Eur Resplr J
1991, 4, 551-560
Platelet-activating factor impairs mucociliary transport
and increases plasma leukotriene 8 4 in man
M.M. Nieminen*, E.K. Moilanen**, J-E.J. Nyholmt, M.O. Koskinent,
J.l. Karvonent, T.J. Metsa-Ketela**, H. Vapaatalo**
Platelet-activating factor impairs mucociliary transport and increases plasma
/eukotriene B4 in man. M.M. Nieminen, E.K. Moilanen, J-E.J. Nyholm, M.O.
Koskinen, J./. Karvonen, T.J. Metsa-KeteUi, H. Vapaata/o.
ABSTRACT: We assessed the effect of inhaled platelet-activating factor
(PAF) on tracheobronchial clearance, pulmonary function and blood
pressure In seven healthy volunteers. After inhalation of 500 1-1g of PAF,
retention of radloaerosol in ciliated airways measured at 4 h was 80%
higher than in the control recording, and the clearance was reduced by
33% (p<O.OOS). Acetylsalicylic acid (ASA) did not abolish the phenomenon. PAF also decreased forced expiratory volume in one second (FEV1 )
by 16% (p<O.Ol), which was markedly attenuated by acetylsalicylic acid.
The decrease in blood pressure after PAF (p<0.01) was not Influenced by
acetylsallcyllc acid. Plasma leukotriene B4 (LTB4) was increased at 20
min after PAF Inhalation (without and with ASA: mean 240 and 299
pg·ml·1, respectively) as compared to the baseline (144 and 166 pg·mJ'l)
and the values at 60 min after the chaiJenge (133 and 178 pg·mJ'l; p<O.OS
and p<O.Ol, respectively). Only three out of seven subjects showed a
bronchial hyperresponsiveness to methacholine measured 24 h after PAF.
The PAF-induced reduction of mucociliary transport seems to be
independent of cyclo-oxygenase products of arachidonic acid metabolism.
These autacoids are, however, believed to contribute to the acute bronchial
obstruction after PAF inhalation. In addition, inhaled PAF causes a
transient increase In plasma LTB 4•
Eur Respir J., 1991, 4, 551-560.
Platelet-activating factor (PAF) has been shown to
cause a wide spectrum of effects including acute
bronchoconstriction [1-4], and increased airways reactivity [1, 4-8], as well as vascular events similar to
those seen in acute inflammation [9], neutrophil [10]
and eosinophil chemotaxis [11], degranulation and
mediator secretion [12, 13]. Furthermore, inhaled or
intravenously administered P AF causes hypotension in
animals and in man [1, 14]. Hence, it is speculated that
the generation of PAF may be important to the
pathogenesis of asthma and anaphylaxis. However, it is
poorly understood whether these pathophysiological
events are direct actions of PAF on target tissues like
smooth muscle [15] or mediated via secondary
generation or release of leukotrienes [13, 16], cycleoxygenase metabolites of arachidonic acid [6, 16, 17],
or histamine [4, 18].
Tracheobronchial clearance is impaired in many airway diseases, and reduced mucus transport may have a
contributing role in pathogenesis by preventing the
clearance of airway secretions [19-21]. Impaired clearance is a typical characteristic of asthma exacerbations
induced by allergen, which may be caused by release of
Depts of • Pulmonary Diseases and t Clinical
Physiology, Tampere University Central Hospital,
Pikonlinna, Finland.
•• Dept of Biomedical Sciences, University of
Tampere, Finland.
Correspondence: M.M. Nieminen, M.D., Tampere
University Central Hospital, SF-36280 Pikonlinna,
Finland.
Keywords: Bronchial obstruction; leukotriene B,;
plasma catecholamines; platelet-activating factor;
tracheobronchial clearance.
Received: January 19, 1990; accepted after revision
November 6, 1990.
Supported by grants from The Academy of Finland,
The Foundation of Id a Montin, Tampere Foundation
for Tuberculosis Research, and The Foundation of
Tampere City.
autacoid mediators from immunoglobulin E (IgE)antigen reaction with resident or inflammatory cells in
airways. It has been suggested that leukotrienes might
be crucial to allergic inhibition of mucus transport
[22, 23]. Preliminary studies have also indicated that
PAF reduces tracheobronchial mucus velocity in animals
[24, 25].
The purpose of the present investigation was, firstly ,
to assess the effe.c t of inhaled PAF on tracheobronchial
clearance and it's possible relation to the PAP-induced
bronchial hyperresponsiveness in man. Secondly, we
were interested in the role of secondary inflammatory
mediators and activation of circulating platelets in PAFinduced bronchial responses. Therefore, the level of
plasma leukotriene B4 , and the aggregation and the
thromboxane B1 production of platelets were measured
during PAF challenge. On the other hand, the significance of cycle-oxygenase products of arachidonic acid
metabolism in PAP-induced bronchial effects was further evaluated by acetylsalicylic acid pretreatment.
Finally, we wanted to delineate whether noradrenaline
or adrenaline release play any role in the modulation of
pulmonary or circulatory effects of PAF in man.
M.M. NIEMINEN ET AL.
552
Methods
Subjects
All subjects were nonsmoking healthy volunteers,
recruited from the staff of Tampere University Central
Hospital. They gave informed consent according to the
Helsinki Declaration, and the study was approved by
the Ethical Committee of Tampere University Central
Hospital.
The PAF study was conducted on seven subjects, three
men and four women (mean age 40 yrs, range 30-58
yrs). Six of them also participated in the second PAF
study with acetylsalicylic acid pretreatment, where 500
mg of acetylsalicylic acid was given twice per os, at
approximately 12 h and 2 h before the PAF challenge.
In addition to these seven subjects, the baseline
(diluent) mucociliary clearance was also tested twice in
eight others, at the same time of day at least 2 wks
apart. Thus, the repeatability of the method was assessed in 15 subjects, nine women and six men, with a
mean age of 36 yrs (range 21-58 yrs). None had a
respiratory disease including upper respiratory viral
infection within the previous six weeks. No medication
was allowed during the previous 2 wks, or caffeinecontaining beverages during the 12 h prior to the study.
Method for aerosol delivery
PAF, radioaerosol, and methacholine were delivered
with an automatic, inhalation-synchronized dosimeter
jet nebulizer (Spira Elektro 2, Respiratory Care Center,
Hameenlinna, Finland). This dosimeter is triggered by
a very low inspiratory flow rate (a threshold <33
ml·s-1), which enables the delivery of the aerosols with
tidal breathing. The volume of each inhalation is
displayed on digital readout, and inhalation flow rate is
controlled by a flow indicator. The breath-actuated,
variable-time circuit regulates air through a solenoid
valve to a nebulizer set at a flow rate of 7.5 l·min·1, which
produces aerosol with a particle size of 1.6 11m mass
median aerodynamic diameter (MMAD) (geometric so
1.4). The volume output of the dosimeter under these
operating conditions, and with 0.5 s nebulization
periods is 7.1 11l·breath'1 (mean±O.S so) [26].
Nebulization was practised by each subject with
saline before the study began. With noseclip and
mouthpiece in place, the subject controlled his tidal
breathing with the flow indicator so that the inspiratory
flow rate of each breath reached but did not exceed
0.5 [-s·1, with intra-individual variation in tidal volume
of ±10%.
PAF administration
A mixture of C16 and C 18 analogues of 1-0-alkyl-2acety1-sn-glycery1-3 -phosphorylcholine (Novabiochem,
Laufelfingen, Switzerland) at a ratio 3:1 was diluted to
a concentration of 3.6 mg·ml-1 with 0.9% saline
containing 0.25% human serum albumin (HSA). After
the nebulization of this diluent, PAF was delivered with
the dosimeter in four successive doubling cumulative
doses (1, 2, 6 and 11 inhalations, respectively), from 25
11g (0.048 11mol) to 500 11g (0.96 11mol), with 3 min
interval between each dose.
Monitoring of immediate bronchial obstruction after
PAF
After the inhalations of diluent and of 500 11g of
PAF, spirometric measurements (Vitalograph,
B uckingham, UK) were performed. At least two
technically correct manoeuvres for the forced maximal
expiratory flow-volume curves with a variation of less
than 5% were done, and the best curve with the greatest sum of forced expiratory volume in one second
(FEY) and forced vital capacity (FVC) was utilized in
obtaining the data.
Measurement of tracheobronchial clearance
Mucociliary transport rate was evaluated by calculating
the clearance of inhaled radioaerosol particles according to the method of TAPLIN et al. [27] as modified by
1SAWA et a/. (28).
For the radioaerosol, 99mTc-traced human albumin
particles with MMAD 1.4 11m were diluted with 0.9%
saline to contain 0.25% HSA. Thus, the diluent was
identical to that of PAF. The radioactivity of the
nebulizer chamber was recorded before the nebulization
by a well counter (Capintec CRC 10, Montvale, NJ,
USA), and the radioactivity of solution adjusted to about
30 mCi·2 mi-1 • The radioaerosol was given as 0.5 s
nebulizations during 15 inhalations, which delivered a
total amount of 106.5 111.
The lungs were imaged with a gamma camera (GE
400 A{f Maxicamera, General Electrics, Horsholm,
Denmark), in a frontal projection. Data were collected
for 10 min immediately after the nebulization (total lung
deposition), and again after 1, 2 and 4 h (tracheobronchial clearance) and then repeated after 24 h for 20 min
(retention in alveoli and nonciliated airways).
Gamma images were stored onto magnetic disk of
Gamma-11 computer-system using 64 x 64 matrix. A
special computer program was written to analyse the
data. Firstly, separate images were moved on the display so that the same region of interest can be used in
the study. The program uses the count numbers from
manually drawn lung areas for calculations. Corrections
of physical decay of 99mTc and differences in collecting
times are then carried out. The constant background
activity of the room is collected as well. The counts of
the 24 h image are then subtracted from the counts of
the other images, because this residual activity is
supposed to be trapped in the nonciliated part of
lungs. Finally, the program computes the fraction of
activity still apparent at different time points (retention
values).
EFFECI' OF PAF ON AIRWAYS FUNCI'ION
Methacholine bronchial challenge
Methacholine bronchial challenge was performed
according to a dosimeter method described previously
[29). After nebulization of 36 f..t8 of saline to establish
a baseline, methacholine was delivered in ten successive
cumulative doses from 18 f..t8 to 2,300 f..tg. The concentration of methacholine was 2.5 mg·ml·1 for the doses
18-180 f..tg, and 25 mg·ml·1 for the doses 360-2,300 f..t8At least two maximal flow-volume curves
(Vitalograph, Buckingham, UK) were measured before
and 3 min after normal saline and each dose of
methacholine with the subject seated. The best curve,
with the greatest sum of FEV1 and FVC, was recorded.
The challenge was terminated if the maximal expiratory
flow when 50% FVC remained to be exhaled (MEF5~
fell by at least 35% from the post-saline value. The fall
in MEF50 was plotted against dose methacholine on a
log scale, and the provocative dose causing a 35% fall
in MEF50 (PD 35MEF5J was calculated.
Blood pressure recording
After the inhalations of diluent, and each dose of P AF,
blood pressure in the left brachial artery was measured
with the subject seated using a mercury manometer,
cuff size 12 x 35 cm. The cuff pressure at which the
sounds of Korotkoff were first heard was the systolic
pressure. The diastolic pressure was recorded at the
fifth phase of the sounds of Korotkoff.
553
(HPLC) [30] or Amprep C2 alone. Concentrations
of LTB 4 were quantitated with RIA using a commercial
kit from Amersham International, Buckinghamshire,
UK.
Concentrations of adrenaline and noradrenaline in
plasma
Adrenaline and noradrenaline concentrations in plasma
were measured by HPLC using electrochemical detection with dihydroxybenzylamine as internal standard as
described (31).
TxB 2 synthesis in platelets
Five ml of blood was allowed to clot at 3rC for 30
min. The reaction was stopped by cooling in an icebath for 10 min. TxB2 concentrations in diluted sera were
assayed by RIA using antibody obtained from Prof. C.
Taube, Martin Luther University, Halle, DDR, and
3 H-labelled TxB
from Amersham International,
2
Buckinghamshire, UK.
Platelet aggregation
The measurement of leukotriene B4 (LTBJ, adrenaline and no radrena l ine in plasma, secretion of
thromboxane B2 (TxB2) from thrombocytes and platelet
reactivity to adrenaline, adenosine diphosphate (ADP)
and PAF were performed from the blood samples taken
after the inhalation of diluent, and 20 and 60 min after
the inhalation of the first dose of PAF (5 and 45 min
after the last dose of PAF).
Twenty ml of blood was collected in citrate (9 volumes blood and 1 volume 3.8% citrate) and centrifuged
at 150 x g for 20 min to obtain platelet-rich plasma.
The platelet count was adjusted to 300,000·mm·3, 450 1-1-l
of the suspension was transferred into measuring cuvette
and preincubated at 37°C for 5 min. The aggregation
was induced by adding adrenaline (final concentration
0.1-10 1-1-M; Sigma Chemical Co., St. Louis, MO, USA),
ADP (0.1-10 1-1-M; Sigma Chemical Co., St. Louis, MO,
USA) or PAF-C18 (0.02-20 1-1-M; Novabiochem,
Uiufelfingen, Switzerland) in 50 14!. The aggregation
was measured by Die Kyoto aggregation recorder (Model
PA-3210; Kagaku Co. Ltd, Kyoto, Japan) for 5 min
against platelet-poor plasma (obtained by centrifugation
at 2,500 x g for 20 min).
Concentrations of LTB 4 in plasma
Statistical evaluation
Heparinized plasma was extracted with Amprep
C2 minica r tridge (Amersham I n ternational,
Buckinghamshire, UK) and quantitated with radioimmunoassay (RIA) as follows. One ml of plasma,
acidified to pH 3.5 with HCI, was placed in the
minicartridge prewashed with 2 ml of methanol and 2
ml of distilled water. The column was washed with 5
ml of distilled water, 5 ml of 10% ethanol and 5 ml of
hexane and, thereafter, LTB4 was eluted with 5 ml of
methylformiate. The procedure resulted in >88%
recovery for LTB4 • The extraction described was tested
to be sufficient by comparing LTB4 concentrations
measured from the same samples (n=24) purified with
Amprep C2 + high performance liquid chromatography
For statistical analysis, the Student's t-test for paired
observations and analysis of variance was used. A
probability value less than 0.05 was considered to be
significant. The repeatability of the measurement of
mucociliary transport was evaluated by the method of
ALTMAN and BLAND [32) by relating the difference
between the first and the second measurement with their
mean value in log10- units to ensure that within subject
variation was independent of the size of the measurement. Further, the intra- and intersubject coefficient of
variation were calculated. From the standard deviation
of the differences between measurements the 95% range
for a single measurement was calculated from the
formula 10 .05 (so)JV2.
Mediator levels and platelet function
M.M. NIEMINEN ET AL.
554
Bronchial obstruction
Results
Repeatability of the measurement of tracheobronchial
clearance
To test the reproducibility of the method, tracheobronchial clearance was measured twice in 15 normal
subjects. The intra- and intersubject variabilities of 4 h
tracheobronchial clearance were 11 and 22%, respectively. No relationship between within subject variation
and the size of the retention of radioaerosol in ciliated
airways was found, calculated after logarithmic transformation of the results. The mean difference between
replicates was 0.06 (so 0.10) at 4 h measurement. The
95% confidence interval of retention % based on a
single measurement was the observed value ±0.48
doubling increment.
Effect of PAF on tracheobronchial clearance
After inhalation of PAF, retention of radioaerosol in
ciliated airways at 4 h measurement was 80% greater
than in the control recording (p<0.005), and the clearance was reduced by 33%. Acetylsalicylic acid had no
significant effect on the PAF-induced impairment in
mucus transport (fig. 1).
There were no significant differences between the two
groups (with or without acetylsalicylic acid pretreatment)
in the measures of baseline airway function determined
just prior to the inhalation of PAF (fig. 2). Inhalation
of PAF caused an acute, tfansient bronchial obstruction.
FEV1 decreased by 16% (SEM 3.6) (p<O.Ol) and MEF$0
by 27% (sEM 6.8)(p<0.025). Pretreatment with acetylsalicylic acid almost totally abolished this effect of PAF
(fig. 2). In both groups, the subjects also had slightly
increased coughing for a couple of hours after the
inhalation of PAF.
Bronchial responsiveness to methacholine
Control methacholine test showed no bronchial
hyperresponsiveness in our seven subjects. The inhalation of 500 J..l.S of PAF caused a marked bronchial
hyperresponsiveness in the next day in three out of the
seven individuals, PD35MEF50 : 350 J,.~.g, 250 J,.~.g and 1,600
J,.~.g, respectively. After acetylsalicylic acid pretreatment,
these three subjects still had increased bronchial
responsiveness; PD35MEF50 : 255 J,.~.g, 330 J,.~.g and 560
J,.~.g, respectively.
Circulatory effects
0
~. 100
=~
.2 ~ 80
"i 'i
-51
c.!!
PAF+ASA
PAF
60
o= 40
1.1 u
~.5
a:~
Control
20
0
~~--~--~-L--~~--~--L-~
2
0
3
4
Time h
Fig. 1. - Effect of 500 I'& of inhaled platelet-activating factor (PAF)
on tracheobronchial retention of radioaerosol (mean~sEM, n=6-7) with
and without acetylsalicylic acid (ASA) treatment. • ••: p<0.005 .
5I
IL
Ill
2
'!
L
6
Both without and with acetylsalicylic acid, plasma
LTB 4 levels were increased in the samples taken 20 min
after PAF inhalation (240±65.8 and 299±42.5 pg·ml·l,
mean±SEM, respectively) as compared to the baseline
4
IL
2
"
10
5!
IL
0
c2
-,
·10
Ill
3
~
Leukotriene B 4
LIS
5
•...
~
In all subjects inhalation of PAF caused facial flushing, warmth and a slight decrease in systolic and diastolic
blood pressure (p<O.Ol) (fig. 3). There wa·s a slight
increase in heart rate, not however achieving significance. Pretreatment with acetylsalicylic acid did not
influence the flushing, warmth nor the decline of blood
pressure (fig. 3).
~~
u~
IL
·20
-30
0 -40
~
0
·50
WlthASA
WlthoutASA
BaHIIne
Fig. 2.- Baseline and effect of 500 1'8 of inhaled platelet-activating factor (PAF) on FYC (- ). FEY1 (I'Zl.a) a nd MEF50 ( - ) (mean:tSEM,
n=6-7) without and with acetylsalicylic acid (ASA) treatment. •: p<0.025; • • : p<O.Ol. FYC: forced vital capacity; FEY1: forced expiratory
volume in one second; MEF, 0: maximal expiratory flow when 50% FYC remains to be exhaled.
555
EFFECT OF PAF ON AIRWAYS FUNCTION
PAFtASA
PAF
mmHg
140
e
Syst. BP
:I
••
f
mmHg
140
130
~ 120
• 110
Syst. BP
:~ 100
Cl.
'0
'0
8
m
Dlast. BP
!
90
Dlast. BP
80
70
100 200 300 400 500 600 1!9
0
100 200 300 400 500 600 1!9
Cumulative dose of PAF
Cumulative dose of PAF
Fig. 3. - Effect of cumulative doses of inhaled platelet-activating factor (PAF) on systollc and diastolic blood pressure (meanzsEM, n=6-7)
without and with acetylsalicylic acid (ASA) treatment. ..: p<0.025; •••: p<O.Ol. Syst.: systolic; Diast.: diastolic; BP: blood pressure.
r1
pg·m
r - p<O.OS-r----- p<0.01 -
(144±20.5 and 166±17.3 pg·ml-1) or to the values at 60
min after the challenge (133±17 .3 and 178±26.5
pg·ml· 1; p<0.05, p<0.01, respectively) (fig. 4).
--,
350
ea
e
Ill
ea
Q.
.5
•
~
300
Catecholamines
250
200
PAFtASA
PAF
150
' - - - - p<O.OS
100
--...J
50
Plasma concentration of noradrenaline but not that of
adrenaline increased significantly due to PAF-inhalation
when measured at 20 min (p<0.01) (fig. 5) and then
declined. This pattern remained unchanged after
acetylsalicylic acid pretreatment (fig. 5).
0
Pre PAF
20mln
post PAF
60mln
postPAF
Fig. 4. - Effect of inhaled PAF on plasma LTB4 concentration
(mean:tSEM, n=6-7) with and without acetylsalicyclic acid (ASA)
treament.
Thromboxane production by platelets
Thromboxane B 2 released from platelets during 30
min incubation at 37°C remained unchanged at 20 and
60 min after PAF inhalation when compared with the
PAF
PAFtASA
pmol·ml·1
•
.5
pmol·ml·1
Gl
4
i
c
i
c
r p<0.01--,
c
4
!
I!
3
'0
'0.!
2
'0.!
·-
CQ.
la
·-.,
2
CQ.
la
c
c
c
.5
c
i
c
i
!
~
.....,
!
3
I! la
oE
c Ill
'0
~a
oe
c 10
rP<0.025
..
0
Pre PAF
20mln
post PAF
60mln
post PAF
~
0
Pre PAF
20mln
post PAF
60mln
post PAF
Fig. S. - Effect of inhaled platelet-activating factor (PAF) on plasma adrenaline (I?ZlJ) and noradrenaline ( - ) concentrations (mean:tSEM,
n=6-7) without and with acetylsalicylic acid (ASA) treatment.
M.M. NIEMINEN ET AL.
556
prechallenge value (fig. 6). In the second study, acetylsalicylic acid pretreatment virtually abolished
thromboxane production (fig. 6).
ng·ml-1
300
c
0
:g
::I
Platelet aggregation
200
'8...
Aggregability of platelets to ADP, PAF and adrenaline was similar whether measured in vitro before, 20 or
60 min after PAP-inhalation (fig. 7). Acetylsalicylic
acid pretreatment decreased adrenaline-induced
aggregation (p<0.005), but had no clear effects on the
responses to ADP or PAF (fig. 7).
Q.
N
m
~
100
0
Pre PAF
20mln
post PAF
60mln
post PAF
Discussion
Fig. 6.- Thromboxane (TxBJ production (mean:tsEM, n=6-7) from
platelets incubated for 30 min at 37°C before, 20 and 60 min after
PAF-inhalation, without (- ) and with (~) acetylsalicylic acid
(ASA) treatment.
The present data indicate that inhaled PAF causes
secondary generation of LTB 4 and impairs tracheobronchial clearance in man. These phenomena may be
PAF
PAF +ASA
%
~
~
%
100
100
80
c 80
60
i 60
0
~
~ 40
01
01
~ 20
40
cc 20
0
0
0
2
4
6
8
10
+-~~~~~~~~~~~
12
0
2
ADP concentration 1-1M
0
=
~
F
"'
100
80
60
80
c
~ 60
40
F 4o
20
~ 20
I'll
01
0
.001
.01
.1
1
10
100
.001
F
f
.1
1
10
100
%
%
100
100
i
.01
PAF concentration 1-1g ·m1·1
PAF concentration 1-1g·mr1
~
12
%
100
0
10
8
6
ADP concentration 1-1M
%
c
4
80
c
0
60
i
80
60
40
F
40
20
cc
20
01
01
0
0
0
2
4
6
8
10
12
Adrenaline concentration lAM
0
2
4
6
8
10
12
Adrenaline concentration J.lM
Fig. 7. - Aggregation (mean:tsEM, n=6) of circulating platelets to ADP, PAF and adrenaline before (O ), 20 min (O) and 60 min ( • )
after PAF-inhalation, without and with acetylsalicylic acid (ASA) treatment. ADP: adenosine diphosphate; PAF: platelet-activating factor.
EFFECT OF PAF ON AIRWAYS FUNCTION
important contributing factors to PAP-induced airways
inflammation, and they are very reminiscent of
exacerbations in allergic asthma. Surprisingly, pretreatment with acetylsalicylic acid attenuated the acute
PAP-induced obstruction, indicating the importance of
cycle-oxygenase products of arachidonic acid, but was
ineffective on the other recorded changes in bronchial
functions or blood pressure. Inhalation of PAP had no
effects on aggregation or thromboxane production from
platelets in vitro, indicating a very local, intrapulmonary
response.
For the measurement of tracheobronchial clearance,
we standardized a new system based on the administration of radioaerosol with an inhalation synchronized
dosimeter technique, which enabled us to standardize
the breathing pattern and minimizes loss of aerosol
outside the respiratory tract [26, 29). Previously, considerable variation in the clearance rates has been found
even among healthy subjects [21, 33, 34]. Mucus
transport is primarily dependent on the aerosol's initial
deposition pattern, i.e. the more central (closer to the
mouth) the aerosol is deposited, the faster is the clearance (19, 35). On the other hand, the degree of aerosol
penetration to lower airways is found to depend mainly
on the inhalation flow rate [36). The major factors for
standardized aerosol deposition are considered to be
quantitative aerosol generation and a controlled and
determinable mode of inhalation [37). With continuous
aerosol delivery, intersubject coefficient of variation
(CV) has been reported to be 42-43% and intrasubject
CV 16-20% (38, 39) in healthy nonsmokers. In the
present study, with the use of a dosimeter technique
combined with controlled tidal breathing, there seems
to be an improved reproducibility. Our data agree with
the report by DEL DoNNO et al. [40), who found
intersubject CV 13% by using dosimeter technique and
controlled deep breaths from functional residual capacity (FRC) followed by 3 s breath-holding.
PAF caused a pronounced impairment on mucus
transport. Our findings confirm preliminary data from
animal models, in which intratracheally but not intravenously administered PAP in the guinea-pig [24) and
aerosolized PAP in the sheep [25) decreased tracheal
mucus velocity. In the present study, the decline in
mucus transport was more pronounced in smaller airways. This could be explained by the PAP-induced
cough, which may have increased the clearance of large
airways during the first part of the measurement. The
PAP-induced impairment of tracheobronchial clearance
may be due to a direct "ciliotoxic" effect or an increase
in mucus viscosity and volume. Previous reports have
shown that PAP increases tracheal mucus and fluid
secretion in the ferret in vitro and in vivo [41] and in
the pig in vitro [42). In the guinea-pig, intravenously
administered PAP increased the protein content of airway secretions, presumably by causing extravasation of
plasma, but there was no increase in mucus secretion
[43).
Theoretically, inhaled PAP might also decrease the
mucociliary clearance by causing a nonspecific leak
in airways. That view is strongly argued by previous
557
animal studies. A specific PAF antagonist, WEB 2086,
has been shown to prevent the PAP-induced decrease in
tracheal mucus velocity in the sheep [25). In addition,
PAF (10·7 to 10·5 M) has been reported to decrease mean
surface liquid velocity and ciliary beat frequency in
sheep trachea in a dose-dependent fashion while having
no effects on the rheological properties of mucus (44 ].
Another main finding of our study was the increase
of plasma LTB 4 following PAP-inhalation. PAF
stimulates in vitro the synthesis of leukotrienes in
various cell types, including neutrophils [ 45) and
macrophages [46]. The enhanced synthesis has also
been found in tissue samples taken from gastrointestinal
tract of the rat after PAF-infusion [47]. LTB4 appears
to be a major mediator of leucocyte activation [48), is
chemotactic for neutrophils and eosinophils [10, 11] and
induces adhesion of polymorphonuclear neutrophils
(PMNs) to endothelial cells [49]. Thereby an induction
of LTB4 secretion by intraluminal PAF might further
enhance the PAP-induced (i.e. direct effect) accumulation of inflammatory cells in airways. In addition, the
increased secretion of leukotrienes may also contribute
to the slowing of the mucociliary transport, as indicated
by the previous studies in the sheep (23) and in man
[22).
The PAP-induced bronchial obstruction is suggested
to be platelet dependent, because at least in two species
of experimental animals, PAP elicits bronchoconstriction
only if platelets are present [2, 50). It has also been
reported that in isolated human smooth muscle, platelets are required to induce bronchospasm [51). On the
other hand, the bronchial obstruction is not seen in the
rat since PAP binding sites in platelets are absent in this
species [52]. A plausible cycle-oxygenase product to
mediate the PAP-induced bronchospasm is plateletderived thromboxane, which is a powerful bronchoconstrictor with a high potency approaching that of the
sulphidopeptide leukotrienes [53). Using a variety of
agonists and antagonists, it has recently been shown
that thromboxane shares the same receptor on airways
smooth muscle with other prostaglandins which mediate constriction (54, 55). One PAF antagonist, BN52063
has been shown to attenuate PAF-induced
bronchoconstriction [56] as well as chlorpheniramine in
canine trachealis in vivo [18) and in man [4).
In the present study, PAF caused a marked acute
bronchial obstruction, which was attenuated by aspirin
pretreatment. Our results are in accordance with a
previous report by ANDERSON et al. [57], who found in
the guinea-pig that acetylsalicylic acid, but not indomethacin, attenuated PAP-induced increases in intratracheal pressure. However, SMITII et al. [4] found in
man that indomethacin did not significantly inhibit PAPinduced bronchoconstriction, although the data presented
from their study did show an attenuating tendency for
acetylsalicylic acid. Furthermore, chlorpheniramine
reduced the PAP-response. On the basis of the present
knowledge, PAP induced bronchoconstriction seems to
be the result of a cascade of mediators including
histamine and cycle-oxygenase metabolites of arachidonic acid. For instance LTB 4, which was increased after
M.M. NIEMINEN ET AL.
558
PAP-inhalation in the present study, is spasmogenic for
airway smooth muscle indirectly via stimulated
biosynthesis of constrictor cyclo-oxygenase products
[58].
One of the interesting properties of PAF is the ability
to induce a nonselective increase in bronchial reactivity
both in experimental animals and in man (1, 4-8). The
mechanisms underlying PAF-induced hyperreactivity are
not clear, but it is of interest that this phenomenon is
reducible by selective depletion of platelets in guineapigs (9) or neutrophils in the sheep [59], suggesting a
link between the activation of inflammatory cells and
the induction of bronchial hyperreactivity. Of the
has been
platelet-derived mediators, thromboxane
implicated in the dog models of induced bronchial
hyperresponsiveness [60] and established as a factor of
bronchial responsiveness of asthma [61). On the other
hand, in guinea-pigs, acetylsalicylic acid and
indomethacin have been reported to enhance airways
response to histamine [57) after PAF-infusion.
Unfortunately, the PAF-induced bronchial
hyperresponsiveness seems not to be easily repeatable in
man, as recently stressed by HOPP et al. (62]. Also in our
study, only three out of seven subjects showed a bronchial
hyperresponsiveness to methacholine after inhaled PAF.
Acetylsalicylic acid did not abolish the response in these
three subjects, which contradicts the role of thromboxane
in the basic mechanism of PAF-induced
hyperresponsiveness in man. In addition, our data indicate that the appearance of PAF-induced bronchial
hyperresponsiveness is not directly related to slowing of
the mucociliary escalator.
In all subjects, inhalation of PAF caused facial
flushing, warmth and a decrease in blood pressure
confirming the previous studies in animal models [14,
63] and in man (1). Acetylsalicylic acid did not change
these effects. Plasma noradrenaline concentration rose
after inhalation of PAF reflecting increased sympathetic
nervous activity. No marked changes were found in the
plasma adrenaline level. This pattern of noradrenaline
and adrenaline release is identical with that seen in
bronchoconstriction induced by exercise, hyperventilation, propranolol, inhaled histamine or methacholine,
which cause no major adrenomedullary response (64).
PAF is a potent activator of platelet functions, i.e.
aggregation and secretion in vitro (65, 66]. Probably
phosphatidylinositol turnover resulting in protein
phosphorylation is the underlying messenger system,
which controls PAF-induced activation of platelets [65).
In the present study, however, inhaled PAF did not
change ADP-, PAF- or adrenaline-induced aggregation
or thromboxane production from platelets in vitro. Even
though intrapulmonary platelets may be responsible for
many pulmonary effects of PAF [67], our data suggest
that circulating platelets are not activated due to PAF
inhalation.
In conclusion, in healthy normal volunteers we
observed that PAF reduces mucociliary transport.
Whether this is a direct effect of PAF on epithelial cell
lining or secondary to activation of recruited inflammatory cells remains to be established. PAF-induced
Az
generation of leukotrienes may be a further contributing
factor in the slowing of tracheobronchial clearance and
in induction of sustained inflammatory response in the
airways.
Acknowledgements: The authors thank S.L. !sola,
H. Keskinen, T. Siponen, M.L. Lamp~n and N. Railo
for expert technical assistance.
References
1. Cuss FM, Dixon CMS, Barnes PJ. -Effects of inhaled
platelet activating factor on pulmonary function and bronchial
responsiveness in man. Lancet, 1986, ii, 189-192.
2. Vargaftig BB, Lefort J, Chignard M, Benveniste
J. - Platelet-activating factor induces a platelet-dependent
bronchoconstriction unrelated to the formation of
prostaglandin derivates. Eur J Pharmacol, 1980, 65,
185-192.
3. Pinckard RN, McManus LM, Halonen M, Hanahan DJ.
- Immunopharmacology of acetyl glyceryl ether phosphorylcholine (AGEPC). In: Immunopharmacology of the Lung.
H.H. Newball ed., Marcel Dekker, New York, 1984, pp.
73-103.
4. Smith LJ, Rubin AE, Patterson R. - Mechanism of
platelet-activating factor-induced bronchoconstriction in
humans. Am Rev Respir Dis, 1988, 137, 1015-1019.
5. Mazzoni L, Morley J, Page CP, Sanjar S.- Induction of
airway hyperreactivity by platelet-activating factor in the
guinea-pig. J Physiol, 1985, 365, 107.
6. Chung KF, Aizawa H, Leikauf GD, Ueki IF, Evans TW,
Nadel JA. - Airway hyperresponsiveness induced by platelet-activating factor: role of thromboxane generation. J
Pharmacal Exp Ther, 1986, 236, 580-584.
7. Patterson R, Bernstein PR, Harris KE, Krell RD. Airway responses to sequential challenges with plateletactivating factor and leukotriene D4 in rhesus monkeys. J Lab
Clin Med, 1984, 104, 340-345.
8. Nieminen MM, Irvin CG, Henson PM. - Bimodal
effects of platelet-activating factor (PAF) on airways responsiveness in the rabbit. Am Rev Respir Dis, 1988, 137, 308.
9. Mojarad M, Hamasaki Y, Said I. - Platelet-activating
factor increases pulmonary microvascular permeability and
induces pulmonary oedema. Bull Eur Physiopathol Respir,
1983, 19, 253-257.
10. Czarnetzki BM, Benveniste J.- Effect of synthetic PAFacether on human neutrophil function. Agents Actions, 1981,
2, 549-552.
11. Wardlaw AJ, Moqbel R, Cromwell 0, Kay AB. Platelet-activating factor. A potent chemotactic and chemokinetic factor for human eosinophils. J Clin Invest, 1986, 78,
1701-1706.
12. O'Fiaherty JT. - Neutrophil degranulation: evidence
pertaining to its mediation by the combined effects of
leukotriene B4, platelet-activating factor, and 5-HETE. J Cell
Physiol, 1985, 122, 229-239.
13. Voelkel NF, Worthen S, Reeves JT, Henson PM,
Murphy RC. - Nonimmunological production of leukotrienes
induced by platelet-activating factor. Science, 1982, 218,
286-289.
14. Halonen M, Palmer JD, Lohman IC, McManus LM,
Pinckard RN. - Respiratory and circulatory alterations
induced by acetyl ether phosphorylcholine, a mediator of IgE
anaphylaxis in the rabbit. Am Rev Respir Dis, 1980, 122,
915-924.
EFFECf OF PAF ON AIRWAYS FUNCTION
15. Stimler NP, O'Flaherty JT.- Spasmogenic properties of
platelet-activating factor: evidence for a direct mechanism in
the contractile response of pulmonary tissue. Am J Pathol,
1983, 113, 75-84.
16. Beaubien BB, Tippins JR, Morris HR. - Plateletactivating factor stimulation of peptidoleukotriene release:
inhibition by vasoactive polypeptide. Biochem Biophys Res
Commun, 1984, 125, 105-108.
17. Burhop KE, Van Der Zee H, Bizios R, Kaplan JE, Malik
AB. - Pulmonary vascular response to platelet-activating
factor in awake sheep and the role of cyclooxygenase
metabolites. Am Rev Respir Dis, 1986, 134, 584-554.
18. Leff AR, White SR, Munoz NM, Popovich KJ, Shioya
T, Stimler-Gerard NP. - Parasympathetic involvement in
PAF-induced contraction in canine trachealis in vivo. J Appl
Physiol, 1987, 62, 599-605.
19. Pavia D. - Lung mucociliary clearance. In: Aerosols
and the Lung: Clinical and Experimental Aspects. S.W. Clarke,
D. Pavia eds, Butterworths, London, 1984, pp. 127-155.
20. Wanner A. - The role of mucociliary dysfunction in
bronchial asthma. Am J Med, 1979, 67, 477-485.
21. Yeates DB. - The role of mucociliary transport in the
pathogenesis of chronic obstructive pulmonary disease. In:
Mucus in Health and Disease. II. E.N. Chantler, J.B. Elder,
M. Elstein eds, Plenum, New York, 1982, pp. 411-415.
22. Ahmed T, Greenblatt DW, Birch S, Marchette B,
Wanner A. - Abnormal mucociliary transport in allergic
patients with antigen-induced bronchospasm: role of slow
reacting substance of anaphylaxis. Am Rev Respir Dis, 1981,
124, 110-114.
23. Russi EW, Abraham WM, Chapman GA, Stewenson JS,
Codias E, Wanner A. - Effects of leukotriene D 4 on
mucociliary and respiratory function in allergic and nonallergic
sheep. J Appl Physiol, 1985, 59, 1416-1422.
24. Aursudkij B, Rogers DF, Evans TW, Alton EWFW,
Chung KF, Barnes PJ. - Reduced tracheal mucus velocity
in guinea-pig in vivo by platelet-activating factor. Am Rev
Respir Dis, 1987, 135, A160.
25. Homolka J, Abraham WM, Rubin E, Nieves L, Wanner
A. - Effect of platelet-activating factor on tracheal velocity
in conscious sheep. Am Rev Respir Dis, 1987, 135, A160.
26. Nieminen MM, Holli H, Lahdensuo A, Muittari A,
Karvonen J. - Aerosol deposition in automatic dosimeter
nebulization. Eur J Respir Dis, 1987, 71, 145-152.
27. Taplin GV, Poe ND, Greenberg A. - Lung scanning
following radio-aerosol inhalation. J Nucl Med, 1966, 7,
77-87.
28. Isawa T, Teshima T, Hirano T, Ebina A, Konno K. Mucociliary clearance mechanism in smoking and nonsmoking
normal subjects. J Nucl Med, 1984, 25, 352-359.
29. Nieminen MM, Lahdensuo A, Kellomaeki L, Karvonen
J, Muittari A. - Methacholine bronchial challenge using a
dosimeter with controlled tidal breathing. Thorax, 1988, 43,
896-900.
30. Moilanen E, Alanko J, Seppiilii E, Vapaatalo H. Effects of antirheumatic drugs on leukotriene B 4 and
prostanoid synthesis in human polymorphonuclear leukocytes
in vitro. Agents Actions, 1988, 24, 387-394.
31. Goldstein DS, Feurstein G, Izzo JL Jr, Kopin IJ, Keiser
HR II. - Validity and reliability of liquid chromatography
with electrochemical detection for plasma levels of
norepinephrine and epinephrine in man. Life Sci, 1981, 28,
467-475.
32. Altman DG, Bland JM. - Measurements in medicine:
the analysis of method comparison studies. Statistician, 1983,
32, 307-317.
33. Stahlhofen W, Gebhart J, Heyder J. - Biological
559
variability of regional deposition of aerosol particles in
human respiratory tract. Am Ind Hyg Assoc J, 1981, 42,
348-352.
34. Yeates DB, Pill BR, Spector DM, Karron GA, Albert
RE. - Co-ordination of mucociliary transport in human
trachea and intra-pulmonary airways. J Appl Physiol: Respirat
Environ Exercise Physiol, 1981, 51, 1057-1064.
35. Chan TL, Lippman M. - Experimental measurements
and empirical modelling of the regional deposition of
inhaled particles in humans. Am Ind Hyg Assoc J, 1980, 41,
399-408.
36. Agnew JE, Sutton P, Pavia D, Clarke SW.
Radioaerosol assessment of mucociliary clearance: towards
definition of a normal range. Br J Radio/, 1986, 59, 147-151.
37. Eiser NM, Kerrebijn KF, Quanjer PH. - Guidelines for
standardization of bronchial challenges with (nonspecific)
bronchoconstricting agents. Bull Eur Physiopathol Respir,
1983, 19, 495-514.
38. Yeates DB, Gerrity TR, Garrard CS. - Particle deposition and clearance in the bronchial tree. Ann Biomed Eng,
1981, 9, 577-592.
39. Puchelle E, Zahm JM, Bertrand A. - The influence of
age on bronchial mucociliary transport. Scand J Respir Dis,
1979, 60, 307-313.
40. Del Donno M, Pavia D, Agnew JE, Lopez-Vidriero MT,
Clarke SW. - Variability and reproducibility in the measurement of tracheobroncliial clearance in healthy subjects and
patients with different obstructive lung diseases. Eur Respir
J, 1988, 1, 613-620.
41. Wirtz H, Lang M, Sannwald U, Hahn H. - Mechanism
of platelet-activating factor (PAF)-induced secretion of
mucus from tracheal submucosal glands in ferret. Fed Proc,
1986, 45, 418.
42. Steiger J, Bray MA, Subramanian N. - Plateletactivating factor (PAF) is a potent stimulator of porcine
tracheal fluid secretion in vitro. Eur J Pharmaco/, 1987, 142,
367-372.
43. Adler KB, Schwarz JE, Andersson WH, Welton AF. Platelet-activating factor stimulates secretion of mucin by
explants of rodent airways in organ culture. Exp Lung Res,
1987, 13, 25-43.
44. Seybold ZV, Mariassy AT, Stroh S, Kim CS, Gazeroglu
H, Wanner A. - Mucociliary interaction in vitro: effects of
physiological and inflammatory stimuli. J Appl Physiol, 1990,
68, 1421-1426.
45. O'Flaherty JT, Wykle RL, Miller H, Lewis JC, Waite
M, Bass DA, McCall CE, Be Chatelet LR. - 1-0-alkyl-2acetyl-sn-glyceryl-3-phosphorylcholines: novel class of neutrophil stimulants. Am J Pathol, 1981, 103, 70-79.
46. Hartung HP, Parnham MJ, Winkelmann J, Engelberger
W, Hadding U. - Platelet-activating factor (PAF) induces
the oxidative burst in macrophages. Int J lmmunopharmacol,
1983, 5, 115-121.
47. Wallace JL, MacNaughton WK. - Gastrointestinal
damage induced by platelet-activating factor: role of
leukotrienes. Eur J Pharmacol, 1988, 151, 43-50.
48. Parker CW. - Lipid mediators produced through the
lipoxygenase pathway. Ann Rev lmmunol, 1987, 5, 65-84.
49. Gimbrone MA, Brock AF, Schafer AI. - Leukotriene
B 4 stimulates polymorphonuclear leukocyte adhesion to
cultured vascular endothelial cells. J Clin Invest, 1984, 74,
1552-1555.
50. Halonen M, Palmer JD, Lohman C, McManus LM,
Pinkard RN. - Differential effects of platelet depletion on
the physiologic alterations of IgE anaphylaxis and acetyl ether
phosphorylcholine infusion in the rabbit. Am Rev Respir Dis,
1981, 124, 416-421.
560
M.M. NIEMINEN ET AL.
51. Schellenberg RR, Walker B, Snyder F. - Plateletdependent contraction of human bronchus by plateletactivating factor. J Allergy Clin Immunol, 1983, 71, 145-150.
52. Inarrea P, Gomez-Cambronero J, Nieto M, SanchezCrespo M. - Characteristics of the binding of plateletactivating factor to platelets of different animal species. Eur
J Pharmacal, 1984, 105, 309-315.
53. Svensson J, Hamberg M, Samuelsson B. - Prostaglandin
endoperoxides. IX. Characterization of rabbit aorta contracting substance (RCS) from guinea-pig lung and human
platelets. Acta Physio/ Scand, 1975, 94, 222-228.
54. Robinson C, Holgate ST. - The generation of
prostaglandins by human lung and their effects on airway
function in man. B11ll Eur Physiopatho/ Respir, 1986, 22
(Suppl. 7), 81-90.
55. Curzen N, Rafferty P, Holgate ST. - Cyclo-oxygenase
inhibition and HI-histamine receptor antagonism alone and
in combination on allergen-induced bronchoconstriction in
man. Thorax, 1987, 42, 946-952.
56. Roberts NM, McMusker M, Chung KF, Barnes PJ. Effect of a PAF antagonist, BN52063, on PAF-induced
bronchoconstriction in normal subjects. Br J Clin Pharmacal,
1988, 26, 73-77.
57. Anderson GP, White HL, Fennessy MR. - Increased
airways responsiveness to histamine induced by plateletactivating factor in the guinea-pig: possible role of
lipoxygenase metabolites. Agents Actions, 1988, 24, 1-7.
58. Sirois P, Roy S, Borgeat P. - The lung parenchyma!
strip as a sensitive assay for leukotriene B4• Prostaglandins
Med, 1981, 6, 153-159.
59. Christman BW, Portes DK, King GA, Leffers PL,
Snapper JR. - Synthetic platelet-activating factor alters pulmonary haemodynamics, lung mechanics and fluid/solute
exchange in awake sheep: role of platelets and granulocytes
and effects of synthetic platelet-activating factor on airway
reactivity. Am Rev Respir Dis, 1987, 133, A174.
60. Chung KF, Aizawa H, Becker AB, Frick 0, Gold WM,
Nadel JA. - Inhibition of antigen-induced airway
hyperresponsiveness by a thromboxane synthetase inhibitor
(OKY-046) in allergic dogs. Am Rev Respir Dis, 1986, 134,
258-261.
61. Fujimura M, Sasaki F, Nakatsumi Y, Takahashi Y,
Hifumi S, Taga K, Mifune J, Tanaka T, Matsuda T. - Effects
of a thromboxane synthetase inhibitor (OKY-046) and a
lipoxygenase inhibitor (AA-861) on bronchial responsiveness
to acetylcholine in asthmatic subjects. Thorax, 1986, 41,
955-959.
62. Hopp RJ, Bewtra AK, Agrawal DK, Townley RG. Effect of platelet-activating factor inhalation on nonspecific
bronchial reactivity in man. Chest, 1989, 96, 1070-1072.
63. Denjean A, Arnoux B, Masse R, Lockhart A, Benveniste
J. - Acute effects of intratracheal administration of plateletactivating factor in baboons. J App/ Physio/: Respirat Environ
Exercise Physiol, 1983, 55, 799-804.
64. Ind PW, Barnes PJ. -Adrenergic control of airways in
asthma. In: Asthma: basic mechanisms and clinical management. P.J. Barnes, I.W. Rodger, N.C. Thomson eds,
Academic Press, London, 1988, pp. 357-380.
65. Block LH, Abraham WM, Groscurth P, Qiao BY,
Perruchoud AP.- Platelet-activating factor (PAF)-dependent
biochemical, morphologic, and physiologic responses of
human platelets: demonstration of translocation of protein
kinase C associated with protein phosphorylation. Am J Respir
Cell Mol Bioi, 1989, 1, 277-278.
66. Pinkard RN, Ludwig JC, McManus LM. - Plateletactivating factors. In: Inflammation: basic mechanisms and
clinical correlates. J.l. Gallin, I.M. Goldstein, R. Snyderman
eds, Raven Press Ltd, New York, 1988, pp. 139-167.
67. Lefort J, Rotilio D, Vargaftig BB. - The plateletindependent release of thromboxane ~ by PAF-acether for
guinea-pig lungs involves mechanisms distinct from those
for leukotriene C, and bradykinin. Br J Pharmacol, 1984, 82,
525-530.
Le facteur activateur des plaquettes freine le transport
muco-ciliaire et augmente le leucotri~ne B 4 p/asmatique chez
l'homme. M.M. Nieminen, E.K. Moilanen, J -E.J. Nyholm, M.O.
Koskinen, J.l. Karvonen, T.J. Metsii-Ketelti, H. Vapaatalo.
RESUME: Nous avons apprecie les effets du facteur activateur
des p l aquettes (PAF) inhale sur la clearance
tracbeo-bronchique, la fonction pulmonaire et la pression
sanguine, chez 7 volontaires sains non fumeurs. Apres inhalation de 500 !A& de PAF, la retention du radio-aerosol
dans les voies aeriennes ciliees mesuree a la 4e heure est de
80% superieure a celle de l'enregistrement de contr~le, et la
clearance est reduite de 33% (p<0.005). L' acide
acetylsalicylique (1000 mg) n'a pas d'effet sur le freinage de
clearance tracheo-bronchique induit par le PAF. L'inhalation
de PAF provoque egalement une obstruction bronchique aigue,
en diminuant le VEMS de 16% (p<O.Ol), diminution fortement
attenuee par l'acide acetylsalicylique. La chute de pression
systolique et diastolique apres PAF (p<0.01) n'est pas
influencee par l'acide acetylsalicylique. Le taux de
noradrenaline plasmatique, mais non celui d'adrenaline,
augmente significativement apres inhalation de PAF (p<0.01).
Le leucotriene B4 plasmatique (LTB..) est augmente dans les
echantillons sanguins pris 20 minutes apres inhalation de PAF
(avec et sans acide acetylsalicylique: moyennes 240 et 299
pg/ml respectivement) par comparaison aux valeurs de base
(144 et 166 pg/ml) et aux valeurs obtenues 60 minutes apres
la provocation (133 et 178 pg/ml; p<0.05, p<0.01
respectivement). Seuls 3 des 7 sujets ont montre une
hyperreactivite bronchique a la methacholine, lors d'une
mesure realisee 24 h apres !'inhalation de PAF. No us
concluons que !'inhalation de PAF reduit le transport mucociliaire chez l'homme. Le phenomene semble independant des
produits du type cyclo-oxygenase dus au metabolisme de
l'acide arachidonique. L'on suggere toutefois que ces
autacoi'des contribuent a !'obstruction bronchique aigue apres
inhalation de PAF. En outre, !'inhalation de PAF entralne une
augmentation transitoire du LTB4 plasmatique, qui pourrait
favoriser par ailleurs !'inflammation des voies aeriennes induite
par le PAF.
Eur Respir J., I991, 4, 55I-560.