Uptake and Effects of Carbon Nanotubes - Safety of Nanomaterials along Their Lifecycle - page 217

against lung diseases that are increased to counteract ROS-induced cellular stress
initiated by CNTs.

10.4 PATHOLOGICAL EFFECTS

10.4.1 f iBrosis and g ranuloma f formation
In some ways CNTs share features of asbestos fibers, mainly with regard to their
fiber-like shape and aspect (length to width) ratio. Asbestos fibers are a known cause
of fibrosis and mesothelioma in humans. However, CNTs also have uniquely dif-
ferent properties from asbestos, including nanoscale width and highly conformal
structure. Also, different kinds of CNTs (e.g., multiwalled vs. single-walled) could
produce different pathologic effects.
Rodent inhalation and instillation studies demonstrate that CNTs cause pulmo-
nary inflammation (Li et al. 2007; Shvedova et al. 2008; Ryman-Rasmussen et al.
2009a, 2009b; Ma-Hock et al. 2009; Pauluhn et al. 2010). Pulmonary fibrosis is
also a common pathologic feature observed in rodent studies of CNT exposure (Li
et al. 2007; Shvedova et al. 2007; Ryman-Rasmussen et al. 2009a, 2009b; Pauluhn
et al. 2010). CNT exposure also affects the upper respiratory tract, and goblet cell
hyperplasia and inflammation have been observed in the nasal cavity and upper air-
ways of rodents (Ma-Hock et al. 2009; Pauluhn et al. 2010). Pulmonary inflamma-
tion and fibrosis resulting from intratracheal instillation of CNTs generally produce
granulomatous lesions, which is likely due to CNT aggregation into micron-sized
bundles in aqueous media (Mangum et al. 2006; Lam et al. 2004; Muller et al.
2005; Shvedova et al. 2005; Warheit et al. 2004). Foci of granulomatous lesions
and collagen deposition in mice are associated with dense particle-like SWCNT
agglomerates (Murray et al. 2012). In contrast, interstitial pulmonary fibrosis is
associated with dispersed CNTs that require transmission electron microscopy for
detection (Ryman-Rasmussen et al. 2009a). Improved methods for CNT dispersion
in aqueous media result in pathology that more closely resembles that caused by
inhalation exposure. For example, dispersal of MWCNTs by bovine serum albumin
(BSA) and dipalmitoylphosphatidylcholine has been reported to influence cytokine
and growth factor production by lung cells in vitro and predict pulmonary fibrosis
in vivo in mice. Well-dispersed MWCNTs were readily taken up by macrophages
and induced more robust growth factor (PDGF-AA, TGF-β1) and IL-1β production
than nondispersed MWCNTs. These results indicated that the dispersal state of
MWCNTs affected profibrogenic cellular responses that correlate with the extent
of pulmonary fibrosis.
Comparisons of the lung pathological effects between inhalation and other meth-
ods of pulmonary exposure have been performed. Comparison of instillation with
inhalation methods for delivery of MWCNT in mice showed a more diffuse pat-
tern of deposition with inhalation than that was observed after intratracheal instil-
lation of a bolus dose of MWCNT and greater interstitial pulmonary fibrosis (Li
et al. 2007). Also a study utilizing SWCNT that compared inhalation exposure
with oropharyngeal aspiration (OPA) showed that the pulmonary effects were simi-
lar in both cases, but were more severe for the inhaled SWCNTs, which caused