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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.

and

substance 1056.

Pulmonary

1981.

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130,

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activation:

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mcd-

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enhanced

peroxide

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and

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by pneumoconiosis J. Ind.

Rola-Pleszczynski.

tumor

and and

Br.

in a murine

Macrophages ,

certified

asbestosis.

and

,

of

Fidler,

hydrogen

be

and

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.

methacin. In view of this, PGE-, production was sured in AM supernatants and found to be stimulated

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

populations (alveolar macrophages, blasts). Silica particles do not affect These two inhalated toxic particles on AM different

was

emerged a stimulation,

cells to release against tumor

20

done.

macrophages

seemed

explain the inhibition of AM cytotoxicity

fibers

observed

elucidated.

ulates mast cytotoxicity

ND

detectable.

correlation

that

of arachidonic

50

hpg/ml. cnot

We

189.31 192.83

ND

by asbestos

This could by asbestos point

of PGE2 production It is known that

is not (ig/ml)

P815

133

tion, mast cell hyperplasia is observed in chronic inflammation and fibrosis [6, 10,30], but the role of these cells

Cells

Asbestos

production

by asbestos

cells.

Cytotoxicity

than the stimulation of TNF produccould stimulate both AM and L929

important

modulation

amounts

TABLE

of PGE2

cells to produce PGE2. rather than stimulation against L929 cells.

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