Respiratory and Cardiovascular Effects of Metals in Ambient Particulate Matter: A Critical Review - Reviews of Environmental Contamination and Toxicology - page 191

associated with health in the studies we reviewed, only Ni and V do not have a
known role in normal physiological processes. Thus, it is not surprising that high
level exposures to these two metals can elicit signifi cant toxic responses.

3.3.3 In Vitro Studies

Evidence from the in vivo studies previously described indicates that transition metal
constituents may have a role, either alone or in mixtures, in producing the responses
observed in animals exposed to PM from various sources. Several investigators have
studied the mechanisms by which metals may produce infl ammation, ROS, and/or
altered gene expression, by conducting in vitro studies with human or animal cell
cultures and/or with cell-free systems. The studies that we summarize in this section
have generally shared a common experimental design. That design usually involved
exposing cells in culture to ambient particulate extracts and/or to solutions of the
target individual transition metals and then measuring the production of infl amma-
tory cytokines or upstream markers of genes active in the infl ammatory process and/
or cell death at time intervals after exposure. As with many in vivo studies, chelating
agents were often added to in-vitro systems to confi rm that observed effects were
fully or partially attributable to transition metal exposures, especially iron.
The in vitro studies that we reviewed fell into two major groupings according to
the responses that were examined. In one group, indicators of cell death (release of
LDH), metabolic activity (e.g., glutathione, mitochondrial succinate dehydroge-
nase) and indicators of infl ammation were examined: Alley ( 2009 ), Aust et al.
( 2002 ), Carter et al. ( 1997 ), Duvall et al. ( 2008 ), Dye et al. ( 1999 ), Ghio et al.
( 1999a , b ), Jalava et al. ( 2009 ), Smith et al. ( 2000 ), Okeson et al. ( 2004 ), Riley et al.
( 2003 ), and Zhou and Kobzik ( 2007 ). In the second group, the expression of specifi c
genes and upstream signaling pathways involved in infl ammation were examined:
Graff et al. ( 2004 ), Gutierrez-Castillo et al. ( 2006 ), Jaspers et al. ( 2000 ), Kennedy
et al. ( 1998 ), Klein-Patel et al. ( 2006 ), Nadadur et al. ( 2009 ), Prophete et al. ( 2006 ),
Salnikow et al. ( 2004 ), Wu et al. ( 2003 ), Wang et al. ( 2003 ), and Kim et al. ( 2006 ).
The major fi ndings of these studies are summarized in Table 10 .
We have concluded from the analysis of in vitro studies we reviewed that metals
associated with particulate matter, especially Ni, V and Zn (in ROFA) can signifi -
cantly affect the viability and metabolic activity of airway cells in culture, possibly
by producing ROS and altering expression of genes involved in infl ammation and
macrophage anti-microbial activity. Vanadium appears to be the most toxic of the
transition metals associated with ROFA and may infl uence the expression of genes
in the signaling pathway that ultimately produces the infl ammatory cytokines. There
is evidence both for and against the role of Fe as either a participant in inducing the
release of infl ammatory markers or as a moderating factor in the hypoxic stress
produced by other metals (e.g., Ni). These putative cell and molecular-level mecha-
nisms of action are consistent with the fi ndings of the in vivo studies demonstrating
that exposures to high levels of metals increase markers of infl ammatory response
in respiratory tract tissues.