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Neurokinin a Is the Predominant Tachykinin in Human Bronchoalveolar Lavage Fluid in Normal and Asthmatic Subjects

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Neurokinin a Is the Predominant Tachykinin in Human Bronchoalveolar Lavage Fluid in Normal and Asthmatic Subjects Thorax 1998;53:357–362 357 Neurokinin A is the predominant tachykinin in human bronchoalveolar lavage fluid in normal and Thorax: first published as 10.1136/thx.53.5.357 on 1 May 1998. Downloaded from asthmatic subjects L G Heaney, L J M Cross, L P A McGarvey, K D Buchanan, M Ennis, C Shaw Abstract bronchial epithelial endocrine cells.1 Peptides Background—Multiple sensory neuro- localised to nerves can be divided into those peptides are present in human airways that are localised to the parasympathetic and and may contribute to diseases such as sympathetic nerves in the airways and those asthma. This study quantified and charac- that are associated with sensory nerves in the terised substance P (SP), neurokinin A bronchial epithelium. Peptides associated with (NKA), and calcitonin gene related peptide sensory nerves in humans include the tachy- (CGRP) immunoreactivity in broncho- kinins substance P (SP) and neurokinin A alveolar lavage fluid in asthmatic and nor- (NKA) and the related peptide calcitonin gene mal subjects. related peptide (CGRP), and coexist in the 2 Methods—Using specific radioimmuno- same nerve fibres. Great interest has sur- assay (RIA), SP, NKA and CGRP were rounded these sensory neuropeptides in the measured in bronchoalveolar lavage fluid respiratory tract since in vitro they cause many from asthmatic subjects (n = 5), normal of the features of asthma such as bronchocon- subjects (n = 5), atopic non-asthmatic striction, mucus secretion, and airway subjects (n = 6), and asthmatic subjects oedema.3 four hours after allergen challenge (n = Previous studies have measured levels of SP 12). Peptide immunoreactivity was char- in lavage fluid4–6 but the other sensory neuro- acterised using high performance liquid peptides NKA and CGRP have not been chromatography (HPLC) and RIA. examined. The aim of this study was to meas- Results—No SP or CGRP immunoreac- ure and characterise SP, NKA, and CGRP-like tivity was detected in any of the fractions immunoreactivity in bronchoalveolar lavage from samples after extraction, HPLC, and (BAL) fluid in normal subjects and subjects RIA. Non-specific binding resulted in with mild asthma. The study also determined http://thorax.bmj.com/ spurious SP immunoreactivity being de- whether a diVerence was observed in peptide tected in bronchoalveolar lavage fluid levels in asthmatic subjects four hours after when no extraction process was employed. allergen exposure. NKA was detected in significant amounts Department of in asthmatic (median 550, range 425– Respiratory Medicine, 625 pg/ml) and normal subjects (median Methods Royal Victoria 725, range 350–1425 pg/ml). The level of All subjects (n = 25, age range 18–37 years, Hospital, Belfast NKA was significantly higher in the asth- table 1) were recruited on a voluntary basis and L G Heaney gave informed written consent to take part in on September 26, 2021 by guest. Protected copyright. L P A McGarvey matic subjects after allergen challenge (median 750, range 350–1250 pg/ml) than the study, which was approved by the Faculty Department of in unchallenged asthmatic subjects (me- of Medicine Research ethics committee of The Queen’s University of Belfast. Asthma was Medicine dian 600, range 425–600 pg/ml, p<0.01). L G Heaney defined according to the American Thoracic —Extraction and characteri- L J M Cross Conclusions Society as a history of intermittent wheeze, sation of peptides from bronchoalveolar K D Buchanan cough, or chest tightness on allergen exposure lavage fluid must be performed to ensure C Shaw or exercise.7 Subjects were excluded if there that the measured immunoreactivity rep- was any history of smoking, diabetes, current Department of Clinical resents target peptide. NKA is present in pregnancy, cardiac or renal disease, or any Biochemistry bronchoalveolar lavage fluid in high con- M Ennis chest disease other than asthma. Asthmatic centrations and is the predominant tachy- subjects had current asthma defined as symp- kinin. The concentrations of NKA are The Queen’s toms within the past 12 months and atopy was similar in normal subjects and subjects University of Belfast defined as positive skin test to one or more of with mild asthma. four common environmental allergens (house Correspondence to: (Thorax 1998;53:357–362) Dr L G Heaney, Department dust mite (Dermataphagoides pterynonissimus, of Respiratory Medicine, HDM), mixed grass pollen, cat, and dog; Bio- Level 8, Belfast City Keywords: neurokinin A; substance P; bronchoalveolar Hospital, Lisburn Road, lavage diagnostics). All atopic subjects were sensitive Belfast, Northern Ireland to HDM with a positive skin test and HDM BT9 7AB. specific IgE in the serum measured by radioal- The diVuse neuroendocrine system consists of lergosorbent test (RAST; Pharmacia Ltd). In Received 9 September 1997 Returned to authors specialised endocrine cells and peptidergic atopic subjects sensitive to grasses all studies 24 November 1997 nerves and is present in all organs of the body were performed outside the grass pollen season Revised version received including the respiratory tract.1 Peptides can be (May to July). Asthmatic subjects on theophyl- 7 January 1998 Accepted for publication localised to pulmonary nerves, pulmonary line, inhaled steroids, or cromoglycate or those 7 January 1998 veins, cells of the pulmonary endothelium, and who had taken oral steroids in the preceding 358 Heaney, Cross, McGarvey, et al Table 1 Age, sex, atopic status, baseline spirometric indices and subject group RAST PC20* FEV1 (l) FVC (l) Thorax: first published as 10.1136/thx.53.5.357 on 1 May 1998. Downloaded from Patient no. Age (yr) Sex IgE (U/l) HDM† (mg/ml) (% predicted) (% predicted) EAR‡ (%) Non-atopic non-asthma 1 21 M 12 0 44.2 5.34 (113) 7.46 (131) 2 22 M 14 0 64 4.02 (92) 5.05 (97) 3 22 M 57 0 16 3.89 (96) 5.46 (115) 4 21 M 6 0 128 5.47 (121) 6.44 (119) 5 21 M 7 0 55 4.93 (114) 5.81 (114) Atopic non-asthma 6 21 M 222 2 21.8 5.35 (113) 6.28 (113) 7 29 F 174 2 64 4.69 (151) 6.26 (162) 8 22 M 137 3 >128 4.86 (106) 5.59 (102) 9 26 M 14 2 46 3.91 (96) 5.15 (105) 10 21 M 54 3 6.4 5.62 (125) 6.96 (129) 11 21 M 274 2 32 4.71 (107) 6.12 (118) Allergen challenged asthma 12 36 M 27 3 0.28 3.05 (91) 5.15 (126) 30 13 28 F 266 5 0.2 2.38 (74) 4.34 (108) 37 14 22 M 121 4 0.18 3.24 (78) 5.86 (119) 21 15 23 M 159 5 5.72 6.59 (155) 8.15 (160) 50 16 23 M 291 4 12.9 4.29 (103) 6.0 (121) 48 17 37 F 153 2 0.9 2.48 (87) 3.73 (104) 38 18 18 F 297 6 3.17 2.73 (96) 3.67 (114) 41 19 21 M 152 3 0.8 4.79 (108) 6.59 (128) 21 20 21 F 1556 6 0.45 3.41 (99) 4.53 (99) 52 21 19 M 163 4 8.4 5.3 (128) 5.8 (117) 23 22 22 M 802 5 3.9 4.54 (103) 5.23 (99) 21 23 26 M 161 4 3 4.06 (104) 5.78 (124) 41 Unchallenged asthma 24 19 M 1256 6 0.5 3.95 (91) 5.25 (102) 25 25 M 15 3 7.8 4.67 (107) 6.9 (132) 18 18 F 297 6 2.9 2.62 (96) 5.7 (115) 19 21 M 152 3 1.0 4.08 (92) 6.18 (120) 23 26 M 161 4 3.4 3.82 (96) 4.3 (94) Three asthmatic subjects (nos 18, 19, 23) were studied on two separate occasions (post challenge and unchallenged). *Concentration of methacholine (PC20) causing a 20% fall in FEV1. †Radioallergosorbent test to house dust mite (RAST HDM) is given as 0–6 (0 = negative, 6 = strongly positive). ‡EAR is the maximal recorded fall in FEV1 in the first hour after allergen challenge on the day of bronchoscopy. four weeks were also excluded to ensure challenge was performed in a similar fashion recruitment of asthmatic subjects with mild with inhalation of increasing doses (500 units/ clinical disease and no recent exacerbations. ml, 1000 units/ml, 5000 units/ml HDM http://thorax.bmj.com/ Prior to attending for each study day, asthmatic antigen solution) until forced expiratory vol- subjects were advised to omit inhaled â2 ume in one second (FEV1) fell by at least 20% agonists for the preceding 12 hours. from the baseline value or the maximum concentration of HDM had been inhaled. INHALATION CHALLENGES Three asthmatic subjects were studied on two Methacholine challenge (Sigma-Aldrich Com- separate occasions with and without allergen pany Ltd) was performed using the tidal challenge (subjects 18, 19 and 23, table 1). breathing method of Cockroft .8 Allergen et al After initial recruitment and assessment the 1500 50 subject groups were non-challenged asthma on September 26, 2021 by guest. Protected copyright. NKA-ox (22, 23 min) (unchallenged, n = 5), allergen challenged SP-ox (27 min) asthma (n = 12), atopic non-asthmatic control (ANA, n = 6), and non-atopic non-asthmatic 40 NKA-red (27, 28 min) control (normal, n = 5). 1000 SP-red (32 min) BRONCHOSCOPY AND BRONCHOALVEOLAR LAVAGE NKB-ox (34 min) 30 On a subsequent day subjects attended for bronchoscopic examination. Challenged asth- matics underwent allergen inhalation chal- 20 lenge with HDM (PD20 allergen) at 08.30 % Acetonitrile 500 NKB-red (38 min) hours. All bronchoscopies were performed at Peptide (pg/fraction) 12.30 hours using a standardised technique.
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