Environmental Engineering Reference
In-Depth Information
Paracellular
route
Transcellular
route
Airway epithelium
Basement membrane
Alveolar capillary
FIGURE 9.1 
Diagram of paracellular and transcellular route of transfer through the respiratory epithelium.
large numbers of membrane vesicles within the type I alveolar epithelial cells has been recognized
for many years (reviewed in Gumbleton, 2001). However, the function of these vesicles remains
unclear. It has been hypothesized that vesicular transport may provide a route of transport for sol-
utes from the alveolar to interstitial surfaces of the epithelial cells. Recovery of the lung from edema
requires the removal of protein across the alveolar epithelium, and this is believed to occur via
endocytic transcytosis routes as well as via paracellular routes (Hastings et al., 2004). Endocytosis
is the more important mechanism at low protein concentrations, but the paracellular route becomes
increasingly important on exposure to high protein concentrations. During edema or acute lung
injury, it is suggested that transcellular routes become more active in order to clear protein from the
lung surface (Hastings et al., 2004). Therefore, it is feasible that nanoparticles could cross this bar-
rier by both transcellular and paracellular routes, especially in a diseased lung.
Phagocytic uptake is thought to be restricted to specialized cells such as macrophages and neu-
trophils (Conner and Schmid, 2003) and is generally responsible for the uptake of large materials
(greater than 0.5 μm) such as bacteria or cell debris (Khalil et al., 2006). In the lung this is espe-
cially important as inhaled air provides a route of delivery of foreign particles and microorganisms
into the body; therefore, macrophages are essential for maintaining a clear, sterile, and functioning
respiratory surface. During phagocytosis, the cell recognizes ligands via cell surface receptors.
Receptor binding then triggers the polymerization and rearrangement of the actin cytoskeleton to
form membrane extensions so that the plasma membrane surrounds the material to be internalized
(Liu and Shapiro, 2003; Perret et al., 2005; Khalil et al., 2006). The phagosome that is formed then
fuses with lysosomes so that the cargo can be degraded (Perret et al., 2005).
When the alveolar macrophages' ability to phagocytose becomes impaired, the integrity of the
epithelium can also become compromised. Non-phagocytosed particles interact with epithelial
cells, which can lead to necrosis or apoptosis (Iyer et al., 1996) as well as activation leading to the
release of pro-inlammatory cytokines (Driscoll et al., 1995, 1996; Finkelstein et al., 1997). On
exposure to high particle concentrations, used in many toxicology studies, lung overload is induced
in susceptible species (i.e., rats) (Bermudez et al., 2002), resulting in compromised epithelial cells,
Type I cell hyperplasia and inlammation. The continuing presence of non-phagocytosed particles
on the injured, activated and partially denuded epithelial surface will enhance their likelihood of
being transferred to the interstitium. As these particles become interstitialized, they are likely to
interact with interstitial macrophages that reside in close contact with ibroblast, epithelial, and
endothelial cells (Adamson and Hedgecock, 1995). The proximity of the macrophages to these cells
means that any mediators released by the interstitial macrophage can have a detrimental impact on
the interstitial basement membrane and other interstitial cells leading to interstitial ibrosis. These
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