg·mL-1 concentration Non-steroid-treated 1 19 F 104 4.67 S Der p 10-4 2 21 F 131 2.21 S Der p 10-5 3 23 F 120 0.61 S Der p 10-5 4 27 M 108 3.73 S Der p 10-4 5 27 M 89 3.64 S Der p 10-4 6 20 F 107 2.50 S Der p 10-5 Steroid-treated 1 23 F 103 1.19 BDP (200), S Der p 10-5 2 35 M 112 3.08 BDP (1000), S Der p 10-5 3 20 F 123 - BDP (400), Sm, S GP 10-5 4 29 F 99 0.30 BDP (400), S Der p 10-4 5 29 F 81 0.86 BDP (1000), S Der p 10-3 6 26 F 105 4.79 BDP (800), S Der p 10-3 Ss: subjects; F: female; M: male; FEV1: forced expiratory volume in one second; PC20: provocative concentration of histamine producing a 20% fall in FEV1: BDP: beclomethasone dipropionate, with total daily dose in µg in parenthesis; Sm: salmeterol; S: salbutamol; Der p: Dermatophagoides pteronyssinus; GP: grass pollen.
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