Health Effects of Aerosols - Aerosols: Measurement, Dosimetry, and Health Effects - page 581

and their oxy-derivatives initially activate genes that lead to the induction of hemoxygenase-1 (HO-1)
and superoxide dismutases. “Low-level” oxidative stress is deined as the normal ratio of reduced glu-
tathione to oxidized glutathione (GSH:GSSG). The oxidation of GSH is mediated by several enzymes
that convert reactive oxygen species precursors to less reactive species and is one of the major cellular
pathways for the control of reactive oxygen species [62]. HO-1 is involved in the metabolism of hemo-
globin and leads to the production of antioxidants (bilirubin) and anti-inlammatory (carbon monoxide)
end products [62]. Superoxide dismutases catalyze the conversion of O 2 •2 to H 2 O 2 , which is converted to
water through a catalase-mediated reaction. A decreasing GSH:GSSG ratio indicates a failure of these
and other host defenses against oxidant stress (e.g., antioxidants in lung lining luid and blood [vitamin
C, urea] or in cell membranes [vitamin E]) to “neutralize” the oxidative stress [62,63]. Persistence of
ROM leads to the activation of cell signaling cascades that ultimately lead to the activation of nonal-
lergic and allergic inlammation, peroxidation of cell membranes, programmed cell death, and cell
necrosis [57,62,64]. The inlammatory process itself generates additional ROM that are part of normal
cellular defense mechanisms ([36,65] and Section V in Ref. [66]) and downregulates enzymes involved
in the metabolism of ROM [67], thereby creating an ongoing cycle of cellular injury (see the discussion
in Ref. [68]). Ultraine particles derived from urban formation and receptor sites have been found to be
important sources of the oxidative stress induced by PM in vitro [38] and in animal toxicology studies
[69,70]. Components of ine and coarse PM also lead to oxidant stress either directly [38] or indirectly
through bioaerosol components such as endotoxins that are part of the coarse fraction of PM and are
potent inducers of inlammation [71] (see the following). Several studies of ambient PM have indicated
that endotoxin may be as important a source for inlammation as are metals and organic components
[6,9,72]. Through interactions with speciic lymphocyte receptors, endotoxin activates many of the
same signaling pathways that are activated by organic components of PM created by the activities of
man [73]. This activation is the source of the potent inlammatory potential of endotoxin.
Oxidative stress provides a link between the immunomodulatory effects of DEP with regard to
the immunological mechanisms that underlie asthma and allergic conjunctivitis/rhinitis (so-called
hay fever) [57,74-79]. The ability of the metal content of ROFA to enhance sensitization to house dust
mite in rats indicates the likelihood that a wide variety of redox-active PM sources also contribute
to effects of allergen response enhancement through the generation of ROM and the pathways
summarized in Figure 23.14 [80,81]. Oxidative stress plays an important role in the carcinogenic
potential attributed to diesel exhaust through its capacity to induce mutagenesis, the production of
DNA strand breaks and DNA adducts, and the induction or inhibition of lung metabolic enzymes
[67,82-84].
23.4.2 P article a erosol i nduction oF i nFlaMMation
The production of ROM may be the inal common pathway through which anthropogenic and bio-
logical components of particle aerosols lead to the production of inlammation. Nonetheless, the
ability of PM aerosol to produce inlammation is of suficient importance to justify some expansion
of this component of PM aerosol effects.
Exposure of pulmonary macrophages [6,9,72,85,86], lung epithelial cells [50,87-89], and
peripheral blood monocytes [8] leads to the activation of various molecular signaling pathways for
the induction of inlammation (see Figure 23.14). Transition metals, endotoxins, and organic car-
bon fractions of PM have all been found to trigger inlammation in vitro (see references in previous
sections and [88]). The relevance of these in vitro indings to human health is supported by indings
of increased levels of the pro-inlammatory cytokine interleukin 8 (IL-8) in the airways [90] and
increased neutrophils and myeloperoxidase in the sputum [91] of healthy volunteers exposed to
diesel exhaust in an exposure chamber under controlled conditions. Inhaled PM of anthropogenic
origin has systemic effects evidenced by the stimulation of bone marrow (increased production and
release of polymorphonuclear leukocytes by supernatants from human alveolar macrophages stim-
ulated with PM 10 [85,92,93]). Intratracheal exposure of rats to ROFA has been shown to increase