Uptake and Effects of Carbon Nanotubes - Safety of Nanomaterials along Their Lifecycle - page 219

mediator of collagen production by mesenchymal cells (fibroblasts and myofibro-
blasts). However, MWCNTs containing nickel catalyst produce very little or no
detectable TGF-β1 in the lungs of mice exposed to inhalation or in the lungs of rats
exposed by instillation (Ryman-Rasmussen et al. 2009b, Cesta et al. 2010). Other
factors such as osteopontin (OPN) could serve to stimulate collagen deposition and
fibrosis in the absence of TGF-β1. OPN mRNA levels are highly induced in the
lungs of rats exposed to SWCNTs (Mangum et al. 2006). Alveolar macrophages, as
well as airway epithelial cells and fibroblasts, produce PDGF, TGF-β1, and OPN.
Macrophages are also a rich source of IL-1β and IL-6 (Shvedova et al. 2008), and
these two cytokines promote tissue fibrogenesis and are increased in the lungs of
mice exposed to inhaled SWCNTs. Several chemokines are also induced by CNT
exposure and drive the inflammatory response in the lung. CXCL8 (IL-8), a potent
neutrophil chemoattractant, is produced by a human bronchial epithelial cell line
in vitro after exposure to MWCNTs (Hirano et al. 2010). CCL2, also known as
monocyte chemoattractant protein-1 (MCP-1), is elevated in the lavage fluid of mice
exposed to MWCNT by inhalation (Ryman-Rasmussen et al. 2009a). CCL2 is also
produced by pleural mesothelial cells (Visser et al. 1998), and is a candidate that
mediates mononuclear cell accumulation that occurs at the pleura of mice after
inhalation of MWCNTs (Ryman-Rasmussen et al. 2009a). In addition to soluble
mediators, cell-cell interaction stimulated by CNTs could play a role in the patho-
genesis of inflammatory or fibrogenic reactions. For example, understanding how
CNTs affect the physical interaction between epithelial cells and underlying mes-
enchymal cells (termed the epithelial-mesenchymal cell trophic unit) could yield
important insight into airway remodeling events. Likewise, since inhaled CNTs
migrate to the subpleural tissues and remain there for months, it will be important
to gain an understanding of how CNTs influence the interaction between mesothe-
lial cells and subpleural mesenchymal cells.
10.4.2 P leural d isease and C anCer
As mentioned earlier in this chapter, CNTs are cleared from the lungs via mac-
rophage-mediated mechanisms and one route that macrophages take to remove
particles from the lungs is across the pleural lining via the lymphatic drainage.
Therefore, CNTs have the opportunity to interact with the mesothelial lining
that makes up the pleura. The durable nature of CNTs along with their fiber-like
shape could pose a problem of long-term lung persistence, which might result
in asbestos-like behavior and carcinogencity (i.e., mesothelioma). As shown in
Figure 10.4, inhaled CNTs migrate to the subpleural tissue in mice and produce
transient proinflammatory lesions on the pleural surface that have been referred to
as mononuclear cell aggregates (Ryman-Rasmussen et al. 2009a). As illustrated in
Figure 10.5, the accumulation of mononuclear cell aggregates could be facilitated
by increased levels of the chemokine CCL2, which is increased in the lungs of
mice exposed to MWCNTs (Ryman-Rasmussen et al. 2009a). Moreover, CCL2
is produced by cultured pleural mesothelial cells stimulated with PDGF, which is
produced by activated alveolar macrophages. In addition to mononuclear cell accu-
mulation at the pleura, MWCNT inhalation exposure caused subpleural fibrosis