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Platelet-Activating Factor Increases Leukotriene B4 Release in Stimulated Alveolar Macrophages from Asthmatic Patients

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Platelet-Activating Factor Increases Leukotriene B4 Release in Stimulated Alveolar Macrophages from Asthmatic Patients Copyright ©ERS Journals Ltd 1998 Eur Respir J 1998; 11: 1098–1104 European Respiratory Journal DOI: 10.1183/09031936.98.11051098 ISSN 0903 - 1936 Printed in UK - all rights reserved Platelet-activating factor increases leukotriene B4 release in stimulated alveolar macrophages from asthmatic patients K. Shindo, K. Koide, M. Fukumura Platelet-activating factor increases leukotriene B4 release in stimulated alveolar macro- First Dept of Internal Medicine, Yokohama phages from asthmatic patients. K. Shindo, K. Koide, M. Fukumura. ©ERS Journals Ltd City University School of Medicine, 3-9 1998. Fukuura, Kanazawa-ku, Yokohama, Japan ABSTRACT: This study was designed to examine further the role of platelet-activat- Correspondence: K. Shindo ing factor (PAF) in asthma, comparing leukotriene B4 (LTB4) release, 5-lipoxygenase First Dept of Internal Medicine 2+ activity and intracellular calcium levels ([Ca ]i) in macrophages. Yokohama City University School of Med- LTB 4 and other lipoxygenase metabolites in macrophages in bronchoalveolar lav- icine age fluids obtained from 23 asthmatic patients and 20 control subjects were measured 3–9 Fukuura 2+ by reverse-phase high-performance liquid chromatography. [Ca ]i was monitored Kanazawa-ku using the fluorescent probe fura-2. Yokohama 236 Japan The basal LTB4 release of resting macrophages was not different between groups (0.02±0.01 versus 0.05±0.02 ng·10-6 cells). When stimulated with calcium ionophore Fax: 45 787 2509 A23187 (2.5 µM), however, macrophages from asthmatic patients released more LTB 4 Keywords: Intracellular Ca2+ than cells from control subjects (30.2±3.4 versus 13.7±2.1 ng·10-6 cells). Although PAF leukotriene B4 alone did not alter LTB4 release, it enhanced the response to subsequent A23187 stim- 5-lipoxygenase ulation. This effect was noted following short treatment (i.e., 5 min) at concentrations macrophage of Š1.0 µM PAF, with the maximal effect noted after treatment with 5.0 µM PAF + 2.5 platelet activating factor µM A23187 (105.1±6.7 versus 15.3±2.6 ng·10-6 cells). Treatment of macrophages with 2+ Received: September 23 1996 PAF also increased 5-lipoxygenase activity and [Ca ]i more in cytosols from asth- matic patients than in cytosols from control subjects. Accepted after revision April 5 1997 These findings support a role of intracellular calcium in the activation of 5-lipoxy- genase which, in turn, augments the release of leukotriene B4. Because levels of plate- let-activating factor may be increased in the lung during asthma and can increase the subsequent release of a chemotactic mediator leukotriene B4, from macrophages, these findings suggest that platelet-activating factor may prime the constitutive cells of the lung to augment inflammatory effects important in the pathogenesis of asthma. Eur Respir J 1998; 11: 1098–1104. Platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn- the involvement of PAF in the development of bronchial glycero-3-phosphocholine, AGEPC) is the first example asthma remains controversial [8]. of a phospholipid that acts as a cell-to-cell mediator, a pot- The broad objective of this study, therefore, was to ent platelet activator, and a potent mediator of inflamma- define the role of PAF in the pathogenesis of bronchial tion and allergy. It was designated PAF when the release asthma. The in vitro study investigated whether PAF may from rabbit basophils sensitized with immunoglobulin prime the release of leukotriene LTB4 from stimulated (Ig)E was reported in 1972 [1]. Subsequent studies dem- macrophages obtained from asthmatic and nonasthmatic onstrated its presence in humans, its effect on human patients, by examining simultaneously the effect of PAF platelets in vitro, and its physicochemical characteristics on 5-lipoxygenase activity and intracellular Ca2+ levels 2+ and structure, particularly its glycerophosphocholine back- ([Ca ]i). bone [2, 3]. A complex and distinctive inflammatory process in the airway of asthmatics is known to be associated with the Materials and methods contraction of airway smooth muscle, the presence of air- way oedema, the extravasation of plasma, the hypersecre- tion of mucus and the hyperresponsiveness of the bronchi Materials [4–7]. The inflammatory activities of PAF resemble those seen in bronchial asthma, suggesting that PAF is inti- PAF C-18 (1-O-octadecyl-2-O-acetyl-sn-glycero-3-phos- mately involved in its pathogenesis. Nevertheless, an phocholine) and lyso-PAF (1-O-hexadecyl-sn-glycero-3- orally active PAF antagonist, WEB 2086, failed to reduce phosphorylcholine) were obtained from Sigma Chemicals the dosage requirement for inhaled corticosteroid in pati- (Tokyo, Japan). (S)-5-hydroxy-6-trans-8,11,14-cis-eicosa- ents with atopic asthma [8]. Although the importance of tetraenoic acid (5-HETE), Hanks' balanced salt solution PAF in pulmonary disorders has been established [9, 10], (HBSS), foetal calf serum (FCS) and arachidonic acid PRIMING OF ALVEOLAR MACROPHAGES BY PAF 1099 were purchased from Pharmacia Fine Chemicals (Piscata- Stimulation way, NJ, USA). Fura-2/AM was obtained from Molecular Probes (Oxford, MI, USA). All other chemicals were Cells were stimulated either with A23187 (2.5 µM) from Sigma and were of the finest grade available. alone for 15 min, or with A23187 (2.5 µM) for 15 min fol- lowing pretreatment with PAF C-18, or lyso-PAF at con- centrations of 0.1, 1.0, 5.0 or 10.0 µM for 5 min. The Subjects reaction was quenched by adding cold methanol. Prostag- landin (PG) B2, 100 ng, was added as an internal standard. The study evaluated 23 Japanese patients with bron- Samples were acidified to pH 4.0–4.5 with 1 M H3PO4. chial asthma and a mean age of 37.2 yrs (range 26–49 The samples were chilled at -20°C for 1 h, then centri- yrs), and 20 control subjects without bronchial asthma, fuged at 13,000×g to remove the precipitated protein. The with a mean age of 37.4 yrs (range 24–44 yrs) (table 1). supernatants were transferred to new tubes and evaporated None of these subjects had ever smoked, and none had to dryness under a stream of N2. They were then dissolved taken medication for 2 months prior to the study. The in methanol, centrifuged again, transferred and stored at patients with bronchial asthma met the diagnostic criteria -70°C until further analysis. In a preliminary study (data proposed by the American Thoracic Society [11]. Patients with asthma had a history of paroxysms of dyspnoea, not shown), the optimal pretreatment period for PAF was determined to be 5 min and the optimal concentration of wheezing, and coughing. All patients were atopic, as µ defined by the presence of a wheal >3 mm in diameter in A23187 was found to be 2.5 M. It was confirmed that response to skin-prick testing with at least two common exogenous PAF C-18 remained stable during the incuba- airborne allergens, compared with that caused by the dilu- tion conditions, and there was no significant reduction in ent control and radioallergosorbent (RAST) positive to at the aggregation of washed guinea-pig platelets following least one inhalant allergen (table 1a). No apparent skin such incubation (data not shown). allergies were clinically found in the subjects. The aller- gens tested were cat hair, cat dander, mixed grass pollens, dog hair, dog dander, feathers, a mixture of molds, house- Cytosolic preparations dust mite, Dermatophagoides pteronyssinus and Dermat- ophagoides farinae (Bencard, Brentford, UK). Isolated macrophages were suspended in 1 mL of soni- The group with bronchial asthma was clinically stable at cation medium (100 mM Tris, 1 mM EDTA, pH 7.8). The the time of the study. Patients were excluded from the study cells were then sonicated. Phenylmethane sulfonyl fluo- if their forced expiratory volume in one second (FEV1) was ride was added to a final concentration of 1.0 mM. The <1.5 L; or if there was evidence of active pulmonary disrupted cells were transferred to a microcentrifuge tube infection. This study was approved by the Committee on and centrifuged at 13,000×g for 30 min at 4°C. The sup- Clinical Investigation of Yokohama City University. In- ernatant was removed and placed in another microcen- formed consent for participation was obtained from each trifuge tube, and the centrifugation was repeated. This subject prior to the study. supernatant was termed cytosol [12, 13]. Total protein in When the subjects were undergoing bronchoscopy for the cytosol was assessed by the Bradford technique [14]. diagnostic purposes, all bronchoalveolar lavage fluids (BALF) were collected. Topical anaesthesia was achieved by administering lidocaine using a nebulizer and by direct Assay of 5-lipoxygenase activity in cytosolic fractions topical application. Meperidine or midazolam, or both, was administered to induce sedation. A bronchoscope 5-Lipoxygenase activity was measured by a modifica- (Olympus BF P10; Olympus, Tokyo, Japan) was introd- tion of a previously described technique [12, 13, 15]. It uced through the nares. The anterior portion of the right was assessed by measuring 5-HETE and 5(S)-hydroper- middle lobe of the lung was lavaged with four aliquots of oxy-6,8-trans-11,14-cis-eicosatetraenoic acid (5-HPETE), normal saline of 25 mL each. The BALF was immediately in 50 µL samples of cytosol mixed 1:1 with 2× assay placed on ice. Cell counts were performed on unprocessed buffer (final concentration, 100 mM Tris, 2 mM CaCl2, 1.6 BALF using a haemocytometer. The viability of cells was mM EDTA, pH 7.4). Samples were then preincubated in determined by the trypan blue exclusion method using a the presence or absence of 1 or 5 µM of PAF (or 5 µM of 0.04% solution of the dye. Cells were prepared by cyto- lyso-PAF) at 37°C for 30 min.
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