Asbestos Fibers and Other Elongate Mineral Particles: State of the ...

of the phagocytic response. It may also affect
the generation or release of reactive species
or membranolytic digestive enzymes into the
still-exterior annulus. Another possible effect
is to alter the maturation of the annular frustrated
phagocytic membrane from the normal
structural and functional evolution of a
closed phagolysosomal vesicle fully interior to
the cell. Even in the response to such a frustrated
phagocytosis, there might be some mineral
specificity beyond morphology alone for EMPinduced
release of reactive species. Amosite fibers,
MMVF, silicon carbide fibers, and RCF-1
fibers all stimulated modest release of SO that
was not dose-dependent in isolated rat alveolar
macrophages. However, when IgG, a normal
component of lung lining fluid, was adsorbed
onto the fiber surfaces, SO release was strongly
enhanced for all but the silicon carbide fibers.
SO release correlated with fibers’ IgG- adsorptive
capacity, except for the amosite, which required
only poorly adsorbed IgG for strong activity,
suggesting some mineral specificity beyond
morphology alone for the EMP-induced cellular
respiratory burst [Hill et al. 1996].
2.9.4.3.4 Cellular Responses to Initiation
of Toxicity
Subsequent to initiating damage by direct or induced
ROS generation—by direct membranolysis
generated by interactions of mineral surface
sites with membrane lipids or glycoproteins,
or by not-fully-defined toxic response to morphology-based
frustrated phagocytosis—a standard
model for consequent complex cellular response
has evolved and has been the subject of
extensive and detailed analyses [Mossman et
al. 1997]. EMP-generated primary toxic stimuli
to the cell are subject to signal transduction by
mitogen-activated protein kinase (MAPK), beginning
an intracellular multiple kinase signal
cascade, which then induces transcription factors
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in the nucleus such as activator protein (AP)-1 or
nuclear factor kappa beta (NF-κB), which in turn
regulate the transcription of mRNA from genes
for TNF-α or other cytokines involved in cell proliferation
or inflammation.
Fibers of the six asbestos minerals generate
MAPK in lung epithelium in vitro and in vivo,
increasing AP-1 transcription activation, cell
proliferation, death, differentiation, or inflammation.
This is synergistic with cigarette smoke
[Mossman et al. 2006]. Macrophage release of
oxidants or mitogenic factors through such a
pathway could then cause cell proliferation or
DNA damage [Driscoll et al. 1998]. In contrast
to MMVF-10 and RCF-4, amosite and two other
carcinogenic fibers (silicon carbide and RCF-1)
produced significant dose-dependent translocation
of NF-κB to the nucleus in A549 lung epithelial
cells. It was hypothesized that carcinogenic
fibers have greater free radical activity, which
produces greater oxidative stress and results in
greater translocation of NF-κB to the nucleus
for the transcription of pro-inflammatory genes
(e.g., cytokines) [Brown et al. 1999]. Crocidolite
induced AP-1 in vitro in JB6 cells and induced
AP-1 transactivation in pulmonary and bronchial
tissue after intratracheal instillation in transgenic
mice, apparently mediated by activation of
MAPK [Ding et al. 1999]. Chrysotile challenge
to blood monocytes co-cultured with bronchial
epithelial cells resulted in elevated levels in epithelial
cells of protein-tyrosine kinase activity,
NF-κB activity, and mRNA levels for interleukin
(IL)-1β, IL-6, and TNF-α. Protein-tyrosine kinase
activity, NF-κB activity, and mRNA synthesis
were inhibited by antioxidants, suggesting
ROS-dependent NF-κB-mediated transcription
of inflammatory cytokines in bronchial epithelial
cells [Drumm et al. 1999].
Chemokines known to be associated with particle-induced
inflammation were found to be
NIOSH CIB 62 • Asbestos