Asbestosis and slllcosis are chronic, fibrosing lung diseases due to prolonged. Inhalation of asbestos fibers or silica particles. However, little is known about the ...
Journal
of Leukocyte
Biology
47:129-134
Inhibition of Alveolar Macrophage Cytotoxicity Asbestos: Possible Role of Prostaglandins Elyse
Bissonnette,
Brigitte Immunology
Carr#{233}, Claire Division,
Dubois,
and
Marek
Faculty of Medicine, University Sherbrooke, Qu#{233}bec,Canada
(1990)
by
Rola-Pleszczynski
of Sherbrooke,
Asbestosis and slllcosis are chronic, fibrosing lung diseases due to prolonged Inhalation of asbestos fibers or silica particles. However, little is known about the implication of these toxic dusts on cell-mediated cytotoxicity. Among the first types of cells that are in contact with the dusts are the alveolar macrophages (AM). We studied the effect of different concentrations of UICC chrysotile asbestos and silica on 18-h cytotoxlclty of AM against tumor necrosis factor (TNF)-resistant P8i 5 target cells or TNF-sensltlve L929 target cells. Rat AM, obtained by bronchoalveolar lavage, were incubated for 2 h with 20, 50, or 100 Lg/ml chrysotile or silica before the addition of target cells. AM cytotoxiclty was significantly Inhibited at > 20 .tg/ml of chrysotile. In contrast, silica did not Inhibit AM-mediated cytotoxlcity at any concentration used. Asbestos, but not silica, caused significant production of PGE2 by macrophages and target cells. Addition of the cycleoxygenase inhibitor indomethacin to our system abolished all inhibitIon by asbestos. These results suggest that the inhibition of AM-mediated cytotoxicity by chrysotlle was caused by prostaglandins, and that fibrogenic particles differ in their capacity to modulate AM function. Key words:
silica,
tumor
necrosis
factor,
INTRODUCTION
MATERIALS
Prostaglandins
(PG),
a group
fatty acids, were discovered half a century ago [5,29]. noted that
the presence the
lung
was
of PG not
of 20-carbon
in the
only
the
lung. major
and Goldblatt and Vane [22]
Later
it was
organ
for
been
shown
phages (AM)
to release PG [ 1 2,26,27] represent the best defense
that
asbestos
fibers
can
shown
synthesis
stimulate
. Alveolar of the
PG PG and has
macro-
macrophages organism against
air pollutants and bacterial addition, macrophages have
and viral infection been shown to be
[9] . In tumori-
cidal
target
1],
various
may also represent against neoplasia. We particles
report
here
tumor an
important
cells
[3,20,3
defense
and
Wistar
rats
weighing
200
to
250
g were
pur-
Inc. (St. Constant, from a pathogen-
free
barriers.
colony
kept
and
in the
shipped
animal
behind
facility
filter
of our
institute
They for two
were weeks
before use.
Cell
Lines
P815 mastocytoma sion culture in RPM! 10% heat-inactivated
cells 1640 foetal
were maintained as suspenmedium supplemented with bovine serum (complete me-
dium). The murine L929 fibroblast cell line was grown as adherent cell monolayers in Earle’s complete medium and was passaged by trypsinization.
Reagents the effects
on rat AM
Wiley-Liss,
Male
chased from Charles River Canada Qu#{233}bec). These animals were derived
mechanism
cytotoxicity,
of asbestos using
fibers two
and kinds
silica of tar-
gets: the tumor necrosis factor (TNF)-sensitive L929 cell line and the TNF-resistant P8 1 5 mastocytoma. We found an inhibition of rat AM cytotoxicity by asbestos fibers but not by silica particles. This inhibition seems to be principally due to PGE2 production.
© 1990
AND METHODS
Rats
unsaturated
by von Euler In 1969, Piper
of PG but that it could also take up and catabolize released into the circulation from other organs [17]. are not stored in the lung but synthesized de novo released in response to a variety of stimuli [ 1 7] . It
against
pneumoconiosls
Inc.
Chrysotile preparation) Received
A asbestos fibers and min-U-Sil-5
March
Reprint
requests:
Faculty
of
North.
22.
Medicine,
Sherbrooke.
1989;
Marek
accepted
(UICC standard reference particles (Pennsylvania June
12,
Rola-Pleszczynski University
Qu#{233}bec, Canada
of
.
Sherbrooke. J IH
5N4.
1989. Immunology 3(X)I
Division. 12th
Avenue
130
Bissonnette
Glass
Sand
dave,
Co.
,
et al.
Pittsburgh,
suspended
in
PA)
sterile
were
sterilized
in auto-
phosphate-buffered
(PBS), sonicated, and used indicated. Asbestos fibers
saline
at different concentrations were quite homogeneous,
Sigma
Chemical
(St.
Louis,
on
Briefly, as
92% being less than 0.25 p.m in diameter and 20 jim in length. Silica particles were 5 pm in diameter. Indomethacin, a cyclo-oxygenase inhibitor, was purchased from
assay
MO).
(Na51CrO4; three times,
Lavage
500
New and
(containing
assay. Dilution standard curve
Haver-Lokhart, Mississauga, Canada), and bronchoalveolar lavage was performed as described elsewhere [ 1 6]. Briefly the abdominal aorta was severed and the trachea was canulated. The lungs were lavaged with a total vol-
Prostaglandin
ume of 60 ml PBS containing aliquots. After recovery, each fluid and was
was
added
centrifuged washed
complete
to 20
ml
0.002 M EDTA in 6-8 ml 30 ml aliquot ofthe lavage
of Earle’s
in 50 ml conical twice and finally
medium
containing
complete
10%
fetal
proximately 20 lected from each specific esterase
Cytotoxic
X l0
wells
and
were
incubated
for
bovine
cells (determined
this incubation, different were added and the cells
distributed
concentrations were incubated
test
and Ap-
were colby non-
into
micro-
At the end
of
oftoxic particles at 37#{176}C for 2 h.
Cytotoxic activity of macrophages was measured by using a 5tCr-release microassay. Target cells were labeled with 5tCr (Na51CrO4; New England Nuclear, Boston, MA) during 2 h, washed rophages at a concentration
three of
an effector to target cells wells contained medium
(E:T) alone
toxicity
measuring
was
18-h
culture
pressed lowing
where
assayed supernatants.
as percent formula: . . % specific RE
by
times, and added 5 x l0 cells/well, ratio of or toxic
Cytotoxic
specific
-
.
Cr release cpm
=
in
the
phages; RS, cpm due to spontaneous cpm due to total releasable 51Cr.
RT
of
for
in culture determined
by
in each
TNF
were compared units [25].
paired
to the
macrophages I h. After this
asbestos without
(20, 50, indomethacin
and
time,
all concentrations non-significant hibitor The
used (Fig. in the presence
of PG synthesis. same experiments
particles
(Fig.
2),
any concentration Neither asbestos indomethacin,
but
t-
added with or then incubated
AM
(less
than
no significant
2.6%
5tCr
particles
we observed 30% with by itself
the
observed
silica
AM
In addi-
as latex
beads
cytotoxicity
of
with of the
trypan blue cytotoxicity
of chrysotile At the highest a 20%
release).
such
shown). AM viability was assessed and 51Cr release at the end in the presence indomethacin.
tos and explain
with
of on
significantly
assays, without
out
at
change
(data not Finally, exclusion
carried
had
became an in-
used, on AM-mediated cytotoxicity. nor silica, in the presence or absence had any significant cytotoxic effect
not
cells
cells, P8 15. inhibited at
effect,
does
supernatants of bronchoalveoin a biological 5tCr release
an-
1). This inhibition of indomethacin,
were silica
of inert
RT,
were were
for 2 h at 37#{176}C before the addition of target AM-mediated cytotoxicity was significantly
presence
and
were Student’s
were adhered in microtiter different concentrations of
100 ig/ml) ( 1 i.M). Cells
target
macro-
using
Effect of Toxic Particles on AM Cytotoxicity Against TNF-Resistant Target Cells
the
of
by
data.
P815
100,
of experiments
significance
tion,
Assay
TNF activity lar cells was
groups
statistical
ex-
release;
be inhibited
RESULTS
particles,
TNF
between
for
fol-
X
can
measured
Analysis
the
RS
51Cr
2 h, washed medium con-
measured by the commercial kit (Seragen, Advanced MagMA).
was
by using
-
was
activity
presence
that
curves of samples to calculate TNF
content
RE-RS
represents
units was
5tCr
51Cr-release
SI
to macgiving
100: 1 Alternate particles. Cyto-
the
cells.
with
Assay
Statistical alyzed
serum.
chamber, exclusion.
1 h to adhere.
10 TNF
Quantity of PGE2 (3H) Radio-immunoassay netics Inc. , Cambridge,
Alveolar wells for
macrophages
target
labeled
Nuclear) during in complete
anti-TNF)
Differences
cell pellet in Earle’s
Assay
Five titer
x 106 bronchoalveolar rat, with 98% AM staining).
were
medium
tubes. The resuspended
Cells were counted in a hemocytometer viability was determined by trypan blue
L929
fibroblasts
England resuspended
U of murine
Animals were anesthetized by intramuscular injection ml/kg) of a 6.5: 1 mixture of ketamine ( 100 mg/ml) and xylazine (2 mg/ml; rogar/STB, Montreal, and (0.5
D-treated
L929
taming 1 pg/m1 actinomycin D. Target cells were added to six different dilutions of TNF sample in 96-well microtiter plates. After 18 h of incubation, the plates were centrifuged and 5tCr release measured. One standard sample
Bronchoalveolar
actinomycin mouse
AM
or silica, with concentration
mortality
with
asbes-
silica. This mortality, however, fails the inhibition of cytotoxic activity
with
asbestos
(and
not
with
the
or of
equally
to of
Asbestos
Inhibits
Alveolar
Macrophage
131
Cytotoxicity
20
U
control
asbestos
0
shca
15
z
U
0
10
0
0 U
5
0
20
40
60
pg/mI
80
Medium
100
asbestos
Fig. 1 . Effect of asbestos fibers on rat AM cytotoxicity. AM are Incubated with different concentrations of asbestos in presence or absence of Indomethacin (106M) 2 h before addition of P815 target cells. A significant inhibition (P < 0.05) is observed at 20, 50, and 100 ig/ml of asbestos without indomethacin. Data represent means ± SEM of six separate experiments.
Fig. 3. Stimulation by toxic particles of TNF production by AM. An augmentation was seen at 50 .tg/mI of asbestos and silica (P < 0.05). Furthermore, indomethacin (10#{176}M)significantly (P < 0.01) enhanced TNF production Induced by asbestos. Data represent means ± SEM of four separate experiments.
Effect of Asbestos and Silica Against TNF-Sensitive Target Asbestos
fibers
dust, tion,
and
silica
on AM Cytotoxicity Cells
particles
can
there was significant which was higher
silica particles. asbestos seems
augmentation with asbestos
0 0
But the inhibition of AM cytotoxicity to be higher than stimulation of
asbestos fibers. Addition this inhibition. Neither nificant cytotoxic effect 51Cr release).
U
Effect
of Alveolar
Prostaglandin 0
20
40
60
80
1
00
inhibition verify
pg/mI
silica
Fig. 2. Effect of sIlIca particles on rat AM cytotoxicity against P815 cells. No significant change in cytotoxicity Is observed. Data represent means ± SEM of six separate experiments.
toxic silica), AM resulted activity (29
since parallel experiments using 20% fewer in a non-significant decrease in cytotoxic ± 3.3% vs. 33.5 ± 3.9%).
release toxicity.
the
of TNF producfibers than with
production. Figure 4 shows a significant AM cytotoxicity against L929 target cells
U
stimulate
ofTNF by mouse AM 121. We observed simwith rat AM (Fig. 3). At 50 ig/m1 of toxic
production ilar results
>.
Indo
of AM whether
inhibition in presence
of of
of indomethacin can reverse asbestos nor silica had any sigon L929 target cells (< 1.8%
Macrophages production
Supernatants
seems
cytotoxicity asbestos
by TNF
to be important
by asbestos.
We
fibers
could
stimulate
soluble mediators that Alveolar macrophages
would were
inhibit incubated
in the wanted AM AM
tions of asbestos AM cytotoxicity.
(50 This
to
cytoat 37#{176}C
with different concentrations of asbestos fibers during h. At the end of this incubation, cells were centrifuged and cell-free supernatants, containing no fibers, removed and added at 50% v/v to 5 x l0 assay against P815 cells. Figure supernatants from AM incubated
to
AM for cytotoxicity 5 shows the results: with high concentra-
p.g/ml and 100 ig/ml) inhibited inhibition became non-significant
2
132
Bissonnette
et al.
0
Medium
...
Indo
20 >.
>,
0
U
x
0
0 0
0 U
0
10
0 20
40
60
pg/mI
80
100
0
120
20
40
ig/ml
asbestos
Fig. 4. Dose-dependent inhibitory effect AM cytotoxicity against the TNF-sensitive nificant Inhibition (P < 0.01) is observed at of asbestos without indomethacin. Data SEM of five separate experiments.
60
of asbestos fibers on cell line, L929. A sig20, 50, and 100 ig/ml represent means ±
80
100
asbestos
Fig. 6. Inhibitory effect of supernatant from asbestospretreated mastocytoma P815 on AM cytotoxicity. A significant inhibition (P < 0.01) is seen at all asbestos concentrations used without indomethacin. Data represent means ± SEM of four separate experiments.
incubated
with
asbestos
during
2 h.
Cell-free
tions when
30 >‘
used. AM cytotoxicity PG production was
ing P815 pretreatment. AM cytotoxicity when
U K 0
0
20
not
U
was inhibited Silica added
particles did not affect the to P8 15 target cells (data
of PGE2 Production
In view of our findings verse the asbestos-induced
10
not affected, however, by indomethacin dur-
shown).
Measure
that indomethacin inhibition of AM
activity, we measured PGE, production by bated with different concentrations of asbestos 20
40
60
pg/mI
80
120
100
asbestos
FIg. 5. Effect of supernatants from asbestos-pretreated AM on fresh AM cytotoxicity against P81 5 cells. The inhibition is significant (P < 0.05) at 50 and 100 .tg/ml of asbestos without indomethacin. Data represent means ± SEM of four separate experiments.
when
superna-
tants were added to AM for the cytotoxic assay against P815 cells. Figure 6 shows the results: a strong inhibition of cytotoxicity was observed at all asbestos concentra-
40
PG
synthesis
was
inhibited
during
AM
preincuba-
silica
particles
suits.
High
during
PGE2
production
( 1 i.M)
inhibited
asbestos.
We
(Table duction sured target sults
20 h. Table
concentrations than
of did
PGE2 made
2). Asbestos, but not silica, by P815 cells and L929 PGE, production cells, and toxic (data not shown).
re-
more
Indomethacin
except
experiments
the
stimulated
particles.
production
similar
AM incufibers or
1 summarizes
asbestos
silica
could recytotoxic
at 100 with
target
g/ml cells
stimulated PGE2 procells. When we mea-
in supernatants of particles, we observed
mixed AM, similar re-
tion.
Effect
of Supernatants
Finally, target
cell
we verified line
P815.
of P81 5 Target the effect The
of asbestos
mastocytoma
DISCUSSION
Cells fibers P815
cells
on the were
A high been
incidence
observed
of pleuro-pulmonary
in asbestosis
neoplasms
has
[ 1 ,7 , 1 3 , 18 , 19] , but no such
Asbestos TABLE 1 . or Silica
PG Production
by AM Stimulated
Particle
Asbestos Asbestos
With
concentratio
Asbestos
The
50
1(X)
0
1
ND’
ND
ND
ND
ND
ND
59.77
ND
ND
37.30
55.0
44.29
ND
ND
ND
ND
ND
147.8
4341h
I 15.80
+
lndomethacin
( I riM)
Silica Silica
+
ND
stimulation
( 1 p.gM) not
=
detectable.
5pg/ml.
Another is the
2. PG Production
by Target
0 Medium
ND
48.l8
P815
+
Indomethacin
ND
ND
L929
+
Medium
ND
L929
+
Indomethacin
ND
not
=
Silica
20
+
(p.g/ml)
fully
50 ND
with
pulmonary
ND
ND
ND
firm
this
ND
In conclusion, icity by stimulation
ND
-
ND
-
seen
have
with
silica
cytotoxic
particles
activity
[8].
against
Alveolar
tumor
fore,
initiated
the
silica
particles
and
by the stimulated
present
work
could
mast
to verify
modulate
cytotoxicity cytotoxicity
lated
including
many
if asbestos
AM
cytotoxicity, incidence
This
cytotoxic-
work
Research
meaby
substances,
neuropeptides
and
by asbestos. can be modu-
of adenylate of cytokine The modulation
affect icity
cytokines
hormones
cyclase [23] and production [14]. of TNF production
AM cytotoxicity. against the two
resistant
and
reversed
by the
cells
would
a finding of pulmonary
was
supported
Council
[26,
[1 1] and
ical
27,
Asbestos types of
TNF-sensitive). addition
This
G.
be
E. and
Possible 1989. 3. 4.
did
could
in both
that
rat AM cytotoxby different cell
mast cells, fibrorat AM cytotoxicity. have different effects may be relevant cancers between
cases.
role
to the asbes-
from
the
Medical
by studentships
I.J.
therapy.
Gagnon,
L.
(E.B.,
5.
Goldblatt, Chem.
6.
necrosis
Res.
L.G.
MW. (Lond.)
Gupta.
R.K.
Mast
Arch.
Pathol.
Lab.
4714.
Dubois,
,
52, cell Med.
I
silicosis:
A biologic
approach
329.
,
Rola-Pleszczynski.
tumor
cytotoxic
necrosis
Actions
26,
in a seminal
factor 141 fluid.
,
and
1989. J. Soc.
1933. in prostate 302,
to M.
Augmented
Agents
variations 89,
inflam-
and
13.
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1981.
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of
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be
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of workers
fibrosis
cancer
activity
not
AM cytotoxused (TNF-
inhibition
to con-
Scholarship (MR-P.) from the en Sante du Qu#{233}bec. The authors Gingras and Sylvie Turcotte k)r Jacques for preparation of the
as having
Bissonnette, mation
inhibi-
by asbestos
stim-
necessary
by a grant
of Canada
Mortality
panels
Leukotrienes
inhibited target cells
of indomethacin
2.
arachi-
transcriptional
asbestos
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ACKNOWLEDGMENTS
but not by silica particles or latex beads. that PGE2 production could be a major
cause of inhibition of AM Monocyte or macrophage by
In addi-
.
PG. which will inhibit AM cells. Further experiments
asbestos fibers inhibit of PGE2 production
manuscript.
3 1],
line. large
hypothesis.
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29,
[ 1 5]
metabolites
It is possible
We found an inhibition of AM cytotoxicity by asbestos fibers but not by silica particles or latex beads. This inhibition could be prevented by the addition of indo-
fibers, appeared
by asbestos,
mastocytoma P815 cell mast cells secrete
acid
C.D.) and a Research Fonds de la Recherche wish to thank Denis assistance and Carole
asbestos It thus
studies
production
tosis and silicosis.
are among the first cell populations in contact inhaled toxic environmental particles. There-
we
our
cells
and they with the fibers ity.
from of PGE2
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was
emerged a stimulation,
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20
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seemed
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ND
detectable.
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50
hpg/ml. cnot
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ND
by asbestos
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P815
133
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