Uptake and Effects of Carbon Nanotubes - Safety of Nanomaterials along Their Lifecycle - page 215

be due to differences in well-dispersed SWCNTs, which would likely not be readily
taken up by phagocytosis, versus agglomerated SWCNTs, which would more likely
be recognized as a larger particle and engulfed by roaming phagocytes. As discussed
earlier, the aggregation status is also likely an important determinant toward evalu-
ating the toxicity of CNTs and the type of resulting lung pathology (i.e., granuloma
versus interstitial fibrosis).
CNTs taken up by macrophages via phagocytosis are cleared from the lungs
through two primary mechanisms: (a) the mucociliary escalator and (b) the lym-
phatic drainage system. The mucociliary escalator is comprised of a coating of
mucus on the surface of the airways that is constantly moving up the airways
by the coordinated movement of cilia on the airway epithelium (Bonner 2008).
Macrophages with engulfed particles or fibers migrate to the distal portion of
small airways where they are transported by the escalator to larger airways and
ultimately out of the trachea where they are swallowed or expelled through cough-
ing. Migration of macrophages containing CNTs across the pleura could cause
adverse effects (e.g., DNA damage to mesothelial cells) as CNTs could possess
some physical characteristics (e.g., high aspect ratio, durability) similar to asbestos
fibers (Bonner et al. 2010a; Donaldson 2010). However, the possible carcinogenic-
ity of CNTs remains controversial.
The clearance of inhaled MWCNTs from the lungs and lung associated lymph
nodes (LALNs) has been modeled in rats (Pauluhn et al. 2010). This was accom-
plished by measuring concentrations of residual cobalt (Co) catalyst in the lung and
LALN 13 weeks after a nose-only inhalation exposure for 6 hours/day × 5 days/
week, and a 6 month postexposure period. In this study, the authors observed the
half-life for MWCNT elimination at 151, 350, 318, and 375 days to be 0.1, 0.4, 1.5,
and 6 mg/m 3 , resp e ct ively.
10.3.2 C ellular r esPonses to n anotuBes
Macrophages react to CNTs in a variety of different ways, some of which are depen-
dent on the physical and chemical characteristics of the CNTs. Uptake of CNTs
could have a variety of consequences related to macrophage biology and function.
As illustrated in Figure 10.3, CNTs cause inflammasome activation in macrophages
which results in the processing and secretion of the proinflammatory cytokines IL-1β
and IL-18 (Palomäki et al. 2011; Meunier et al. 2012; Sun et al. 2012). Inflammasome
activation by CNTs and other high aspect ratio materials (e.g., asbestos fibers) is
mediated by lysosomal disruption and ROS production. Moreover, the level of resid-
ual nickel catalyst in MWCNTs has been shown to play an important role in inflam-
masome activation in macrophages (Hamilton et al. 2012). Inflammasome activation
and consequent IL-1β production is an important innate immune response for recruit-
ing neutrophils to the lung to participate in microbial killing (Martinon, Mayor, and
Tschopp 2009). Also the dysregulation of inflammasomes has been implicated in a
variety of disease states (Strowig et al. 2012). Macrophages can also be “alternatively
activated” in the presence of Th2 cytokines IL-4 or IL-13 to produce growth fac-
tors (e.g., PDGF, TGF-β1) that are involved in the pathogenesis of fibrosis (Gordon
and Martinez 2010). It is currently unknown whether CNTs stimulate alternative