Zelikoff Metals

422 views
359 views

Published on

Published in: Health & Medicine, Technology
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
422
On SlideShare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
6
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Zelikoff Metals

  1. 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 Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 5 | OCTOBER 2002
  2. 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). 872 110 | SUPPLEMENT 5 | OCTOBER 2002 • Environmental Health Perspectives VOLUME
  3. 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). 873 Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 5 | OCTOBER 2002
  4. 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 874 110 | SUPPLEMENT 5 | OCTOBER 2002 • Environmental Health Perspectives VOLUME
  5. 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- centrator for use in inhalation toxicology studies. Inhal in clinical and experimentally induced Fe defi- the role of transition metals in PM-associated Toxicol 11:71–87 (1999). ciency (36), patients with clinical diseases of immunosuppression, results contribute to a 19. Cohen MD, Sisco M, Li Y, Zelikoff JT, Schlesinger RB. Fe overload (i.e., thalassemia major) have better understanding of the possible mecha- Immunomodulatory effects of ozone upon in situ cell- decreased bactericidal, fungicidal, and oxida- nism(s) by which exposure to PM2.5 may act mediated responses in the lungs. Toxicol Appl Pharmacol 171:71–84 (2001). tive burst activities (33); neutrophil-associated to increase host mortality in exposed elderly 20. Cohen MD, McManus TP, Yang Z, Qu Q, Schlesinger RB, 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 Appl Pharmacol 138:110–120 (1996). REFERENCES AND NOTES Although inhaled Fe may have led to 21. Zelikoff JT, Parsons E, Schlesinger RB. Immuno- increased pulmonary burdens of S. pneumo- modulating activity of inhaled particulate lead oxide dis- 1. Pope CA. Respiratory hospital admissions associated with niae in this study by interfering with phago- rupts pulmonary macrophage-mediated functions PM10 pollution in Utah, Salt Lake, and Cache Valleys. Arch important for host defense and tumor surveillance in the cyte-mediated killing, another possibility is Environ Health 46:92–97 (1991). lung. Environ Res 62:207–222 (1993). that freely available inhaled Fe may have even- 2. Seaton A, MacNee W, Donaldson K, Godden D. 22. Schlesinger RB, Cohen MD, Gordon T, Nadziejko C, Particulate air pollution and acute health effects. Lancet tually overwhelmed the binding capacities of Zelikoff JT, Sisco M, Regal JF, Menache M. Ozone differ- 345:176–178 (1995). entially modulates airway responsiveness in atopic vs the nascent Fe-binding proteins transferrin 3. Thurston GD, Ito K, Kinney PL, Lippmann M. A multi-year non-atopic guinea pigs. Inhal Toxicol 14:431–457 (2002). and lactoferrin normally operational in lung study of air pollution and respiratory hospital admissions 23. Imrich A, Ning YY, Kobzik L. Insoluble components of con- fluid (37), thereby allowing bacteria that in three New York state metropolitan areas: results for centrated air particles mediate alveolar macrophage 1988 and 1989 summers. J Expo Anal Environ Epidemiol responses in vitro. Toxicol Appl Pharmacol 167(2):140–150 require Fe as an essential nutrient (including 2:1–21 (1992). (2000). S. pneumoniae) to freely incorporate the metal 4. Schwartz J. Total suspended particulate matter and daily 24. Dockery DW, Schwartz J, Spengler JD. Air pollution and and proliferate. mortality in Cincinnati, Ohio. Environ Health Perspect daily mortality: associations with particulates and acid 102:186–189 (1994). Mn, a dissociable cofactor for several aerosols. Environ Res 59:362–373 (1992). 5. Schwartz J. Air pollution and daily mortality: a review and 25. Lebowitz MD. Epidemiological studies of the respiratory enzymes including one of great importance in meta-analysis. Environ Res 64:35–52 (1994). effects of air pollution. Eur Respir J 9:1029–1054 (1996). the lungs, superoxide dismutase, is also 6. Schwartz J. What are people dying of on high air pollution 26. Coonrod JD, Yoneda K. Comparative role of complement days? Environ Res 64:26–35 (1994). required for growth of virtually all living cells. in pneumococcal and staphylococcal pneumonia. Infect 7. Ware JH, Ferris BG, Dockery DW, Spengler JD, Stram DO. Immunol 37:1270–1277 (1982). Like Fe, shifts in Mn levels in either direction Effects of ambient sulfur oxides and suspended particles 27. Heumann D, Barbas C, Severin A, Glauser MP, Tomasz A. can bring about immune dysfunction. on respiratory health of pre-adolescent children. Am Rev Gram-positive cell-walls stimulate synthesis of tumor Respir Dis 133:824–842 (1986). Inhalation of high concentrations of Mn by necrosis factor-α and interleukin-6 by human monocytes. 8. Vial WC, Towes GB, Pierce AK. Early pulmonary granulo- Infect Immunol 62:2715–2721 (1995). occupationally exposed workers has been cyte recruitment in response to Streptococcus pneumo- 28. Janeway CA, Travers P, eds. Immunobiology: The Immune shown to cause Mn pneumonitis and niae. Am Rev Respir Dis 129:87–91 (1984). System in Health and Disease. London/New York:Current 9. Aranyi C, Graf JL, O’Shea WJ, Graham JA, Miller FF. The croupous pneumonia. In rodents, inhalation Biology Ltd./Garland Publishing, 1996. effects of intratracheally-administered coarse mode parti- 29. Zelikoff JT, Chen LC, Cohen MD, Fang K, Gordon T, Li Y et of insoluble Mn at milligram concentrations cles on respiratory tract infection in mice. Toxicol Lett al. Unpublished data. impairs pulmonary bacterial clearance and 19:63–72 (1983). 30. Cohen MD, Zelikoff JT, Schlesinger RB, eds. Pulmonary increases bacterial-associated host mortality 10. Hatch GE, Slade R, Boykin E, Hu PC, Miller FJ, Gardner, Immunotoxicology. Boston:Kluwer Academic Press, 2000. DE. Correlation of effects of inhaled versus intratra- 31. Sunderman FW Jr, Hopfer SM, Lin SM, Plowman MC, (30). Other studies have demonstrated that cheally-injected metals on susceptibility to respiratory Stojanivic T, Wong SH, Zaharia O, Ziebka L. Toxicity of exposure of hosts already bearing a viral lung infection in mice. Am Rev Respir Dis 124:167–173 (1985). alveolar macrophages in rats following parenteral injec- infection for 24 or 48 hr prior to a 3-hr expo- 11. Zelikoff JT. Woodsmoke, kerosene heater emissions, and tion of nickel chloride. Toxicol Appl Pharmacol diesel exhaust. In: Pulmonary Immunotoxicology (Cohen sure to insoluble Mn had a shorter time to 100:107–118 (1989). MD, Zelikoff JT, Schlesinger RB, eds). Boston:Klewar 32. Johansson A, Camner P. Effects of nickel dust on rabbit death than their air-exposed counterparts Academic Press, 2000;369–386. alveolar epithelium. Environ Res 22:510–516 (1980). (38,39). Furthermore, although the effects of 12. Zelikoff JT, Nadziejko C, Fang K, Gordon T, Premdass C, 33. Omara FO, Brousseau P, Blakley BR, Fournier M. Iron, Cohen MD. Short-term, low-dose inhalation of ambient soluble Mn on alveolar Mø function are still zinc, and copper. In: Immunotoxicology of Environmental particulate matter exacerbates ongoing pneumococcal and Occupational Metals (Zelikoff JT, Thomas PT, eds). being debated, in vitro studies have demon- infections in Streptococcus pneumoniae-infected rats. In: London:Taylor and Francis, 1999;231–262. strated reductions in phagocytic activity. Proceedings of the Third Colloquium on Particulate Air 34. Ballart IJ, Estevez ME, Sen L, Diez RA, Giuntoli RA, de Pollution and Human Health (Phalen R, Bell Y, eds). Irvine, Discrepancies between these studies and those Miani SA, Penalver J. Progressive dysfunction of mono- CA:University of California, Section 8, 2000;94–101. cytes associated with iron overload and age in patients performed herein that demonstrated no effects 13. Dreher KL, Jaskot RH, Lehmann JR, Richards JH, McGee with thalassemia major. Blood 67:105–109 (1986). of inhaled Mn on pulmonary bacterial clear- JK, Ghio AJ et al. Soluble transition metals mediate resid- 35. Jiang X, Baldwin CL. Iron augments macrophage-medi- ual oil fly ash induced acute lung injury. J Toxicol Environ ance may be due, in part, to differences in ated killing of Brucella abortus alone and in conjunction Health 50:285–305 (1997). with interferon-γ. Cell Immunol 148:398–407 (1993). metal concentration and/or metal solubility. 14. Carter JD, Ghio AJ, Samet JM, Devlin, RB. Cytokine pro- 36. Murakawa H, Bland CE, Willis WT, Dallman PR. Iron defi- Taken together, findings from this study duction by human airway epithelial cells after exposure to ciency and neutrophil function: different rates of correction support the notion that a single exposure to an air pollution particle is metal-dependent. Toxicol Appl of the depressions in oxidative burst and myloperoxidase Pharmacol 146:180–188 (1997). activity after iron treatment. Blood 69:1464–1468 (1987). concentrated ambient PM2.5, at concentra- 15. Costa DL, Dreher KL. Bioavailable transition metals in par- 37. LaForce FM, Loose D. Release of lactoferrin by polymor- tions equal to or just above the promulgated ticulate matter mediates cardiopulmonary injury in healthy phonuclear leukocytes after aerosol challenge with 24-hr NAAQS value, compromise host abil- and compromised animal models. Environ Health Perspect Escherichia coli. Infect Immunol 55:2293–2295 (1987). 105:1053–1059 (1997). ity to adequately handle an ongoing S. pneu- 38. Maigetter RZ, Ehrlich R, Fenters JD, Gardner DE. 16. Kodavanti UP, Hauser R, Christiani DC, Meng ZH, McGee Potentiating effects of manganese dioxide on experimen- moniae infection. These investigations also J, Ledbetter A, et al. Pulmonary responses to oil fly ash tal respiratory infections. Environ Res 11:386–391 (1976). provide biologic plausibility for the role of particles in the rat differ by virtue of their specific soluble 39. Cohen MD. Other metals: aluminum, copper, manganese, metals. Toxicol Sci 43:204–212 (1998). PM-associated metals, particularly Fe and Ni, selenium, vanadium, and zinc. In: Pulmonary 17. Zelikoff JT, Thomas PT, eds. Immunotoxicology of Immunotoxicology (Cohen MD, Zelikoff JT, Schlesinger in exacerbating S. pneumoniae infections in Environmental and Occupational Metals. London:Taylor RB, eds). Boston:Kluwer Academic Press, 2000;267–299. CAPS-exposed hosts. Although more research and Francis, 1999. 875 Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 5 | OCTOBER 2002

×