Polish Journal o f Occupational Medicine and Environmental Health Vol. 4, N o. 2, 115 —125, 1991
REVIEW PAPERS
MACROPHAGE ACTIVITY IN ASBESTOS RELATED
DISEASES
M A C IEJ TARKOWSKI and PAW EŁ GÓRSKI
Clinic o f Occupational D iseases, Institute of Occupational Medicine, Lodz, Poland
Key words: M acrophage, Asbestos
Abstract. This p a p e r indicates som e im m unological aspects o f asbestos-related diseases and
especially concerns th e activity of m acrophages — cells of im m unological surveillance.
M acrophages estab lish a very im p o rta n t p o p u latio n of cells w hich initiate or suppress specific
im m une response; th ey are responsible for effective T-cell activation, express a n titu m o u r
activity. The process o f lung fibrosis generated by the in h alatio n and deposition of asbestos
fibres is also closely related to m acrophage activity. An open question w hich is still to be
resolved concerns asbestos-induced fibrosis; it m ay arise as a consequence of tissue injury and
re p air or change collagen synthesis. A nother question is, to w hat extent m acrophages m ay be
protective cells a n d w hen they becom e undesirable? Since their overstim ulation o r dam age in
the case of chronic exposure to asbestos d u st m ay be the reason of the increased release of
inflam m atory m ed iato rs, reactive oxygen interm ediates w hich m ay in tu rn cause tissue injury,
fibrosis or, in final effect, cancer. If so, we could then say th a t lung response (expressed by e.g.
alveolar m acrophage activity) to chem ical insult m ay cause fu rth er dam age to this tissue.
IN T R O D U C T IO N
It is known th a t asbestos fibres are recognized as hazardous pollutants in
the occupational an d genera] com m unity environm ent. Inhaled asbestos fibres
cause:
a) Asbestosis — interstitial fibrosis of the lung;
b) Cancer of th e lung;
c) M esotheliom a of the pleura and peritoneum .
Address reprint requests to M . T arkow ski, Clinic of O ccu p atio n al D iseases, In stitu te of
O ccupational M edicine, P .O . Box 199, 90-950 Lodz, Poland.
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M . Tarkowski and P. Górski
The harm ful action of asbestos fibres involves pathological reactions
w hose final effect is well know n only on pathom orphological bases. However,
the process which lead to these m orphological changes are still unclear, they
involve m any m olecular an d cellular pathological reactions, including, am ong
others, im m unological response. The im p o rtan t role which m acrophages fulfil
in the im m une system an d in asbestos-related diseases is unqestionable. O ur
knowledge, how ever, is still insufficient to correlate the im m unological activity
of m acrophages with the harm ful effect of asbestos dust.
M acrophages, as cells which first encounter inhaled m ineral fibers, beside
their prim itive phagocytositic function, are im p o rta n t in:
1. antigen (Ag) presentation and T-cell activation;
2. differentiation and selection of certain cell populations;
3. suppressive reactions; and
4. an ti-tu m o u r defense mechanisms.
Since alveolar m acrophages (AM) fulfil such a responsible role in th.
defense m echanism s of the host against invading factors and establish the first
line of im m une cells against asbestos dust, their activity must be the subject of
intensive studies. T heir im paired activity m ay be reflected in distem per
regulation of im m une response and finally dim inished o r abandoned
tum ouricidal activity.
Macrophages and T-cell activation
M acrophages, am ong the o th er so-called accessory cells, establish an
im p o rtan t p o p u latio n of cells which initiate specific im m une responses or
indirectly suppress it. The process of im m une response to specific Ag requires
the presence of cells th at exhibit class II o f the m ajor histocom patibility
com plex (M H C ) m olecules, produce an accessory signal (interleukin-1 (IL-1),
process antigen an d present it to specific T-lym phocytes, thus activating them.
All these requirem ents are fulfilled by m acrophages. The process of Ag
p resentation seems to be regulated through com plex m echanism s and the final
effect (im m une response o r unresponsiveness) depends on:
a) The presence of m acrophages expressing II M H C molecules.
They m ay coexist in the sam e tissue w ith m acrophages which do no t
express II M H C , therefore, they’ are no t able to activate T-lym phocytes (21).
b) The com peting Ag for M H C II m olecules expressed by m acrophages.
T he process of Ag presentation involves its specific recognition through
T-cell receptors which tolerate 10 —20% of single am inoacid substitutions in
com plex Ag and M H C molecules expressed by accessory cells.
H ow ever, the M H C molecules in Ag presenting cells are to leran t in
80 —90% of single am inoacid substitutions w h a t makes possible th a t com ­
peting Ag w ould bind to these m olecules, inhibiting the induction o f specific
T-cells (2).
c)The existence of co-stim ulators and specific T-cell subpopulations.
Some T-cells m ay be activated if an ap p ro p ria te co-signal is used (not IL-1
only) (30).
Macrophage in asbestos diseases
117
d) The presence of suppressor of T-lym phocytes.
e) The place where presentation takes place, since it is likely th a t there
exist some “privileged” sites as the central nervous system or the eye where
specialized p o p u latio n s of m acrophages m ay tem per o r prevent im m une
responses (21).
1) C ytokines which enhance or dim inish the process of T-cell activation.
However, the process of T-cell activation m ediated by m acrophages in
hum ans exposed to asbestos fibres is poorly know n, it could be predicted th at
this complex m echanism m ay be easily destroyed by asbestos fibres, causing
pathologic reactions. It m ay be reflected in e.g. dim inished p ro d u ctio n of the
m acrophage inhibition factor released by activated T-lym phocytes (13).
There is n o strict confidence as to which type of fibre is the m ost
hazardous, it is, however, accepted th a t their length is of great significance.
F ro m the studies of Allison et al. (3) it is know n th a t m acrophages are ingested
by phagocytosis fibres n o t exceeding 5 (im, and they refer as to the sh o rt fibres,
whereas long fibres, over 25 ^m , are ingested only partially and the p o rtio n of
them rem ains outside the cell. These long fibres are m ainly suspected of m any
undesired effects as: leak of tw o lysosom al enzymes (beta-glucuronidase,
beta-galactosidase) an d cytoplasm ic enzyme; lactic acid dehydrogenase (5,7).
The increased secretion of these enzymes m ay be a sign of sub-lethal cell
dam age which was confirm ed by Beck at al. (4) who show ed th a t phagocytosis
of long fibres was accom panied w ith increased m etabolic energy an d localized
dam age to the cell. T he harm ful activity of sh o rt fibres, however, is still no t
ruled out. F ro m the studies of Yeager et al. (32) we know th a t naturally
occurring short fibres (RG144) are m ore cytotoxic to m acrophages th a n longer
ones. The process of Ag presentation m ediated by m acrophages m ay be
disregulated or com pletely abolished regardless of fibre type and length. Ag to
be present to specific T-cell m ust be digested and then fixed to the cell surface.
Since asbestos fibres are in m ost cases cytotoxic to m acrophages they will no t
allow presentation to take place. T he process o f m acrophage destruction m ay
in effect cause injury of contiguous tissue th ro u g h inflam m atory reactions
which m ay be the cause of the first stage in cancerogenesis; initiation.
Tumouricidal activity
T um ouricidal activity of m acrophages is w ell-docum ented an d can be
m ediated by a direct cytotoxic effect o r in an indirect way in antibody-dependent cell-m ediated cytotoxicity (AD CC) m echanism . In b o th cases,
target cells are selectively b o u n d to the m acrophage cell surface an d target
cytolysis follows secretion of lytic effector m olecules by the m acrophage. Before
cytolysis, m acrophages m ust be activated by tw o signals acting in defined
sequence. The sam e goes for effective killing and digesting of facultative
intracellular parasites. T he first signal, interferongam m a, released from sen­
sitive T-lym phocytes, prim es responsive m acrophages for subsequent response
to a second signal which finally activates them to produce tum ouricidal
activity. The m ost com m only em ployed as a second signal are bacterial
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M . Tarkowski and P. Górski
lipopolysaccharides (LPS), listeria m onocytogenes and m uram yl dipeptide.
T hose signals activating m acrophage-m ediated tu m o u r cytotoxicity are also
effective in m ediating the A D C C m echanism s. The im portance of A D C C
m echanism s could play some role in asbestos-exposed subjects, especially those
w ho suffer from asbestos-related cancer. T here is som e evidence from the
studies of Scheule et al. (23) th a t m acrophage activity to release radical oxygen
interm ediates (RO I) is IgG -m ediated and specific for asbestos fibres. This could
indicate the role of antibodies in defense m echanism s against asbestos-induced
cancer killing, m ediated through the A D C C m echanism s. It is likely to appear,
since xenobiotics, in co n trast to viruses, can cause expression of different
tu m o u r d eterm inants to which specific antibodies are needed. AM of healthy
subjects exhibit a low level of an titu m o u r activity unless treated by m uram yl
dipeptide o r LPS. Those cells co-cultivated with three different tu m o u r cell
lines an d activated with L PS release as m any cytotoxic factors as A M
incubated w ith o u t tu m o u r cells. F ailure of A M to produce cytotoxic factors in
response to a p o ten t activator could restrict their role in defense of th e
lung (25). P erh ap s asbestos fibres m ay interfere with an activating factor n o t
allow ing the full activation process.
As was m entioned above, in bo th m echanism s of tum oricidal activity, th e
effector m echanism is m ediated through the release of cytotoxic factors. It w as
suggested th at R O I, neutral protease, arginase, tu m o u r necrosis factor (T N F )
co n trib u te to tum ouricidal activity but the exact m echanism of effector
cytotoxicity is still unclear. Recently, M iyakaw a et al., (17) has shown the m ain
role of T N F -lik e molecules in tum our-killing in contrast to R O I-d ep en d an t
way. O th er au th o rs attrib u te the m ain role of tum our killing to n eu tra l
protease (1); others to the process of phagocytosis (19). Different effector
m echanism s against tu m o u r cells m ay arise from the heterogeneity of
individual patients and heterogeneity of m alignan t tissue. Therefore it w ould be
naive to suspect the im m unological m echanism s against tu m o u r cells to be
identical o r even sim ilar in all patients w ith cancer.
Macrophages and fibrosis
It seems likely th a t prod u ctio n of lane of the antitum our factors th a t is
R O I un d er influence of asbestos fibres m ay cause undesirable effects w hich
result in fibrosis of the lung. The process of increased R O I production, a n d in
consequence, tissue injury expressed by m em brane peroxidation, and d am age
to m acrom olecules, is believed to be caused m ainly by long fibres which d o n o t
undergo com plete phagocytosis (18).
Increased p ro d u ctio n of R O I by A M was reported in various an im al
models. C ase et al. (6) showed increased superoxide anion production in vitro
from b ro n choalveolar lavage cells derived from the Syrian golden ham ster. T he
sam e effect was found in mice by G oodglick at al. (8). The enhanced p ro d u c tio n
of superoxide an ion by A M caused by Ig G opsonized asbestos fibres, was also
detected in guinea pigs (23). The oxidative injury of the lung could be elevated
additionally by p olym orphonuclear leukocytes (PM N L), since m acrophages
M acrophage in asbestos diseases
119
can produce a factor which induces their infiltration (16) o r are defective in
releasing a fa c to r th a t inhibits m igration an d chem otaxis of P M N L (24). This is
in agreem ent w ith P etru sk a et al. (20) w ho found altered bronchoalveolar
lavage cell p o p u la tio n characteristics of an acute inflam m atory response after
short-term expo su re of rats to asbestos dust. M acrophages and chem o-attracted P M N L in sites of inflam m ation, being exposed to p o ten t activators
of oxygen ra d ic al p roduction, m ay cause the injury of the lung tissue, and
finally may in itiate the process of fibrosis.
It is well established th a t inflam m atory process is elevated by cytokines
am o n g which are those released from m onocyte/m acrophage cell lineage.
T hose cytokines e.g. T N F -a lp h a are well know n inducers of R O I p ro d u c­
tion (14). T he process of extensive R O I production, which leads to injury, and
m ay in tu rn cause increased IL-1 production, was show n by G ougerot-Pocidalo et al. (9). This process was ascribed to hu m an m onocytes and we can
only predict th a t the sam e effect goes for the cells of the sam e lineage i.e.
m acrophages in the site of the lung injury indirectly caused by asbestos fibres.
E nhanced IL-1 activity m ay in tu rn increase inflam m atory response and cause
o th er changes in regulation m echanism s of im m unological response. This
findings are in agreem ent w ith previous studies (10) which indicated the
enhanced ph y to h aem aglutynine-stim ulated increase of IL-2 pro d u ctio n by
peripheral b lo o d m ononuclear cells in sites o f tissue injury. The explanation,
m entioned by au th o rs, is now evident an d indicates th a t the increased IL-2
production w as th e result of enhanced IL-1 activity. How ever, the proliferation
of lym phocytes w as decreased, since oxygen radicals interfere in early events of
cell cycle. T h is m ay explain the dim inished num ber of T-cells in patients
exposed to asb esto s d u st observed by K ag an et al. (13).
T he process of lung tissue injury an d subsequent fibrosis seems to be
m ainly caused b y increased level of R O I generated by, cells during incom plete
phagocytosis o f lo n g fibres. An elevated p ro d u ctio n of R O I m ay also arise from
decreased activ ity o f an tio x id an t enzymes which protect against toxic oxygen
radicals during n o rm al m etabolism and after oxidative insults (27), as is show n
in Fig. 1.
There is n o evidence th at asbestos fibres cause destruction of protective
systems of enzym es; how ever from the studies of M ossm an and L andesm an
(18) we know th a t these toxic agents m ay cause peroxidation of m em branes
and dam age to th e m acrom olecules of airw ay epithelial cells. This m ay arise
from excessive p ro d u c tio n of R O I and, on the o th er hand, dim inished o r
abandoned activ ity of the protective enzyme system.
T he process o f lung fibrosis show n here as a consequence of tissue injury
and repair m ay also be a cause of direct effect on collagen synthesis. T here is
also th e possibility th a t b o th the m echanism s concerned (injury and repair and
increased collagen synthesis), are active in the process of lung fibrosis through
cellular interactions.
C ellular com plexity of the lung raises a question of cellular interactions in
the induction o f fibrosis. T he hypothetical m echanism of cellular interactions
leading to lu n g fibrosis is show n in Fig. 2. The m ost likely process of
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M. Tarkowski and P. Górski
Fig. 1. T he pathw ays of d etoxication of R O I m ediated by a n tio x id a n t enzym es:
a) S O D — S uperoxide d ism utase which dysm utates tw o m olecules of superoxide anion to form
hydrogen peroxide a n d oxygen molecule,
b) C A T — C atalase. It catalyzes the reaction w hich form s, fro m tw o m olecules of hydrogen
peroxide, tw o m olecules o f w ater and one m olecule o f oxygen,
c) G 6 P D — G lucose-6-phosphate dehydrogenase which catalyzes th e reaction of oxidation of
glucose-6-phosphate to : 6-phosphoglucolactone with c o n c o m ita n t reduction of nicotinam ide
adenine dinucleotide p h o sp h a te (N A D P) to its reduced form N A D P H ,
d) G P — G lu tath io n e peroxidase. It catalyzes reaction of o x id a tio n o f G lu tath io n (G SH ) to its
oxidized form (G SSG ) a t the expense of hydrogen peroxide,
e) G R — G lu ta th io n reductase. It reduces G S S G to G S H w ith c o n co m ita n t oxid atio n of N A D P H .
Macrophage in asbestos diseases
121
Asbestos
Granulocytes
Fig. 2. H ypothetical m echanism s of cellular interactions leading to lung tissue fibrosis.
A. In th e first stage, m acrophages w hich do not phagocyte com pletely long asbestos fibers, release
in a n uncontrolled way an increased level of p roinflam m atory m ediators, radical oxygen
in te rm ed iate d (ROI) and fibroblast grow th factors. M acrophages m ay be additio n aly stim ulated to
release these factors by interferon (IFN ) originating from activated lym phocytes or by endocytosis
of a n tib o d ie s th a t b o u n d asbestos fibres. L ym phocytes in tu rn rem ain un d er influence of
interleukin-1 (IL-1) released by m acrophages.
B. I n th e second stage there is an increased accum ulation o f c hem o-attracted granulocytes which
stim u la te d by the tu m o u r necrosis factor-tx (T N F -a) release an increased level of R O I. T here is also
c o n c o m ita n t accum ulation of fibroblasts which proliferate in response to a transform ing grow th
factor-P), (T G F-p), a n d platelet derived grow th factor (P D G F ), IL-1 w hich results in increased
collagen deposition.
C. A highly increased level o f R O I, originating from m acrophages a n d granulocytes, m ay cause
lung tissue injury. O xidative lung tissue injury m ay in tu rn additionally elevate release of IL-1 by
m ac ro p h ag e s and since then the proliferation of fibroblasts and collagen deposition.
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M . Tarkowski and P. Górski
interactions in asbestos dust fibrosis occurs between m acrophages an d
fibroblasts, as in the case of silica, shown by H eppleston a n d Styles (12).
F ib ro b lasts seem to be attracted to the place of injury by fibronectin released
by m acrophages. O nce attracted, fibroblasts are under the influence of o th er
cytokines released from AM , as IL-1 which stim ulate them to proliferate (22,
28, 33). The process of IL-1 release under the influence of asbestos fibres was
show n by H a rtm a n et al. (11). F ibroblasts m ay proliferate as well as a result of
action of platelet-derived grow th factors (P D G F ) or transform ing grow th
factor beta (T G F-beta) released from activated m acrophages. T h e latter tw o
cytokines (P D G F , T G F -beta) m ay also induce fibrogenic responses by stim u ­
lating the p ro d u ctio n of connective tissue. O th er cytokine, T N F , w as found to
act on fibroblasts in a concentration-dependant m anner, at a low concentra­
tion. It stim ulates fibroblast proliferation an d at higher concentrations it
blocks grow th triggered by other cytokines ((5). The process of cellular
in teractions in lung fibrosis is com plex an d besides the one stated above,
between m acrophages and fibroblasts, includes interactions betw een m acro ­
phages an d P M N L . P M N L s are attra cted to the place of inflam m ation by
ch em o -attractan ts released from m acrophages, however, they a re not well-recognized. O nce attracted, they are under influence of cytokines as in the case
of fibroblasts. P M N L , however, will respond differently to each o f these stimuli.
M acrophages as a source of m any im p o rtan t biological m odifiers are
crucial cells for im m unological regulatory m echanism s tow ards enhanced or
suppressed response. This dual role of cells is nothing new and m a y depend on
the organ, they exist in (21), b u t this m ay be also an effect of h arm fu l activity of
e.g. asbestos fibers.
C O N C L U S IO N S
T he im portance of m acrophages in im m unological processes especially in
asbestos-related diseases is beyond any question. Therefore, their activity
should be the m atter of intensive studies. M acrophages sh o u ld be seen in
asbestos-related diseases as protective cells bu t also as one of th e p o p u latio n of
cells th a t m ay cause directly or indirectly undesired harm ful effects. I t is
suggessted by Strieter et al. (26) th at the physiological role of A M may tem per
the im m unologic reaction in the lung as they are less sensitive to the
im m unom odulating action of some cytokines and in this w ay prevent the
inflam m atory reaction. The chronic action of asbestos fibres m ay, however,'
change the whole regulation m echanism of m acrophage activity a n d cause the
release of m any pro-inflam m atory m ediators, which in consequence m ay be
responsible for tissue injury, fibrosis and cancer. O ne of the m a jo r and m ost
harm ful factors of tissue injury m entioned in this rep o rt m ay be the excessive
p ro d u ctio n of reactive oxygen interm ediates released from m acrophages and
ch em o -attracted p olym orphonuclear leukocytes. Excessive p ro d u c tio n of R O I,
expressing the response of the lung to toxic chem ical insult, m ay cause further
dam age to cells, which in tu rn m ay result in irreversible o r n ea rly irreversible
Macrophage in asbestos diseases
123
lesions which are deleterious to norm al lung function. The m ost deleterious
and, as yet, irreversible effect of lung tissue injury, caused by the h a rmful
activ ity of asbestos dust, and excessive lung response is the initiation,
p ro m o tio n and progression of cancer.
M acrophages, as one of the p o pulation of effector cells in tum our-killing,
are th e subject of studies which try to establish an effective m odel of cancer
th e ra p y i.e. such a therapy th at will leave no living cancer cell th a t will no t
fu rth e r proliferate and m etastasize (31). T he hopes th a t we set on m acrophages
are still only hopes. However, they will never com e true if we do n o t get enough
know ledge ab o u t the activity of these cells from various view-points. O ne of
these view -points could include the prospective studies of m acrophage activity
in p a tie n ts suffering from asbestos-related diseases: a com m only know n agent
of cancer.
REFERENCES
1. A d a m s D O , K a o K J, F a rb R, Pizzo SV. Effector m echanism s of cytolytieally activ ated
m ac ro p h ag e s II. Secretion of a cytolytic factor by activated m acrophages and its re lationship
to secreted neutral proteases. J Im m u n o l 124, 293 —300, 1980.
2. A d o rin i L, N agy ZA. P eptide co m petition for antigen presentation. Im m unol T o d ay 11,
2 1 - 2 4 , 1990.
3. A llison AC. E xperim ental m ethods o f cell and tissue culture: effects o f asbestos particles on
m acro p h ag es, m esothelial cells, and fibroblasts. In: Biological effects of asbestos. Proceedings
o f a W orking Conference, ed. B ogow ski et al. Lyons, 2 —6 O ctober, 1972, Lyons, In tern a tio n a l
A gency for Research on C ancer, 8 9 —93 (IARC Scientific P ublications N o. 8).
4. B eck E G , Brućh J, Friedrichs K H , H ilscher W, P o tt F. F ib ro u s silicates in anim al experim ents
a n d cell-culture m orphological cell a n d tissue reactions according to different physical
chem ical influences. In: In h aled particles. III. P roceedings of an In tern a tio n a l Sym posium , ed.
W H W alton, L ondon, 14 —23 Septem ber, 1970, O ld W oking, Surrey, U nw in, Vol. 1, 477 —487,
1971.
5. B eck E G , H olt P F , M anojlovic N . C om parison o f the effects o n m acrophage culture of glass
fibre, glass pow der, and chrysotile asbestos. Br J In d M ed 29, 2 8 0 —286, 1972.
6. C a se BW , Ip M P C , P ad illa M , K leinerm an J. A sbestos effects on superoxide prod u ctio n . An in
vitro study of ham ster alveolar m acrophages. E nviron Res 39, 299 —306, 1986.
7. D a v ie s R. The effect of m ineral fibres on m acrophages. In: Biological effects of m ineral fibres.
P ro c e ed in g s of a Sym posium held a t Lyons, 25 —27 Septem ber, 1979, ed. JC W agner, L yons,
In te rn a tio n a l Agency for Research on C ancer, Vol. 1, 419 —424, (IA RC Scientific P u b licatio n s
N o . 30), 1980.
8. G o o d g lic k LA, K an e AB. Role of reactive oxygen m etabolites in crocidolite asbestos toxicity to
m o u se m acrophages. C ancer Res 46, 5558 —5566, 1986.
9. G o u g e ro t-P o c id a lo M A, R oche Y, F a y M , P erianin A, Bailly S. O xidative injury amplifies
in te rle u k in -l-lik e activity produced by hum an m onocytes. In t J Im m u n o p h a rm ac 11,
9 6 1 - 9 6 9 , 1989.
10. G o u g e ro t-P o cid a lio M A, F ay M , R oche Y, C hollet-M artin S. M echanism s by w hich oxidative
in ju ry inhibits proliferative response of hu m an lym phocytes to PH A . Effect of thiol com pound,
2-m ercap to -eth an o l. Im m unology 64, 281 —288, 1988.
11. H a rtm a n D P , G eorgian M , O ghiso Y, K agan E. E nhanced interleukin activity follow ing
a sb e sto s inhalation. Clin E xp Im m unol 55, 643 —650, 1984.
124
M. Tarkowski and P. Górski
12. H eppleston AG, Styles JA- Activity of a m acrophage factor in collagen fo rm a tio n by silica.
N a tu re 214, 5 2 1 - 6 2 2 , 1967.
,
13. K agan E, Solom on A, C ochrane JC et al. Im m unological studies of. p a tie n ts w ith asbestosis.
I. Studies of cell m ediated im m unity. C lin E xp Im m unol 28, 261 —267, 1977.
14. K a p p A, Z eck-K app G , Blohm D. H u m an tu m o r necrosis factor is a p o te n t a ctiv ato r of the
oxidative m etabolism in h u m an poly m o rp h o n u clear neutrophilic g ra n u lo c y te s: com parison
with hum an lym photoxih. J Invest D erm ato l 92, 348 —354, 1989.
15. K ovacs EJ. Fibrogenic cytokines: the role of im m une m ediators in the d e v elo p m en t of scar
' tissue. Im m unol T oday 12, 17 —23, 1991.
16. M egyeri P, Sadow ska J, Issekutz TB, Issekutz AC. E ndotoxin-stim ulated h u m a n m acrophages
p ro d u c e a factor th a t induces p o lym orphonuclear leucocyte infiltration a n d is distinct from
in terleu k in -1, tu m o u r n e c ro sis. factor alp h a a n d chem otactic factors. Im m u n o lo g y 69,
• 1 5 5 -1 6 1 , 1990. .
17. M iyakaw a Y, K ag ay a K , W atan a b e K , F u k azaw a Y. C haracteristics of m a c ro p h a g e activation
by gam m a interferon for tu m o r cytotoxicity in peritoneal m acrophages a n d m acrophage cell
line J774.1. M icrobiol Im m unol 33, 1027 —1038, 1989.
18. M ossm an BT, L andesm an JM . Im p o rtan ce of oxygen-free radicals in a sb e sto s-in d u ce d injury
to airw ay epithelial cells. C hest 83, 5 Suppl 50S —51S, 1983.
19. M u n n D H , C heung N K V . P hagocytosis of tu m o r cells by hum an m o n o cy te s cultered in
recom binant m acrophage colony-stim ulating factor. J E xp M ed 172, 2 3 1 —237, 1990.
20. P e tru sk a JM , M arsh J, B ergeron M , M ossm an BT. Brief in halation of a sb e sto s com prom ises
superoxide pro d u ctio n in cells from b ronchoalveolar lavage. Am J R e sp ir Cell M ol Biol 2,
1 2 9 -1 3 6 , 1990.
21. P h ip p s R P, R oper RL, Stein SH. A lternative antigen p resentation p a th w ay s: accessory cells
■ which dow n-regulate im m une responses. Regional Im m unol 2, 326 —339, 1989.
22. R aines EW , D ow er SK, Ross R. Interleukin-1 m itogenic activity for fib ro b la sts a n d sm ooth
m uscle cells is due to P D G F -A A . Science 243, 393 —396, 1989.
23. Scheule R K , H olian A.. Ig G specifically enhances chrysotile asb esto s-stim u lated superoxide
an io n pro d u ctio n by the alveolar m acrophage. Am J R espir Cell M ol B iol 1, 313 —318, 1989.
24. Sibille Y, M errill W W , N aegel G P , C are SB, C ooper AD, Reynolds H Y . H u m a n alveolar
m acrophages release a factor th a t inhibits phagocyte function. Am J R e sp ir Cell M ol Biol 1,
4 0 7 - 4 1 6 , 1989.
25. Sone S, U tsugi T, O g aw ara M , M u tsu u ra S, Ishii K, T su b u ra E. P ro d u c tio n o f tu m o r cytotoxic
factor(s) by hu m an alveolar m acrophages (AM) activated to the tu m o ric id a l state. In:
M acro p h ag e Biology, ed. AR Liśs Inc, N ew Y ork, Vol. 4, 355 —362, 1985.
26. Stricter RM , Fem ick D G , L ynch J P et al. Differential regulation of tu m o r necrosis factor-alpha
in hu m an alveolar m acrophages and peripheral blood m onocytes: a c e llu la r a n d m olecular
analysis. Am J Respir Cell M ol Biol 1, 57 —63, 1989.
27. Sun Y. Free radicals, a n tio x id an t enzym es and carcinogenesis. Free R ad B iol M ed 8, 583 —599,
1990.
28. V an-D am m e J, D e Ley M , O p d e n ak k e r G , Billiau A, D e Som er P , V an Beeum an J.
H om ogenous interferon-inducing 22 K factor is related to e n d o g en o u s pyrogen and
interleukin-1. N a tu re 314, 2 6 6 —268, 1985.
29. W ahl SM . H ost im m une factors regulating fibrosis. In C iba F o u n d a tio n “F ib ro sis”, Pitm an,
L ondon, 1 7 5 -1 8 6 , 1985.
30. W eaver CT, U n an u e ER. T he costim ulatory function of a ntigen-presenting cells. 11, 49 —55,
1990.
31. W hitw orth P W , P a k C C , E sgro J, K leinerm an ES, F id ler IJ. M acrophages a n d cancer. Cancer
M etastasis Rev 8, 319 —351, 1990.
32. Y eager H Jr, Russo DA, Y anuz M et al. C ytotoxicity of short fibre chrysotile-asbestos for
h um an alveolar m acrophages: prelim inary observations. E nviron Res 30, 224 —232, 1983.
Macrophage in asbestos diseases
125
33. Z ucali JR , D in o rello CA, O bion D J, G ross M A, A nderson L, W einer RS. Interleu k in 1
stim ulates fibroblasts to produce granulocyie-m acrophage colony stim ulating activity and
p ro sta g la n d in E2. J Clin Invest 77, 1857 —1863, 1986.
Received for pu b licatio n : Ja n u a ry 25, 1991
A ccepted for p u b lic a tio n : M arch 8, 1991