1. Metals Toxicity
A Role for Associated Transition Metals in the Immunotoxicity of Inhaled
Ambient Particulate Matter
Judith T. Zelikoff, Kimberly R. Schermerhorn, Kaijie Fang, Mitchell D. Cohen, and Richard B. Schlesinger
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA
previously infected with S. pneumoniae were
subsequently exposed to concentrated PM
Epidemiologic studies demonstrate that infection, specifically pneumonia, contributes substan-
with aerodynamic diameter ≤ 2.5 µm
tially to the increased morbidity and mortality among elderly individuals following exposure to
(PM2.5) (at a level at or just above the PM2.5
ambient particulate matter (PM). This laboratory has previously demonstrated that a single
National Ambient Air Quality Standard
inhalation exposure of Streptococcus pneumoniae–infected rats to concentrated ambient PM2.5
(particulate matter with aerodynamic diameter ≤ 2.5 µm) from New York City (NYC) air exacer- [NAAQS]) from New York City (NYC) to
determine whether acute exposure to PM
bates the infection process and alters pulmonary and systemic immunity. Although these results
induces immunologic alterations within the
provide some basis for explaining the epidemiologic findings, the identity of specific PM con-
lungs that could exacerbate an ongoing
stituents that might have been responsible for the worsening pneumonia in exposed hosts remains
S. pneumoniae infection. Results from these
unclear. Thus, studies were performed to correlate the physicochemical attributes of ambient
studies demonstrated that a single inhalation
PM2.5 with its in vivo immunotoxicity to identify and characterize the role of constitutive transi-
exposure of ambient PM2.5 worsened disease
tion metals in exacerbating an ongoing streptococcal infection. Uninfected or previously infected
outcome and compromised both local and
rats were exposed in the laboratory to soluble divalent Fe, Mn, or Ni chloride salts. After exposure,
systemic immune defense mechanisms in
uninfected rats were sacrificed and their lungs were lavaged. Lungs from infected hosts were used
exposed animals (12).
to evaluate changes in bacterial clearance and effects of exposure on the extent/severity of infec-
Studies were also performed to determine
tion. Results demonstrated that inhalation of Fe altered innate and adaptive immunity in unin-
which constituent(s) might be responsible for
fected hosts, and both Fe and Ni reduced pulmonary bacterial clearance in previously infected rats.
the observed worsening of pneumonia in
The effects on clearance produced in infected Fe-exposed rats were similar to those seen in
PM-exposed hosts. Based upon results from a
infected rats exposed to ambient NYC PM. Taken together, these studies demonstrate that
number of in vivo and in vitro investigations
inhaled ambient PM can worsen the outcome of an ongoing pulmonary infection and that associ-
demonstrating the role of particle-associated
ated Fe may play some role in the immunotoxicity. Key words: air pollution, immunotoxicity,
transition metals in mediating PM-related
inhalation, metals, particulate matter, pulmonary immune defenses. Environ Health Perspect
health effects (13–16), as well as the ability of
110(suppl 5):871–875 (2002).
some of the same metals to suppress host
http://ehpnet1.niehs.nih.gov/docs/2002/suppl-5/871-875zppppppppppppppppppelikoff/abstract.html
immunocompetence (17), experimental stud-
ies were performed to characterize the role of
Epidemiologic studies have reported that observed increase in particle-induced constitutive transition metals in exacerbating
exposure to ambient levels of airborne particu- mortality in elderly individuals. Studies ongoing pneumococcal infections.
late matter with an aerodynamic diameter of using rodent models have clearly demon-
≤ 10 µm (PM10) results in consistent increases strated that exposure to inhaled particles Materials and Methods
in morbidity and mortality (1–3), and that (alone or in combination with gaseous air Experimental Animals
elderly individuals seem to be particularly pollutants) can compromise pulmonary host
affected (4,5). Infection, specifically pneumo- Pathogen-free male Fischer 344 rats (Harlan
resistance against microbial infections
nia, contributes substantially to the mortality Sprague Dawley, Indianapolis, IN, USA) 7–9
and/or alter specific immune mechanisms
among elderly individuals exposed to PM, and months of age were quarantined for at least
important for antibacterial defense. For
disproportionate increases in deaths due to 1 week prior to use in any experiments. Rats
example, Aranyi et al. (9) demonstrated that
pneumonia have been observed immediately were housed individually in stainless steel
intratracheal (IT) instillation of mice with
or just after even moderate episodes of particu- cages in temperature- and humidity-con-
either quartz, ferric oxide, calcium carbon-
late air pollution (6,7). These epidemiologic trolled rooms and provided food and water
ate, or sodium feldspar particles increased
findings suggest that PM may act as an ad libitum. In addition to serology testing for
mortality from subsequent infection with S.
immunosuppressive factor that can undermine viral and bacterial pathogens, rats were exam-
pneumoniae. In other bacterial infectivity
the normal pulmonary immune response. ined routinely during the exposure studies for
studies, instillation of aged urban air parti-
Thus, given that older individuals with chronic any gross indication of spontaneous infection
cles (0.4 µm, mass median aerodynamic
respiratory disease are not only at increased risk or for mucosal irritation due to exposure.
diameter [MMAD]) and/or coal fly ash par-
of pneumonia but also are less likely to recover ticles (0.9 µm MMAD) reduced the resis-
from infections (8), alterations in the pul- tance of mice to bacterial infection (10).
This article is part of the monograph Molecular
monary immune system may well play a role Moreover, studies in this laboratory demon-
Mechanisms of Metal Toxicity and Carcinogenicity.
in the observed increase in mortality following strated that inhalation of woodsmoke efflu- Address correspondence to J.T. Zelikoff, New
PM episodes. ents reduced pulmonary clearance of York University School of Medicine, 57 Old Forge
Toxicologic studies demonstrating the IT-instilled Staphylococcus aureus (11). Rd., Tuxedo, New York 10987-5007 USA.
immunosuppressive potential of particles in Although it has been demonstrated that Telephone: (845) 731-3528. Fax: (845) 351-5472.
E-mail: judyz@env.med.nyu.edu
the lungs strengthen the epidemiologic the elderly with preexisting disease appear to
The authors thank L. Wang for her help in initiat-
observations and support the hypothesis that be at higher risk from the adverse effects of
ing this project. This work was supported by U.S.
compromised pulmonary host immunocom- PM than healthy individuals, considerable Environmental Protection Agency Center grant
petence and immune defense mechanisms uncertainty remains about specific biologic R827351 and Health Effects Institute contract
important for resistance against Streptococcus mechanisms that might underlie this effect. 94-03A.
pneumoniae infections contribute to the Thus, studies were performed in which rats Received 2 April 2002; accepted 4 June 2002.
871
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2. Metals Toxicity Zelikoff et al.
•
Infected rats were maintained individually in into fresh Todd Hewitt (TH) broth and which were measured on a percentage scale,
HEPA filter-top cages and housed in an maintained at 37°C in a 5% CO2 atmosphere. the need for arcsine transformation was deter-
onsite Biosafety Level 2 facility. Animals used The cultures were then passaged at 12-hr inter- mined prior to analysis. Differences were
in this research have been treated humanely vals using a protocol that maintained both the considered significant at p < 0.05.
according to institutional guidelines. virulence and capsulated nature of the organ-
Results
ism. On the day of instillation, the bacterial
Experimental Design concentration was spectrophotometrically In studies examining the effects of concen-
Male rats previously infected by IT instillation determined using an absorbance calibration trated ambient PM (CAPS), previously
with 15–20 × 106 S. pneumoniae were exposed curve prepared at 540 nm and a suspension infected rats were sacrificed 4.5, 9, 18, 24,
for 5 hr to either ambient NYC PM2.5 (65–90 diluted with phosphate-buffered saline (PBS) and 120 hr after exposure, and effects upon
µg/m3) or to a single PM-associated transition to a suitable concentration for delivery of 1–2 bacterial burdens were determined (Figure 1).
× 107 organisms in a 100-µL volume.
metal (i.e., iron [Fe2+], manganese [Mn2+], or Results demonstrated that although numbers
nickel [Ni2+]) of a similar concentration and At designated time intervals, cohorts of of pulmonary bacteria were approximately
MMAD (i.e., 0.4 µm; Σg = 2.4 µm) and then four rats each were sacrificed by injection of equal in the two exposure groups at the
sacrificed at different time points postexpo- Nembutal (sodium phenobarbital; 80 earliest postexposure time point (i.e., 4.5 hr
sure. Effects of inhaled transition metals were mg/kg, sc) and the lungs were removed, postexposure), bacterial burdens in the
also determined in uninfected rats. At the weighed, and homogenized (19). To obtain CAPS-exposed animals were approximately
time of sacrifice, lungs were a) lavaged to pro- estimates of total remaining viable organ- 10% above those measured in the air controls
vide fluid for evaluation of markers of lung isms, aliquots of the homogenate were seri- by 9 hr; by 18 hr, burdens were elevated
cell damage (i.e., lactate dehydrogenase ally diluted and plated onto triplicate sheep >300%. After 24 hr CAPS-exposed rats had
[LDH] and total protein) or to provide cells blood-TH agar plates for a 24-hr incubation substantially greater (i.e., 70% change from
for characterization; b) fixed for histopatho- at 37°C (in 5% CO2) before enumeration. control) bacterial burdens than infected con-
logic examination; or c) homogenized for Both the absolute levels of bacteria and the trol rats. At 5 days postexposure, total num-
determination of effects on pulmonary bacter- levels of bacteria per gram lung compared ber of bacteria per gram lung was still 30%
ial burdens. Blood taken from the portal vein with those in three randomly infected rats above that measured in the lungs of the
prior to sacrifice was used to determine rela- sacrificed immediately prior to beginning infected air-exposed controls.
tive percentages of circulating white blood inhalation exposure were used as indices of Uninfected rats exposed nose-only to
either Fe, Mn, or Ni at 65–90 µg/m 3
cells. A total of 100 white blood cells per slide bacterial survival.
(two slides per preparation) were counted for demonstrated significant alterations in blood
Bronchopulmonary Lavage and
differential counts. cell profiles (Figure 2A, B, C, respectively).
Biologic Assays Although polymorphonuclear leukocyte
Exposures At sacrifice, lungs from uninfected rats were (PMN) levels significantly increased,
Ambient PM and filtered air exposures lavaged by washing the left lung in situ
twice with Ca 2 + - and Mg 2 + -free PBS
took place in Teflon nose-only exposure (% change compared with filtered-air control)
units (CH International, Westwood, NJ, according to previously employed methods **
USA) located in a building overlooking a (20). Spleens were also recovered and placed 300
main thoroughfare in Manhattan, NYC. in RPMI 1640 on ice until processed for
Relative bacterial burdens
Concentrated ambient PM 2.5 air was pro- measurement of lymphoproliferative
duced using a Gerber centrifugal concentra- responses. Aliquots of acellular lavage fluid 200
tor; gaseous pollutants such as ozone, sulfur were then used to evaluate LDH activity
dioxide, nitrogen dioxide, and ammonia and total protein (21). Lavaged cell num-
100
were removed prior to exposure (18). The bers and viability were determined by *
exposure atmosphere was continuously mon- hemocytometer counting and trypan blue
itored using a condensation particle counter exclusion, respectively. Recovered lavaged 0
and real-time aerosol monitor. In addition, cell types were subsequently characterized
filter samples were collected during exposure morphologically by differential counting of
on Teflon membrane filters to gravimetri- stained cells. Basal and serum-opsonized, –100
0 4.5 9 18 24 120
cally measure integrated exposure mass con- zymosan-stimulated production of super-
oxide anion (O 2 •– ) by pulmonary macro- Time postexposure (hr)
centrations on a Cahn electrobalance.
For the individual metal exposure studies, phages (Mø) was assessed using a microtiter Figure 1. A single exposure of already-infected rats
previously infected and naive rats were plate assay based upon the reduction of fer- to CAPS significantly increased pulmonary bacter-
exposed by inhalation (i.e., nose-only) for 5 hr ricytochrome c (20). Proliferation of splenic ial burdens of S. pneumoniae in a time-dependent
manner (compared with the infected, air-exposed
to chloride salts of either Fe, Mn, or Ni at a T and B lymphocytes was measured in
control). Estimates of viable bacterial organisms
concentration of 65–90 µg/m3. All atmos- response to stimulation with concanavalin
were determined from colony counts on blood-TH
pheres were generated by passing freshly pre- (Con) A and lipopolysaccharide (LPS), agar 24 hr after plating. Both the absolute levels of
pared solutions of each metal compound respectively (22). bacteria and the levels of bacteria per gram lung
through a collision nebulizer; generated parti- compared with those in three randomly-infected
Statistical Analyses
cles were then delivered to each rat held in rats sacrificed immediately prior to beginning
inhalation exposure were used as indices of bacte-
individual body tubes (CH International) on The effects of PM exposure itself upon each
rial survival. Postexposure time 0 represents those
a single-exposure tree (12). of the assayed parameters (i.e., exposed vs. air
burdens determined immediately prior to exposure.
control), as well as those effects associated Asterisk (*) indicates value significantly different
Pulmonary Bacterial Clearance with length of time post-PM exposure, were from filtered-air control (p < 0.05). Double asterisks
Six days prior to instillation, S. pneumoniae analyzed using a two-way analysis of variance. (**) indicate significantly different from filtered-air
(encapsulated, type 3) was introduced For outcomes such as bacterial clearance, control (p < 0.01).
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3. Metals Toxicity Role of associated metals in PM immunotoxicity
•
lymphocyte values significantly decreased at to inhibit clearance, inhalation of Fe facili- air-exposed control animals (Table 1).
1 hr postexposure; however, by 18 hr post- tated an increase in overall bacterial numbers. Although lung cell viability was unaffected at
exposure, leukocyte values reached control Inhalation of Fe by infected rats also 18 hr postexposure, lavageable cell numbers
levels. Acute inhalation of Mn and Fe had no altered lavageable cell numbers and immune in the Fe-exposed infected rats decreased by
effect upon lavageable cell number or lung cell profile compared with those of infected 35% compared with levels in time-matched
histologic profile, and none of the metals
PMN Lymphocyte Con A-stimulated LPS-stimulated
altered cell viability or LDH activity (com- 0.6
100
A
pared with control). In contrast, inhalation Fe A
Air
Optical density
of Ni significantly reduced lavaged cell num- *
80 Fe
0.4
bers by 25% (i.e., 40 × 106 vs 30 × 106 cells
60
for control and Ni-exposed rats, respectively) 0.2
and increased percent lung involvement and 40
*
alveolar edema/exudate 1 hr postexposure *
0
20
(data not shown). 0.6
Metal exposure also altered certain pul- Ni B
0
Optical density
1 18 48 1 18 48
monary and systemic immune functional
0.4
100
activities in uninfected animals. Inhalation B
*
Air
exposure to Fe significantly increased (com- 80 Mn 0.2
pared with time-matched air controls) basal *
Percentage
production of O2•– by lavaged Mø 18 and 48 60
0
hr postexposure (Figure 3); inhalation of Fe Air 1 18 48 Air 1 18 48
40
had no effects on O2•– production by stimu- *
Time postexposure (hr)
lated Mø at any postexposure time point. 20
Figure 4. Inhalation of Fe (A) and Ni (B) by naive rats
Although exposure of naive rats to Mn had no alters proliferative responses of mitogen-stimulated
0
effect upon lymphoproliferation (data not 1 18 48 1 18 48 B and T lymphocytes, respectively. Each bar (except
shown), inhalation of Fe or Ni significantly 100 pooled air control, which represents the mean of 12
C
altered the ability of splenic lymphocytes to rats) represents the mean (± SD) from four rats per
Air
*
80 Ni exposure group. Asterisk (*) indicates value signifi-
proliferate in response to mitogen stimulation
cantly different from individual time-matched air
(Figure 4A, B). Inhalation of Fe significantly 60
control (p < 0.05).
reduced B-lymphocyte proliferation in
40 10
response to LPS stimulation 48 hr postexpo- *
A Mn Initial burden
sure, but had no effect upon Con A–stimu- Preexposure burden
8
20
18 hr postair
lated T-lymphocyte proliferation at any 18 hr postmetal
6
0
postexposure time point (Figure 4A); at 48 hr 1 18 48 1 18 48
postexposure, inhaled Fe suppressed unstimu- 4
Time postexposure (hr)
lated T-lymphocyte proliferation. On the
2
Figure 2. Inhalation (i.e., nose-only) of Fe (A), Mn
other hand, T cells proved more sensitive to
Streptococcus pneumoniae levels (log10)
(B), or Ni (C) by uninfected rats alters circulating
the immunotoxic effects of inhaled Ni than 0
blood cell profiles. Each bar represents the mean
did B lymphocytes. T-cell proliferation was 10
(± SD) from four rats per exposure group. Asterisk B Ni
significantly reduced (compared with the air (*) indicates value significantly different from time- 8
control) by inhaled Ni 18 hr postexposure and matched air control (p < 0.05).
6
returned to control levels after 48 hr; B-cell *
responses to LPS stimulation were uniformly 2.0 4
Unstimulated
unaffected by Ni exposure (Figure 4B). *
2
Air
Figure 5 illustrates the effects of inhaled Fe
Mn, Ni, and Fe on pulmonary bacterial clear-
nmoles (O2 –)/105 Mø/30 min
0
1.5
ance. Although a single inhalation of Mn had 10
*
C Fe
no significant effect upon bacterial lung bur- *
8
dens (as represented as total burdens) com-
1.0
pared with the time-matched air controls 6
(Figure 5A), exposure to Ni or Fe signifi-
•
4
cantly altered bacterial clearance (Figure 5B,
C, respectively). Although pulmonary pneu- 2
0.5
mococcal levels in air-exposed infected rats 0
dropped significantly 18 hr following expo- Total burdens
sure (compared with burdens measured in Figure 5. Burdens of S. pneumoniae in the lungs of
0
rats sacrificed immediately prior to exposure), 1 18 48
Mn- (A), Ni- (B), and Fe- (C) exposed infected rats
exposure to Ni inhibited clearance and bacte- 18 hr postexposure. Estimates of viable bacterial
Time postexposure (hr)
organisms were determined from colony counts on
rial burdens remained the same as those mea-
Figure 3. Inhalation of Fe by uninfected rats blood-TH agar 24 hr after plating. Absolute levels of
sured just prior to metal exposure (Figure
increased unstimulated O2.– production by lavaged bacteria were used as indices of bacterial survival.
5B). Conversely, inhalation of Fe increased Mø 18 and 48 hr postexposure. Each bar repre- Each bar represents the mean (± SD) from five rats
pulmonary streptococcal levels compared sents the mean (± SD) from four rats per exposure per exposure group. Asterisk (*) indicates value
with preexposure bacterial burdens (Figure group. Asterisk (*) indicates value significantly dif- significantly different from time-matched air con-
ferent from time-matched air control (p < 0.05).
5C). Thus, whereas exposure to Ni appeared trol (p < 0.05).
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4. Metals Toxicity Zelikoff et al.
•
Table 1. Inhalation of Fe by Streptococcus pneumoniae-infected hosts alters lavageable lung immune cell numbers and profiles.
Total cells
Cell type (%)b
Hours post- Hours post- recovered
infectiona (× 107)
Treatment exposure Viability (%) PMN Lymphocyte Macrophage
Air 51 3 3.3 ± 1.0 86.0 ± 4.0 30.0 ± 14.0 9.0 ± 0.2 60.0 ± 14.0
Fe 51 3 2.6 ± 1.0 84.0 ± 3.0 25.0 ± 2.0 14.0 ± 6.0 61.0 ± 4.0
Air 66 18 2.6 ± 0.1 87.0 ± 2.0 26.0 ± 9.0 11.0 ± 2.0 63.0 ± 7.0
Fe 66 18 *1.7 ± 0.3 83.0 ± 5.0 *8.0 ± 7.0 *4.0 ± 2.0 *88.0 ± 6.0
were infected with 10–20 × 106 S. pneumoniae. bMean ± SD of five rats per exposure group.*Indicates significant difference (p < 0.05) from time-matched air control.
aRats
air controls. At this same time point, relative Decreased percentages of PMNs may have of alveolar Mø followed within 2 days by
percentages of lavageable PMNs and lympho- been due, at least in part, to the previously suppressed phagocytic activity and enhanced
cytes in Fe-exposed rats dropped approxi- observed CAPS-induced downregulation of lipid peroxidation (31). Similar findings
mately 3-fold, whereas Mø values increased tumor necrosis factor (TNF)α and/or inter- have also been observed in rabbits exposed
by 29%. leukin (IL)-1α production (12); both of these by inhalation of Ni dust for 1–6 months
cytokines are critical for the mobilization and (32). Alveolar Mø recovered from rabbits
Discussion activation of PMNs in response to many exposed to NiCl2 aerosol for 1 month also
Gram-positive [G + ] microbial organisms
Studies to determine whether inhalation displayed suppressed phagocytic ability as
exposure to concentrated PM2.5 could exacer- including S. pneumoniae (27). Moreover, since well as decreased levels of lysozyme (used by
Mø to break down G+ bacterial cell walls)
bate an ongoing pneumococcal infection TNFα in conjunction with IL-12 enhances
demonstrated that a single 5-hr exposure of the microbicidal capacity of PMNs (28), the both in pulmonary phagocytes and bron-
S. pneumoniae–infected rats to CAPS (at con- immune cells still present in the lungs may chopulmonary lavage fluid. Moreover, a
centrations at or slightly greater than 65 display reduced cytotoxic activities. number of studies have concluded that
µg/m3) exacerbated the infection process in a Inorganic constituents of airborne PM inhalation/instillation of certain Ni com-
time-dependent manner and altered both such as sulfate, nitrate, ammonium, and tran- pounds, including NiCl2, reduces host abil-
pulmonary and systemic immunity (12). This sition metals, which make up a substantial ity to defend against pathogenic lung
was not surprising, given that lungs contain- part of the mass apportionment of ambient infections (30). Given that lysozyme activity
ing extant pulmonary inflammation appear to PM, represent potential causal constituents has been correlated with the ability to clear
certain G + bacterial lung pathogens, and
be primed for injurious responses to air parti- for PM-associated health effects. Although a
cles (23). It appears from these studies that number of different physiochemical factors that the major cellular target of inhaled Ni
CAPS may be acting to alter lung antibacter- have been linked to PM toxicity (i.e., acid appears to be Mø (and other antigen pre-
ial defense mechanisms important in the han- aerosols, particle size, oxidative potential), senting cells), it is likely that Ni-induced
dling of ongoing pneumococcal infections. evidence is rapidly accumulating that much effects upon antibacterial defense may be
This scenario fits temporally with the epi- of the pulmonary toxicity associated with due, at least in part, to suppressive effects on
demiologic data that indicate that deaths inhaled PM is related to the types and this phagocyte-associated enzyme.
among exposed individuals occur relatively amounts of the soluble forms of transition Fe is a key microelement necessary to
quickly following a PM episode, and that metals (13,14,16). maintain cellular homeostasis. Normal func-
individuals with chronic respiratory disease Metals are ubiquitous constituents of tioning of the immune system relies on trace
were less likely than healthy individuals to PM derived from anthropogenic and certain amounts of Fe to serve as a cofactor for spe-
recover from pulmonary infections following types of natural emissions. PM emissions cific metalloenzymes and for the intracellular
PM exposure (1,24, 25). from oil-burning power plants and other formation of reactive oxygen species used for
Although no definitive conclusions can be industries that contribute to air pollution killing phagocytosed pathogens. Both defi-
reached at this time regarding the mecha- contain large amounts of metals such as V, ciency and excessive levels of Fe can lead to
nism(s) by which inhaled concentrated PM2.5 Fe, Ni, Zn, and Cu (15,16). Moreover, immune dysfunction (33). Although most
may have acted to increase pulmonary bur- studies from this laboratory have demon- studies have focused upon the immunomodu-
dens of infectious pneumococci, compromised strated the presence of Mn in concentrated lating effects associated with deficiency, Fe
pulmonary immune defense mechanisms NYC PM (29). Although inflammation was overload has been shown to suppress antibody
important for the removal/killing of S. pneu- not observed in this study, human exposure responses, T-lymphocyte functions (i.e., inter-
moniae (i.e., modified availability of PMNs) to airborne metals have been shown to feron-γ production and delayed contact
or increased bacterial survival as a result of induce pulmonary inflammatory responses hypersensitivity), and nonspecific immunity
CAPS-induced changes in the lung milieu are such as tracheobronchitis, asthma, chemical (33). For example, bactericidal activities of
two plausible hypotheses by which this may pneumonitis, and alveolitis. Recent studies Mø from patients with Fe overload and of
have occurred. In support of the former, have shown that acute exposure of rats to leukocytes treated in vitro with Fe salts were
CAPS exposure of rats with ongoing pneumo- mixtures of metallic compounds derived markedly reduced (34); inhibition of basic
nia reduced the relative percentages of lavage- from ambient air PM or from combustion cationic proteins appeared to be responsible
able PMNs 24, 48, and 72 hr postexposure source emissions (i.e., residual oil fly ash) for these reductions. In contrast, results from
compared with that observed in the air- can induce pronounced pulmonary inflam- experimental studies have suggested that Fe-
exposed infected controls (12). Given that mation characterized by increased permeabil- overloaded Mø have improved bactericidal
PMNs, in the presence of opsonizing comple- ity to protein and neutrophilic alveolitis (13). ability (35). Discrepancies between the studies
ment and immunoglobulins, are the main cell Many transition metals associated with may be due to differences in host species
type responsible for the clearance of S. pneu- PM are potent modulators of pulmonary and/or the particular microorganism being
moniae from the lungs of most animal models and/or systemic immunocompetence (30). targeted by the phagocyte. More consistent
and humans (26), a PM-induced reduction For example, both parenteral and inhalation effects of Fe excess have been observed on nat-
could lead to prolongation of infection. exposure of soluble NiCl2 causes activation ural killer cell cytotoxicity and neutrophilic
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5. Metals Toxicity Role of associated metals in PM immunotoxicity
•
killing of S. pneumoniae. As has been observed is needed to conclusively confirm or refute 18. Gordon T, Chen LC, Fang CP, Gerber H. A centrifugal con-
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decreased bactericidal, fungicidal, and oxida- nism(s) by which exposure to PM2.5 may act mediated responses in the lungs. Toxicol Appl Pharmacol
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oxidative burst activity was also diminished in individuals. Zelikoff JT. Vanadium alters macrophage interferon-γ
proportion to the degree of Fe overload. interactions and interferon-inducible responses. Toxicol
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