Pathology and pathophysiology of pneumoconiosis

Naoki Fujimura, MD, PhD

Cellular and molecular mechanisms, as well as associated Silicosis

gene expressions, in silicosis and asbestosis are widely inves-
tigated, and compound mechanisms involved in initiating
inflammation and progression to fibrosis are comprehensively
studied, though not yet totally understood. Recent advances in
this field, especially concerning pathophysiology of these
pneumoconioses, are reviewed in this article.
Silicosis and asbestosis are two major types of pneumoconio-
sis. Although the clinico-pathologic features presented are
apparently different, silicosis and asbestosis are both intersti-
tial lung diseases caused by chronic exposure to airborne inor-
ganic dusts, and the pathology of these two diseases is
essentially a fibrosis. Curr Opin Pulm Med 2000, 6:140–144 © 2000
Lippincott Williams & Wilkins, Inc.
Department of Medicine, National Hira Hospital, Shiga, Japan.
Silicosis is caused by inhalation of dust containing crys-
talline silicon dioxide (silica) [1]. Quartz is the most
common form of crystalline silica. Occupations such as
quarrying have been recognized to increase the risk of
exposure to crystalline silica [1].
The development and severity of silicosis depend on
the total amount, intensity, and duration of exposure to
quartz, and whether the presence of other minerals
interfered with the toxicity of the silica. The nature and
properties of minerals play a key role (eg, quartz is less
fibrogenic than tridymite and cristbalite)[1]. The higher
the free silica content of the particles, the more the
particles tend to induce silicosis. The worker’s individ-
ual susceptibility is also an important factor in the devel-
opment of silicosis.

Correspondence to: Naoki Fujimura, MD, PhD, National Hira Hospital, 298
Clinical types of silicosis
Wani-naka, Shiga, Shiga, Shiga 520-0526, Japan; tel: +81-77-594-1122; fax: Two types of silicosis occur. Acute silicosis presents as
+81-77-594-1511.
alveolar silicolipoproteinosis, following intense expo-
sure to quartz. Classic silicosis is divided into two
Current Opinion in Pulmonary Medicine 2000, 6:140–144 groups by the chest x-ray film findings—simple,
Abbreviations nodular silicosis and complicated silicosis with large
BAL bronchoalveolar lavage
conglomatous opacities [1].
FGF fibroblast growth factor
ICAM intercellular adhesion molecule
IGF insulin-like growth factor
Pathology of silicosis
IL interleukin Silicotic nodules consist of fibrotic lesions and more
MIP macrophage inflammatory protein
PDGF platelet derived growth factor
apparently distribute in the upper part of the lungs. The
VCAM vascular cell adhesion molecule nodule is typically an “onion skin lesion” of concentri-
TNF tumor necrosis factor
cally arranged collagen fibers. Cells inside the nodule
are dust-laden macrophages and lymphoid cells.
ISSN 1070–5287 © 2000 Lippincott Williams & Wilkins, Inc.
Consequently, nodules become acellular and hyalinized.
Particles of silica may be demonstrated as birefringent
particles under polarized light. The pathology of acute
silicosis is quite different from the classic silicosis, a
sever alveolitis with alveolar filling and a PAS-positive
substance consistent with alveolar lipoproteinosis.

Asbestosis
Asbestosis, one of several asbestos-related diseases,
involves interstitial fibrosis of the lung induced by
chronic exposure to asbestos fibers. Other asbestos-
related diseases include benign pleural effusion and
plaques, malignant mesothelioma, and bronchogenic
carcinoma. Asbestos is a collective term for some of the
metamorphic, fibrous, mineral silicates of the serpentine
and amphibole groups. Asbestos is widely used in indus-
tries for its tensile strength and heat resistance. Major
forms of industrial use are chrysotile (95% of total
140
 Pathology and pathophysiology of pneumoconiosis Fujimura 141

production), crocidolite, and amosite. Anthophyllite,
tremolite, and actinolite are used less. Use of asbestos
and sources of exposure, such as asbestos cement, are
reviewed in detail by Browne [3••].
Clinical and pathologic features of
asbestosis
Asbestosis presents as diffuse interstitial pulmonary
fibrosis in clinical symptoms, physical findings,
pulmonary function tests, chest radiography or
computed tomography, and histopathology. An addi-
tional finding on chest radiologic images is plural thick-
ening or plaques. And specific pathologic finding is the
presence of asbestos bodies in the lung [3••].
Mechanisms of pathogenesis of
pneumoconiosis
The pathophysiology of silicosis and asbestosis is a
chronic inflammation of the lung (alveolitis) and result-
ing fibrosis. These mechanisms are reviewed systemati-
cally and in detail in recent reviews [2,4] (Fig. 1).
Inflammatory process
After reaching the alveoli, silica particles or asbestos
fibers are phagocytosed by alveolar macrophages.
Macrophages are damaged or activated and released
cytotoxic oxidant or protease and inflammatory media-
tors cytokines such as tumor necrosis factor (TNF)-α,
interleukin (IL)-1, and arachidonic acid metabolites,
which provoke recruitment of inflammatory cells into
the alveolar wall and alveolar epithelial surface (initia-
tion of alveolitis) [2,4].
Irritant and associated inflammatory mediators also
increase airway mucin biosynthesis by inducing mucin
gene MUC5AC message levels in epithelial cells, this is
studied in acrolein and inflammatory mediators such as
prostaglandin E2, 15-hydroxy-eicosatetraenoic acid (15-
HETE), TNF-α, and proteinkinase C activator stimu-
lated human lung carcinoma cell line in vitro system [5].
Alveolar macrophages are the main cells forming alveoli-
tis, although lymphocytes and neutrophils are also
involved. These activated inflammatory cells damage
the pulmonary architecture and form the basis of fibrotic
scars [2,4].
Evidence that alveolar macrophages play a key role in
lung inflammation, expression and activation of cytokines,
chemokines, and the transcription of nuclear factor (NF)-
κB are suppressed by depletion of alveolar macrophages
in immune complex-induced acute rat lung injury.
Bronchoalveolar lavage levels of TNF-α, neutrophil
chemotaxins, macrophage inflammatory protein 2, vascu-
lar cell adhesion molecules (VCAM-1), and neutrophils
inducing accumulation and development of lung injury
were also substantially diminished. Initial activation of
NF-κB occurs in alveolar macrophages, and the ensuing
production of TNF-α may propagate NF-κB activation in
other cell types in the lung [6••]. TNF-α induces the

Figure 1. Proposed mechanisms involved in pathophysiology of pneumoconiosis

The chronic inflammation of the lung (alveolitis) and Inorganic dust

resulting fibrosis are main mechanisms of pneumo-
coniosis. 1. Inflammatory process: Inhaled dust parti-
cles are phagocytosed by alveolar macrophages. Lymphocyte Epithelial cell
Macrophages are damaged and activated to release Autoantibodies
cytotoxic O or lysosomal enzymes and inflammatory Altered immune control?
cytokines such as TNF-α, IL-1, AAM, CINC, and
Damage
MIP, which recruit inflammatory cells into the alveoli
(initiation of alveolitis). Epithelial cells are also Macrophages Epithelial cell
damaged, and they release inflammatory cytokines. Damage
Immune reguratory activity of macrophages is altered Cytokines Cytokines
and may induce autoimmune lung injury. Alveolar
TNF Macrophages
macrophages, lymphocytes, and neutrophils are the IL-1
main cells forming alveolitis. These activated inflam- TNF TNF FGF
O–
matory cells damage the pulmonary architecture and NIP AAN IL-1 IL-1 PDGF
form the basis of fibrotic scar. 2. Fibrotic process: CINC Lysosomal Enzymes IGF
Following the inflammatory process, the reparative
and fibrotic phase emerges. Growth factors (TNF, IL- Neutrophil
1, FGF, PDGF, IGF) stimulate the recruitment and Lymphocyte
proliferation of type II pneumocytes and fibroblasts Fibroblast
and induce overproduction of fibronectin and colla- Proliferate
gen, resulting in the development of fibrosis. TNF, Inflammatory
Collagen synthesis
tumor necrosis factor; IL-1, interleukin-1; O, oxygen cell recruitment
radicals; AAM, arachidonic acid metabolites; MIP,
macrophage inflammatory protein; CINC, cytokine-
induced neutrophil chemoattractant; FGF, fibroblast Inflammatory process Fobrotic process
growth factor; PDGF, platelet derived growth factor; = alveolitis
IGF, insulin-like growth factor.
142 Obstructive, occupational, and environmental diseases
intercellular adhesion molecule (ICAM-1) and VCAM-1
on cultured human bronchial epithelial cells in vitro, and
this VCAM-1 expression is inhibited by treatment with
glucocorticoids [7].
Inflammatory and anti-inflammatory
mechanisms of the lung
In addition to classic mechanisms such as antiprotease,
novel factors inhibit or attenuate lung inflammation.
Airway epithelial lining fluid forms an interface between
the airway epithelial cells and external environment,
representing the first biologic matrix to interact with
inhalants. In bronchoalveolar lavage (BAL), obtained
human epithelial lining fluid contains multiple low
molecular-mass antioxidants such as ascorbate, urate,
glutathione, and α-tocophoerol that act as defense
mechanisms against oxidative reactions initiated by
inhaled pollutant and endogenous oxidants generated
during inflammatory process at the respiratory tract
surface [8]. Heme, released from hemoglobin and heme
proteins, promotes the formation of oxygen radicals that
lead to cellular injury. Heme oxygenase-1 (HO-1) catab-
olizes heme and protects from heme-mediated oxidative
injury [9].
15-HETE is one of the major arachidonic acid metabolites
involved in lung inflammation and is catalyzed by 15-
lipoxygenase (15-LO). In cultured normal human tracheo-
bronchial epithelial cells, IL-4 induces enhanced expres-
sion of 15-LO and inhibits inflammatory mucus secretion
attenuating MUC5AC and MUC5B messages [10].
Programmed cell death or apoptosis of macrophages and
expression of TNF-α are induced by particulate matter (a
by-product of the combustion of fossil fuels). This apop-
tosis is mediated by TNF-α. In turn, TNF-α activates
mitogen-activated protein kinase (MAPK) activity, which
also mediates apoptosis and TNF-α release. Whether
these phenomena protect against or aggravate lung injury
is still unclear. TNF-α induced apoptosis in activated
macrophages stops macrophages from releasing major
cytokines and minimizes the inflammatory process; on
the other hand, TNF-α provokes further recruitment and
cellular damage of inflammatory cells, such as
neutrophils, and additional macrophages to release
inflammatory factors [11]. The role of apoptosis in mecha-
nisms in lung inflammation must be investigated.
The result that TNF—induced VCAM-1 expression is
suppressed by some inhaled glucocorticoids, given the
role of some of these agents in controlling of acute inflam-
mation early and in minimizing fibrotic progression [7].
Fibrotic process
The inflammatory process is followed by a reparative
phase in which growth factors stimulate the recruitment
and proliferation of type II pneumocytes, fibroblasts,
fibronectin, and collagen, resulting in the development
of fibrosis [2,4].
As dominant inflammatory cells involved in lesion of
pneumoconiosis, alveolar macrophages release many
pro-fibrosis growth factors—such as the fibroblast
growth factor (FGF), platelet-derived growth factor
(PDGF), and insulin-like growth factor (IGF)—recruit
and proliferate the fibroblasts [2,4]. FGFs are regarded
as an important cytokine in upregulation of collagen
biosynthesis, which leads to fibrosis.
A worker’s individual susceptibility is recognized as a
important factor that influences the disease, although in
human leukocyte antigen (HLA) phenotyping studies
there are controversies [1,3]. A recent study in assess-
ment of polymorphisms in coal workers within the
TNF-α gene revealed significant overpresentation of
the A–308 genotype in mineral-dust-induced lung fibro-
sis [12••], providing some clue to the possible predispo-
sition among workers exposed to dusts.
Pathophysiology of silicosis
In BAL fluids of patients with silicosis, cells, mainly
dust-laden macrophages, are increased. Lymphocytes
and neutrophils are also increased [1,2]. The immuno-
logic process, induced by silica, may play some role in
the inflammatory process through the adjuvant effect
and modulation of immune-control system, resulting in
the formation of antihuman lung autoantibodies [1].
Whether this immunologic process really involves
human silicosis remains to be established.
Recruited inflammatory cells release toxic oxygen deriv-
atives and proteolytic enzymes, which cause cellular
damage and destruction of the extracellular matrix [1,2].
Silica-stimulated macrophages release TNF-α and IL-1
[1,2,]. Even after exposure to silica has ceased, mice
lungs show persistent overexpression of IL-1β and
TNF-α. IL-1β and TNF-α expression localized to
mononuclear cells in the alveolar spaces, cells within the
aggregate lesions, and even cells in BALT and lymph-
noid nodules. Therefore, the continuous cellular
production of IL-1β and TNF-α appears to be strongly
associated with the evolving lesions of silicosis [13].
Recently, an in vitro test-system was developed using
human macrophages, human pneumocyte type II cells,
human diploid lung fibroblasts, and human tracheo-
bronchial epithelial cells. In this test-system, quartz-
treated human macrophages release insulin-like growth
factor (IGF)-1 and transforming growth factor beta
(TGF-β) to stimulate cell proliferation and collagen-
synthesis of fibroblasts [14••]. This system may
contribute to further investigations.

TNF-α induces the macrophage inflammatory protein
(MIP)-2 and cytokine-induced-neutrophil chemoattrac-
tant (CINC) to recruit neutrophils into the lungs after
silica exposure [2••]. The TNF-α release also increases
the expression of ICAM-1 on vascular endothelium cells
to enhance the attachment of neutrophils to the
endothelium of blood vessels in silica-exposed mice
[2••]. In the quartz-induced acute inflammatory phase,
these recruited neutrophils secret TNF-α or IL-1 to
upkeep alveolitis [15], and connective tissue breakdown
is by neutrophil-derived proteases [16].
While silica challenge to lungs induces inflammation by
cytokines, IL-10 expression in rat lungs downregulates
quartz-induced inflammation and cell activation. In
experiments using recombinant murine IL-10 and anti-
IL-10 antisera, this anti-inflammatory action of IL-10
after quartz administration involves, at least in part,
attenuation of MIP-2 expression [17]. TGFs upregulates
collagen-synthesis and leads to fibrosis. TGF-α and
type I procollagen gene expression are coincidentally
observed in silica-exposed rats [2••]. Also, overexpres-
sion of TGF-β is reported in human silicosis [2••].
These inflammatory and fibrotic processes contribute to
the pathogenesis of silicosis.
Pathophysiology of asbestosis
Asbestos fibers injure alveolar macrophages and epithe-
lial cells directly, and they cause macrophages to
produce and release groups of mediators and growth
factors for fibroblast and inflammatory cells. The inflam-
matory reaction followed by the fibrosing repair process,
leaving permanent scars, is “fibrosis”.
The possibility that immunologic events might partici-
pate in the pathogenesis of asbestosis is is pointed out
by the presence of circulating antinuclear antibodies
(ANA) in patients with asbestosis, but this hypothesis
has yet to be established and further investigations must
be conducted [3••]. PDGF, regarded as a important
factor, induces fibroblast proliferation. In vitro exposure
to chrysotile induces PDGF-AA and its matching alpha
receptor upregulation in rat lung fibroblasts and fibrob-
last proliferation [18].
Although in vitro or animal studies indicate that TNF-α,
IL-1 β PDGF, and IGF-1 are involved in proliferation of
fibroblast, a recent report challenges this finding [19].
Human BAL fluids from asbestos-exposed workers with
or without asbestosis induced higher proliferation of
human lung fibroblasts in vitro than those of nonexposed
participants; however, the mitogenic activity of BAL fluids
was not reduced by incubation with neutralizing antibod-
ies to PDGF-AA, PDGF-AB, PDGF-BB, TNF-α, IL-1 β,
and IGF-1. BAL fluids from subjects exposed to asbestos
contain mitogen for human lung fibroblasts, but PDGF,
Pathology and pathophysiology of pneumoconiosis Fujimura 143
TNF-α, IL-1 β, and IGF-1 do not contribute to this activ-
ity [19••]. This finding may lead to a novel proliferation
factor.
Clearly, fiber length and mineralogic characteristics of
asbestos are important in pathogenicity of asbestosis.
For equivalent weights, long fibers produce a much
greater fibrogenic effect than short fibers. Specific
pathogenecity of asbestos fibers only exists at lengths
greater than 5 µm. While chrysotile fibers are frag-
mented and disappear from lung tissue in a relatively
short time, amphibole asbestos as amosite or crocidolite
persist for a long time. The difference in bio-persistence
of these asbestos groups results in chrysotile being asso-
ciated with less disease in human beings [3,4].
A recent investigation, which used dielectrophoresis to
separate glass fibers into groups of different lengths,
studied the effects of length on the interaction between
glass fibers and macrophages by focusing on production
of TNF-α in a mouse macrophage cell line [20]. Long
fibers (17 µm) were significantly more potent than short
fibers (7 µm) in inducing NF-κB activation, the gene
promoter activity, and the production of TNF-α [20••].
The results support the hypothesis that fiber length
plays a critical role in fibrogenic potency.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• Of special interest
•• Of outstanding interest
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144 Obstructive, occupational, and environmental diseases
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19 Mutsaers SE, Harrison NK, McNulty RJ, Liao JYW, Laurent GJ, Musk AW:
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NFκB activation and production of TNF-α.