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N-Formyl-Methionyl-Leucyl-Phenylalanine in Man Thorax: First Published As 10.1136/Thx.47.4.284 on 1 April 1992

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N-Formyl-Methionyl-Leucyl-Phenylalanine in Man Thorax: First Published As 10.1136/Thx.47.4.284 on 1 April 1992 284 Thorax 1992;47:284-287 Haematological effects of inhalation of N-formyl-methionyl-leucyl-phenylalanine in man Thorax: first published as 10.1136/thx.47.4.284 on 1 April 1992. Downloaded from M J Peters, A B X Breslin, A S Kemp, J Chu, N Berend Abstract Background including chemotaxis, lysosomal enzyme N-Formyl-methionyl- release and oxygen free radical generation.4 leucyl-phenylalanine (FMLP) is a bac- It also contracts smooth muscle. There is a terial oligopeptide which stimulates close correlation between chemotactic and neutrophil chemotaxis, degranulation spasmogenic activity5 between the different and superoxide generation. Inhalation of related formyl peptides. Following the finding FMLP produces bronchoconstriction in that inhaled FMLP produces broncho- man; in the rabbit this is in part neutro- constriction in normal phil dependent. subjects,6 we suggested The effects of inhalation that it may cause bronchoconstriction during of FMLP on peripheral blood leucocytes bacterial bronchial infection, particularly in in normal subjects has been studied. patients with chronic airflow limitation. Methods This was an open study in Although FMLP contracts human bron- non-asthmatic subjects. Change in total chial smooth muscle directly in vitro,7 its peripheral white cell count were studied bronchoconstrictor activity in vivo in for 15 minutes after may inhalation of 04 part be neutrophil dependent as neutropenic umol FMLP in six subjects. Change rabbits show a reduced bronchoconstrictor in total and differential white cell count response to FMLP.8 Infusions of substances and spontaneous neutrophil chemi- known to activate neutrophils (FMLP, luminescence were then studied five and platelet activating factor (PAF), C5a, 30 minutes after inhalation of 0 4 pmol granulocyte-monocyte colony stimulating FMLP (n = 7) or diluent (n = 4). Finally, factor (GM-CSF) and endotoxin) produce leucocytes from three subjects were transient leucopenia,913 as a result of reduced http://thorax.bmj.com/ labelled ex vivo with technetium-99m deformability'4 or enhanced adherence to labelled sulphur colloid and reinfused. endothelium.'l" This produces neutrophil The effect of inhalation of FMLP or margination in small vessels, particularly in diluent on pulmonary neutrophil flux was the pulmonary circulation." 12 Activation of studied by continuous gamma scanning leucocytes by inhalation of FMLP in addition of a pulmonary window. to sequestration in the lungs may explain Results Leucopenia occurs rapidly the neutrophil dependent component of after inhalation of FMLP, the nadir of bronchoconstriction. on September 25, 2021 by guest. Protected copyright. the white cell count (53% of baseline) The aims of this study were to determine occurring at four minutes. This was the changes in leucocyte count and neutrophil followed by a rebound increase in white function and distribution after FMLP cell count evident at 15 minutes (154% of inhalation. baseline). Five minutes after inhalation of 0-4 pmol FMLP, neutropenia (17% of baseline) and monocytopenia (40% of Methods baseline) were seen followed again by a The subjects were lifelong non-smokers aged neutrophilia (213% of baseline at 30 25-38 years with no history ofasthma or recent minutes). The eosinophil count was respiratory infection. All were men, apart from reduced at Departments of significantly 30 minutes (24% one woman in study 1. Only one subject Thoracic Medicine of baseline). Neutrophil chemilumines- participated in more than one experiment, and Nuclear Medicine, cence was elevated (186% of baseline) at taking part in all three. All protocols were Concord Hospital, the time of the neutropenia. There Sydney, Australia was approved by the Institutional Ethics Commit- M J Peters no influx of labelled cells to the lung tee of Concord Hospital and all subjects gave N Berend during the period of neutropenia. informed consent to participate. A B X Breslin Conclusion FMLP inhalation All were started J Chu activates experiments between 8.30 circulating leucocytes. In vivo produc- and 10.00 am. FMLP (Sigma Chemicals, St Department of tion Immunology, Royal of FMLP in the airway could con- Louis, Missouri), was dissolved at a concentra- Alexandra Hospital tribute to bronchial inflammation during tion of2-5 mmol/l in 50% dimethyl sulphoxide for Children, Sydney, bacterial infection. (DMSO)/saline. Five breaths of FMLP or Australia DMSO solution were A S Kemp taken from functional residual to total with a Reprint requests to: capacity lung capacity, Dr M J Peters, Bacteria produce low molecular weight de Vilbiss 646 nebuliser. Automated white cell Department of Thoracic chemotactic factors,' such as counts were with a Coulter Medicine, National Heart N-formyl- performed Counter and Lung Institute, methionyl-leucyl-phenylalanine (FMLP), Model S-plus and differential counts performed London SW3 6LY, UK which are formylated oligopeptides.23 FMLP on 100 cells, smears being stained with May- Accepted 10 December 1991 activates a number of neutrophil functions, Griinwald-Giemsa. Total and differential white Haematological effects ofinhalation of1N-formyl-methionyl-leucyl-phenylalanine in man 285 Figure I Mean (SEM) 15- PROTOCOLS change in white cell count ( x 10'/l) over 15 minutes Study 1 after inhalation ofFMLP 12- Six subjects participated in this study. Venous 0 4 /imol in study 1. There blood was taken at baseline and at one minute Thorax: first published as 10.1136/thx.47.4.284 on 1 April 1992. Downloaded from was significant leucopenia o 9' between two and seven intervals for five minutes and at two minute minutes after FMLP intervals for a further 10 minutes after inhala- inhalation and a significant a) 6 + tion of FMLP (0-4 umol). A total white cell increase in white cell count ._ count was performed on each sample. by 15 minutes. 3 3 Study 2 *** ~ ~ Baseline 1 3 5 7 9 11 13 15 Eleven subjects had venous blood taken at Time after FMLP (min) baseline, and five and 30 minutes after inhala- tion of FMLP 0 4 imol or diluent alone (n = 4). These time points were chosen to be cell counts were performed by technicians close to the maximum fall and increase in total unaware of which solution had been given. white cell count. Total white cell count, Neutrophil chemiluminescence was differential white cell count and spontaneous measured as follows: 5 ml whole blood was neutrophil chemiluminescence were deter- separated for 30 minutes on a Dextran- mined on each sample. Hypaque gradient by a modification ofBoyum's method.'8 Cuvettes containing 100 pl of the Study 3 leucocyte fraction, 100 1l ofphosphate buffered The effect of FMLP on phagocytic leucocytes saline and 11 pl of luminol solution (final labelled ex vivo"9 and reinfused was studied in luminol concentration 2 x 10'6 mmol/l) at three subjects. On each of two days, at least 37°C were vortexed for 15 seconds and seven days apart, 10 ml of venous blood chemiluminescence was counted for five was taken and leucocytes labelled with minutes in a Hewlett-Packard luminometer. A technetium-99m labelled sulphur colloid neutrophil count was also performed on a (Radpharm, Canberra). After reinjection and portion ofthe sample. The chemiluminescence equilibration for 45 minutes, five breaths of activity of the cells was then calculated accord- FMLP (0A4 imol) or DMSO diluent were ing to the following formula: inhaled. Gamma scanning was performed continuously over the period of equilibration Chemiluminescence (CPM)- and for 30 minutes after FMLP or DMSO (measured chemiluminescence - background inhalation. Fields of interest were delineated http://thorax.bmj.com/ chemiluminescence)/cell count, for both lungs and minute counts were recorded for each. The half life of lung activity where background chemiluminescence was the was determined for 20 minutes before and 30 cpm in the absence of cells. minutes after FMLP or DMSO inhalation. For each subject the five minute and 30 minute chemiluminescence results were then ANALYSIS OF RESULTS expressed as a percentage of baseline. In study 1, change in white cell count was compared with baseline values by paired on September 25, 2021 by guest. Protected copyright. White cells Neutrophils Students t test. In study 2, change in chemi- 12 10 luminescence after FMLP was compared with that after DMSO by Wilcoxon's rank test. 9 8 Leucocyte counts were expressed as a percen- 6 tage of baseline values and the effect of FMLP 6 and DMSO was compared by unpaired t test. A 4 p value of < 0 05 was taken as significant. 3 2 Baseline 5 30 Baseline 5 30 Results STUDY 1 Monocytes Eosinophils There was a significant fall in white cell count within three minutes of FMLP inhalation with 1o00 025 the nadir occurring at four minutes. At this 080 020 time the mean (SE) total white cell count was x 060 0155 4-1(1-2) 109/l compared with the baseline value of 7-7(0-8) x 109/1. There was a 0*40 0 10 significant rebound increase in white cell count 020 0*05 by l5minutesto 11-9(1-4) x 109/1(figure 1). In five ofthe six subjects the early fall in white cell count was greater than 40% and this was Baseline 5 30 Baseline 5 30 followed by a rise; the sixth subject showed a Figure 2 AMean (SEM) change in white cell count aznd neutrophil, monocyte and late rise without a preceding fall. Facial flushing eosinophil counts ( x 10'/l) in study 2 at five and 30;minutes after inhalation of FMLP was evident in four of the five subjects who 0-4 pmol (open circles) or DMSO (closed circles). A minutes was followed by neutrophilia. Monocytopenia was seen atfive minutes and showed transient leucopenia but not in the eosinopenia only after 15 minutes. sixth subject. 286 Peters, Breslin, Kemp, Chu, Berend Half life ofpulmonary activity of labelled white cells before and after FMLP 0 4 pmolll chemiluminescence activity in unstimulated and DMSO inhalation in study 3 cells, but the activation was transient.
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