Department of Environmental Health Sciences, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205
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ABSTRACT |
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Epidemiologic studies have demonstrated a positive correlation between concentration of acid aerosol and increased morbidity and mortality in many urban environments. To determine whether genetic background is an important risk factor for susceptibility to the toxic effects of inhaled particles, we studied the interstrain (genetic) and intrastrain (environmental) variance of lung responses to acid-coated particle (ACP) aerosol in nine strains of inbred mice. A flow-past nose-only inhalation system was used to expose mice to ACPs produced by the cogeneration of a carbon black aerosol-sulfur dioxide (SO2) mixture at high humidity. Three days after a single 4-h exposure to ACPs or filtered air, mice underwent bronchoalveolar lavage, and cell differentials and total protein were determined as indexes of inflammation and epithelial permeability, respectively. To determine the effect of ACPs on alveolar macrophage (AM) function, lavaged AMs were isolated from exposed animals and Fc receptor-mediated phagocytosis was evaluated. Compared with air-exposed animals, there was a slight but significant exposure effect of ACPs on the mean number of lavageable polymorphonuclear leukocytes in C3H/HeJ and C3H/HeOuJ mice. ACP exposure also caused a significant decrease in AM phagocytosis. Relative to respective air-exposed animals, Fc receptor-mediated phagocytosis was suppressed in eight of nine strains. The order of strain-specific effect of ACPs on phagocytosis was C57BL/6J > 129/J > SJL/J > BALB/cJ > C3H/HeOuJ > A/J > SWR/J > AKR/J. There was no effect of ACP exposure on AM phagocytosis in C3H/HeJ mice. The significant interstrain variation in AM response to particle challenge indicates that genetic background has an important role in susceptibility. The effects of ACPs on AM function, inflammation, and epithelial hyperpermeability were not correlated (i.e., no cosegregation). This model may have important implications concerning interindividual variation in particle-induced compromise of host defense.
inbred mice; sulfate; air pollution; phagocytosis; alveolar macrophage; morbidity; host defense
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INTRODUCTION |
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INCOMPLETE COMBUSTION OF FOSSIL FUEL results in the production of sulfur oxides (e.g., SO2) and carbonaceous particles. This often results in the production of acid sulfates depending on atmospheric conditions such as high relative humidity (RH) (10, 24, 26, 42). Considerable attention has been focused on the adverse respiratory health effects caused by inhalation of these products. Epidemiologic studies in a number of industrialized countries throughout the world have reported significant association of acute and chronic lung health effects in the general population with increases in these products (e.g., Refs. 2, 27, 30, 33). In addition to decrements in lung function, these exposures may also enhance respiratory illness (e.g., chronic cough, bronchitis, pneumonia) in children and other sensitive subpopulations (27, 28). High particle and SO2 concentrations have also been attributed to a number of significant acute mortality episodes (7, 8). Interestingly, although the epidemiology of the health effects of combustion pollutants is becoming clear, the physiological and/or toxicologic mechanisms of the effects have not been identified.
Because of the potential impact that exposure to combustion products may have on public health, identification of the intrinsic and extrinsic factors that may influence susceptibility to the pulmonary responses to airborne pollutants remains an important issue. The contribution of genetic background as a host factor for susceptibility to pollutant effects on the lung [e.g., nitrogen dioxide (NO2) and ozone (O3)] has been suggested (2, 13, 19, 23). An understanding of the genetic basis for interindividual variation in response to air pollutants will clarify the mechanism(s) of host response to the exposure and provide a potential means to identify genetically susceptible individuals who may be at risk to adverse effects of air pollutants.
In the present study, we hypothesized that genetic background contributes significantly to the variation in inflammation and alveolar macrophage (AM) dysfunction induced by inhalation of acid sulfate-coated particles (ACPs) in the mouse. The carbonaceous ACPs employed represent a specific type of acid aerosol that behaves differently from acid sulfate droplets. Although acid sulfate droplets may be primarily absorbed in the upper airways, submicrometer carbonaceous ACPs can readily traverse the airways and reach the lung parenchyma, thereby delivering a more concentrated acid sulfate to the alveolar region. To test our hypothesis, we partitioned the interstrain (genetic) and intrastrain (environmental) variance in pulmonary responses to ACPs in nine inbred strains of mice. Results from these studies demonstrated a significant genetic component of susceptibility to ACP-induced AM dysfunction. However, ACP challenge caused minimal to no infiltration of inflammatory cells or airway hyperpermeability in all strains tested and therefore suggested that the effect of particles on AM function was independent of inflammation. Furthermore, a significant correlation between the strain distribution patterns for susceptibility to ACP- and O3-induced inflammation [previously determined (22)] may suggest that a common mechanism(s) exists for these end points.
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MATERIALS AND METHODS |
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Animals. Male (6-8 wk of age) mice of the following inbred and hybrid strains were purchased from Jackson Laboratories (Bar Harbor, ME): A/J, AKR/J, B6C3F1/J, BALB/cJ, C3H/HeJ (C3), C3H/HeOuJ, C57BL/6J (B6), SJL/J, SWR/J, and 129/J. The animals were housed in an antigen- and virus-free room. Water and mouse chow (Agway ProLab RMH 1000) were provided ad libitum. Sentinel animals were examined periodically (titers and necropsy) to ensure that the animals in this room remained free of infection. The mice were handled in accordance with the standards established by the US Animal Welfare Acts set forth in National Institutes of Health guidelines and by the Johns Hopkins University (Baltimore, MD) School of Hygiene and Public Health Animal Care and Use Committee.
ACP generation and exposures. Carbon Black Regal 660 (a
generous gift of Cabot, Billerica, MA) with a specific surface area of
90 m2/g was used for these studies (composition, 96.90%
carbon, 0.30% hydrogen, and 1.42% oxygen; empirical formula
C910H34O10; 25 nm parent size). The
chamber characteristics, aerosol and SO2 generation and
monitoring, particle-size analysis, and particle-associated SO24 analysis have been previously
described (11, 12). Briefly, a flow-past nose-only inhalation chamber was used for exposure of the animals to a mixture of carbon black aerosol and SO2 at 85% RH. The carbon black aerosol was
generated with a Wright dust feed (BGI, Waltham, MA) and monitored with a real-time monitor (RAM-1, Monitoring Instruments for the Environment Technologies, Bedford, MA). Time-weighted carbon black aerosol concentrations were measured with 25-mm, 0- to 2-µm pore size membrane filters (HT200, Gelman Sciences, Ann Arbor, MI) held in an
electrically conductive 25-mm-diameter open-faced filter cassette
(01-038-1, Fisher Scientific, Pittsburgh, PA). Aerodynamic aerosol size
distributions were measured with a 10-stage Sierra cascade impactor
(Anderson, Atlanta, GA). Metered SO2 from a pressurized tank containing 1.5% SO2 in air (Matheson Gas, E. Rutherford, NJ) was mixed with diluent before it entered the exposure
chamber. The concentration of SO2 was monitored
continuously with a pulsed fluorescence SOX monitor (Thermo
Environmental Instruments, Franklin, MA). Particle-associated
SO2
4 analysis was performed with a
modification of American Standard Test Methods method no. 4500-SO2
4 E (5). Mice were exposed for
4 h at a RH of 85% to a target concentration of 10 mg/m3
of carbon black aerosol and 10 parts/million (ppm)
SO2. Average concentration of particle-associated sulfates
was 285.4 ± 30.6 µg/m3. Mass median aerodynamic
diameter was 0.29 µm, with a geometric standard deviation of 2.7.
Experimental design and exposure condition. Mice from each
strain were divided randomly into 2 groups/strain and placed in restrainers. One group was exposed to ACP for 4 h. Age- and
strain-matched mice were simultaneously exposed to filtered air to
serve as control animals. Exposure conditions and recovery period were
determined in previous studies with Swiss-Webster mice (11, 16). The pollutant target concentration was chosen mainly based on the biological end points but was relevant to other studies concerning acid
SO24 formation. The carbon black
aerosol (10 mg/m3) and SO2 (10 ppm)
concentrations used exceeded normal ambient levels by about two orders
of magnitude. However, these levels of carbon black aerosol (15, 17,
18) and SO2 (38) were reported to be nontoxic in normal
animals. AM phagocytotic function was significantly suppressed in
Swiss-Webster mice with coexposure to 10 mg/m3 of carbon
black aerosol and 10 ppm SO2 at 85% RH, the only
circumstance in which significant chemisorption of the gas and
oxidation to SO2
4 occurred. AM
phagocytosis was suppressed most significantly 3 days after exposure,
followed by a full reestablishment of phagocytotic potential by day
14. Exposure conditions for the present study were based on these considerations.
In another set of experiments, the kinetics of ACP exposure effects on AM phagocytotic function were determined in a susceptible strain, C57BL/6J. Mice (n = 4-8/group) were exposed to ACPs or filtered air as described above, and AM Fc receptor-mediated phagocytosis was measured 0, 1, 3, 7, and 14 days after exposure.
Bronchoalveolar lavage and cell preparation. Bronchoalveolar lavage (BAL) was performed for the measurement of pulmonary inflammation and retrieval of AMs for the phagocytotic assay. Mice were killed by cervical dislocation, and the lungs were lavaged four times in situ with sterile PBS supplemented with 0.1% EDTA (35 ml/kg). PBS contained (in g/l) 5.43 NaCl, 0.50 Na2EDTA, 0.57 Na4EDTA, 4.73 NaH2PO4, and 0.40 KH2PO4. For each mouse, the first BAL return was isolated from the remaining three BAL returns, which were pooled. The BAL returns were then centrifuged (500 g and 4°C), and the supernatant of the first BAL return was decanted. The total protein concentration in this supernatant was measured and used as an indicator of lung permeability. The remaining supernatants were discarded. A bovine serum albumin protein assay kit (Pierce, Rockford, IL) that follows the method of Bradford (3) was used. This assay is accurate from 10 to 2,000 µg/ml. The cell pellets from all four lavages were combined and resuspended in 0.8 ml of RPMI 1640 medium (GIBCO BRL, Life Technologies, Grand Island, NY) supplemented with 10% newborn calf serum, and the cells were counted with a hemocytometer. Aliquots (50 µl) were cytocentrifuged (Shandon Southern Products, Pittsburgh, PA), and the cells were stained with Diff-Quik (Baxter Scientific Products, McGaw Park, IL) for differential cell analysis. Differential cell counts were done by identifying 300 cells according to standard cytological techniques (34). Airway epithelial cells were identified by the presence of cilia. Cell viability was determined with the trypan blue stain exclusion method.
Fc receptor-mediated phagocytosis assay. AM phagocytosis was determined as previously described (41). Three 200-µl aliquots of each cell suspension were allowed to adhere to 22-mm2 bovine albumin-coated glass coverslips in 35 × 10-mm plastic petri dishes (Becton Dickinson, Franklin, NJ) for 45 min (37°C in 5% CO2 at 95% RH). After the cells formed monolayers, the fluid was removed and immediately replaced with 1.5 ml of 0.5% sensitized sheep red blood cells (RBCs) in RPMI 1640 medium, and the resulting suspension was incubated at 37°C for 45 min. After removal of the RBCs by aspiration and washing of the monolayers with RPMI 1640 medium, noningested RBCs were hypotonically lysed for 10 s followed by several rinses with culture medium. The monolayers were then dried, fixed with methanol, and stained with Wright-Giemsa. The stained monolayers were read microscopically (Zeiss Instruments, Oberkochen, Germany) at ×1,000 to quantify the percentage of AMs containing RBCs and the number of RBCs ingested per phagocytic AM. One hundred AMs were scored on each coverslip monolayer, with three monolayers counted per animal. Values (phagocytotic index) are expressed as percent of the air-exposed control mean. For each exposure group, an identical number of nonexposed animals were tested.
Statistics. The effects of exposure (particle vs. air) and strain on pulmonary responses were assessed by two-way analysis of variance (ANOVA) with the SuperANOVA software package (Abacus Concepts, Berkeley, CA). Tukey's test was used for a posteriori comparisons of means. All percent data were transformed (arcsine) before statistical analyses to conform to assumptions of normality and homoscedasticity. The strain distribution patterns (SDPs) for lung responses to O3 and NO2 [previously determined (22)] were compared with the SDPs for ACPs by nonparametric Spearman rank correlation (43). Significance was accepted at P < 0.05.
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RESULTS |
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ACP-induced lung inflammation. The total number of cells in BAL
fluid, differential cell analysis, and the total protein level in BAL
fluid were used as indicators of lung inflammation (Table 1). Statistical analysis by two-way ANOVA
indicated a significant effect of strain on the mean total number of
cells (× 103/ml) recovered by BAL (P < 0.05). However, neither exposure nor the interaction of exposure and
strain affected the total number of cells. Significant strain effects
on the mean number of BAL fluid AMs, lymphocytes, polymorphonuclear
leukocytes (PMNs), and epithelial cells were also detected (Table 1).
No exposure or interaction effects were detected for AMs, lymphocytes,
or epithelial cells. However, compared with that in air-exposed
animals, ACP exposure significantly affected the mean number of PMNs
recovered (P < 0.05 by ANOVA). The ACP exposure effect was
significant only in the C3H/HeOuJ and C3H/HeJ strains (P < 0.05 by Tukey's test; Table 1).
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No effects of strain, exposure, or interaction of strain and exposure were detected for the total protein concentration in BAL fluid (P > 0.05 by ANOVA; Table 1).
Fc-receptor-mediated phagocytosis. Fc-receptor-mediated AM
phagocytosis was used as an indicator of ACP effects on immune function. ANOVA indicated significant effects of strain, exposure, and
the interaction of strain and exposure on the mean AM phagocytotic responses (Table 2). Compared with that in
air-exposed control animals, ACPs suppressed mean (±SE) AM
phagocytotic function in B6 (56.5 ± 2.8% of air-exposed control
value), 129/J (81.3 ± 6.2%), SJL/J (82. 6 ± 7.3%), BALB/cJ
(83.2 ± 8.7%), C3H/HeOuJ (85.6 ± 4.2%), A/J (86.4 ± 8.8%), SWR/J (89.0 ± 4.9%), and AKR/J (93.1 ± 4.4%) mice (Fig. 1). ACPs did not
significantly suppress AM phagocytotic function in C3 mice. Multiple
comparisons of the mean Fc-receptor phagocytotic index by Tukey's test
revealed significant interstrain differences in the AM phagocytotic
function after ACP exposure. Significant interstrain differences were
detected between B6 and all other strains of mice (P < 0.001). Compared with that in ACP-exposed C3 mice, the phagocytotic
indexes of all other strains were significantly suppressed.
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The kinetics of the ACP effect were determined in the susceptible B6
strain. No effects of ACP challenge on AM function were found
immediately and 1 day after a 4-h challenge. The maximum effect of ACPs
on AMs was found 3 days after exposure; AM function was still
significantly suppressed 7 days after exposure to ACPs (Fig.
2). AM function was not affected 14 days
after exposure. Results are consistent with the kinetics of the ACP
effect in Swiss-Webster mice (15) and indicated that the effect on AMs is reversible in the B6 strain. There were no detectable effects of ACP
challenge on AM function in the resistant C3 strain at any time (data
not shown).
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To obtain insight about the mode of inheritance of susceptibility to
the ACP-induced decrease in AM phagocytotic function, B6C3F1/J mice
derived from a cross between susceptible B6 mice and resistant C3 mice
were phenotyped for their response to ACPs. Compared with that in
air-exposed control animals, ACP exposure had no significant effect on
the mean AM phagocytotic function (99.1 ± 6.1%). The range of
responses to ACPs by B6C3F1/J AMs largely overlapped that of the C3
progenitor, and there was a slight overlap with the range of responses
in the B6 mouse (Fig. 3). The mean response
of B6C3F1/J AMs was not significantly different from the mean response
of AMs from C3 mice (P > 0.05) but was significantly
different from AMs of ACP-exposed B6 mice (P < 0.05).
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Comparison of SDPs for responses to ACPs,
O3, and
NO2. SDPs can be utilized to
investigate genetic relatedness between phenotypes. That is, because
inbred strains are homozygous at essentially all loci, discordant SDPs
suggest that genetic mechanisms controlling the two phenotypes are not
the same. Conversely, if SDPs are concordant, similar genetic
mechanisms may be involved in the determination of phenotypes, although
further studies (e.g., linkage analyses) are required to verify the
hypothesis. To determine whether the mechanisms of susceptibility to
ACPs may have genetic relatedness to susceptibility to other common air
pollutants, we compared the SDPs for AM responses to ACPs with
phenotypes of the susceptibility to O3 and NO2
that were previously determined in our laboratory (22).
Strains were phenotyped for total protein, PMNs, and epithelial cells
recovered by BAL after an acute (3-h) exposure to O3 (2 ppm) and NO2 (15 ppm). The Spearman rank correlation
procedure was used to compare the SDPs. The ACP phagocytotic index was
not significantly correlated with any of the NO2 SDPs
(Table 3). The number of lavageable PMNs
but not total BAL fluid protein or lavageable epithelial cells elicited
by exposure to O3 was significantly correlated with the ACP
phagocytotic index SDP (Spearman rank correlation = 0.88; P < 0.05; Table 3).
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DISCUSSION |
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Clear epidemiologic associations between exposure to particulate matter
and adverse health effects have been well documented. Lower airway
infection is one pulmonary outcome of particle exposure (6, 29, 36),
and is likely due to effects of lung defense and AM function (44). It
is becoming clear that some populations are particularly at risk to the
toxic effects of particulate exposure. These include patients with
preexisting cardiopulmonary disease such as chronic heart disease,
chronic obstructive pulmonary disease, and asthma (2, 37, 39, 40).
Cancer patients and the aged (65 yr of age) have also been identified
as particularly susceptible to the effects of exposure to particulates
(37). However, all particle-associated morbidity and mortality cannot
be attributed solely to preexisting disease or age. Therefore,
alternative explanations or susceptibility factors must be sought.
One of the major objectives of this study was to establish whether susceptibility to the toxic effects of exposure to combustion products has a genetic component. To address this question, we studied the relative susceptibility to ACP exposure in inbred strains of mice. The process of inbreeding (i.e., >20 generations of sib-sib crossing) results in genetic homogeneity at virtually all loci, and different inbred strains of mice may be homogenous for different alleles at the same loci. Generally, strains with greater evolutionary divergence will have a greater degree of polymorphism than strains that are closely related. These characteristics thus enable investigations into the genetic (mechanistic) basis for a physiological and/or toxicological response of interest or phenotype. That is, if a difference in a chosen phenotype is found after a screen of a number of inbred strains to provide sufficient variation across the species (i.e., interstrain variation), then it may be concluded that one or more loci contributes to the genetic variance observed among the strains. The present study evaluated inflammation and AM function after exposure to sulfate-associated carbon particles in nine inbred strains of mice that were chosen based on their differing lineage and common usage in genetic studies. The significant interstrain variation (genetic) in the AM response to ACP exposure supports the hypothesis that susceptibility to ACPs in inbred mice has a significant genetic component.
To determine whether susceptibility to ACP-induced AM dysfunction is inherited as a dominant or recessive trait, the AM response to ACPs was determined in B6C3F1/J mice that were obtained from a cross between differentially susceptible B6 female and C3 male progenitors. Because the phagocytotic response to ACP challenge in B6C3F1/J mice was not different from that in the resistant C3 mice, it suggests that susceptibility is recessive in this model. Susceptibility to acute lung injury induced by the inhaled pollutants NO2 and O3 are also inherited as recessive traits. Further characterization of the mode of inheritance will require formal segregation analyses in segregated backcross and intercross populations derived from B6 and C3 mice as previously done by Holroyd et al. (13) and Kleeberger et al. (21).
The mechanism(s) of the effect of ACP exposure on AM phagocytotic function is not well understood. Qu et al. (32) found that short-term exposure of guinea pigs to sulfuric acid aerosol induced decreased intracellular pH in AMs. These authors suggested that the effect may be due to facilitated H+ influx through an increased passive diffusion rate caused by an acid microenvironment. Simultaneously, the acid may cause downregulation of intracellular pH through inhibition of the Na+/H+ exchanger (32). These changes in intracellular environment may alter normal cellular function including phagocytotic activity. Additional insight into the mechanism may be provided by a previous study (4) that examined the effect of O3 exposure on AM phagocytotic function. Canning et al. (4) demonstrated that continuous exposure to 0.5 ppm O3 elicited reversible depression of the AM phagocytotic index, similar to the effect observed in the present study. Pretreatment with cyclooxygenase inhibitors (D-naproxen, indomethacin) significantly attenuated but did not abolish the oxidant effect on AM function. This result and the presence of significant increases in lavageable prostaglandin E, a putative immunosuppressant, in O3-exposed lungs led to the conclusion that prostanoids may contribute to AM dysfunction. Similar mechanisms of action may be involved in the effect of ACPs, but further experimentation is required to verify these possibilities.
In the present study, the differential effect of ACPs on AM function appeared to occur independent of pulmonary inflammation. The number of lavageable PMNs in two strains (C3H/HeJ and C3H/HeOuJ) was only slightly increased, and total protein in BAL fluid was not significantly increased in any of the nine strains after ACP exposure. However, the changes in PMNs did not correlate with particle effects on AM phagocytosis because particle exposure did not have an effect on the phagocytotic response in C3H/HeJ mice. These results were consistent with previous results by Jakab et al. (16) with outbred Swiss-Webster mice that demonstrated significant depression of AM phagocytosis after exposure to acid-coated carbon black particles in the absence of demonstrable inflammation. In contrast, Amdur et al. (1) reported significant elevation in PMNs and total protein at a concentration of 20 mg/m3 of H2SO4 with a mixture of particles and SO2. However, the difference between studies is likely due to the ZnO particles used by Amdur et al. (1) because the concentration of these particles may have direct inflammatory effects (9).
Interstrain and interspecies differences in pulmonary responses to particle exposure in mice have been previously demonstrated (14, 25, 35). Ichinose et al. (14) found that in ovalbumin-sensitized mice, interstrain differences existed in the amount of eosinophilic airway inflammation, goblet cell proliferation, and ovalbumin-specific plasma IgG1 production induced by diesel exhaust particles (DEPs). Another study from this laboratory (25) demonstrated that C3H/He mice were more responsive to repeated intratracheal instillation of DEPs than were BALB/c mice. After 5 wk of DEP challenge, C3H/He mice developed greater respiratory tract eosinophilia and lung tissue inflammatory cytokine levels (interleukin-5, granulocyte-macrophage colony-stimulating factor) compared with those in BALB/c mice. These studies demonstrated a strain-specific effect of DEPs to induce inflammation and stimulate an immune response and implied the role of genetic background in the models.
Because genetic background has an important role in differential susceptibility among inbred strains of mice to lung injury induced by ACPs, O3 (21), and NO2 (13), we asked whether similar genetic mechanisms control responses to these exposures. To address this question, nine strains were ranked in order from high (one) to low (nine) for each parameter of response and the rank orders (SDPs) were compared for concordance. Results showed a significant correlation between SDPs for susceptibility to ACP and O3 exposures but no significant correlation between SDPs for responses to ACP and NO2. These comparisons indicate that similar genetic mechanisms may control responses to acute exposures to ACP and O3. To further evaluate this hypothesis, a formal linkage analysis of the ACP susceptibility phenotype(s) in segregated populations derived from two differentially susceptible strains is required as done for susceptibility to O3 (21, 31). These analyses will identify quantitative trait loci that may be searched for candidate genes that explain the differences in response to ACPs. These studies are currently being conducted in our laboratory.
In summary, we have found that significant interstrain variation exists in the reversible, suppressive effect of inhaled ACPs on AM phagocytotic responses. The effect of ACPs on AM function apparently occurs independent of inflammation. From this, we conclude that susceptibility to ACP effects on AM function has a significant genetic component. Furthermore, susceptibility to ACP effects is inherited as a recessive trait. Comparison of strain distribution patterns for susceptibility to ACPs and acute O3 and NO2 suggests that susceptibility to ACPs and O3 may have common genetic mechanisms. This model will be useful to understand the mechanisms through which particle exposure induces suppression of immune defenses and may help to understand the epidemiologic relationship between particulate exposure and respiratory morbidity.
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ACKNOWLEDGEMENTS |
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This study was supported by Environmental Protection Agency Grant EPA R-825815 and National Institute of Environmental Health Sciences Grant ES-03819.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. R. Kleeberger, Division of Physiology, Rm. 7006, Johns Hopkins Univ., 615 N. Wolfe St., Baltimore, MD 21205 (E-mail: skleeber{at}jhsph.edu).
Received 30 December 1998; accepted in final form 18 October 1999.
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REFERENCES |
---|
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---|
1.
Amdur, M. O.,
and
L. C. Chen.
Furnace-generated acid aerosols: speciation and pulmonary effects.
Environ. Health Perspect.
79:
147-150,
1989[ISI][Medline].
2.
Bascom, R.,
P. A. Bromberg,
D. A. Costa,
R. Devlin,
D. W. Dockery,
M. W. Frampton,
W. Lambert,
J. M. Samet,
F. E. Speizer,
and
M. Utell.
Health effects of outdoor air pollution.
Am. J. Respir. Crit. Care Med.
153:
3-50,
1996[Abstract].
3.
Bradford, M. M.
A rapid and sensitive method for the quantification of microgram quantities of protein using the principle of protein-dye binding.
Anal. Biochem.
72:
248-254,
1976[ISI][Medline].
4.
Canning, B. J.,
R. R. Hmieleski,
E. W. Spannhake,
and
G. J. Jakab.
Ozone reduces murine alveolar and peritoneal macrophage phagocytosis: the role of prostanoids.
Am. J. Physiol. Lung Cell. Mol. Physiol.
261:
L277-L282,
1991
5.
Clesceri, L.,
A. E. Greenberg,
and
A. D. Eaton.
Method no. 4500-SO24E. Turbidimetric method: sulfate.
In: Standard Methods for the Examination of Water and Waste Water (20th ed.). Washington, DC: Am. Public Health Assoc., 1998, p. 4-178-4-179.
6.
Dockery, D. W.,
J. Cunningham,
A. I. Damokosh,
L. M. Neas,
J. D. Spengler,
P. Koutrakis,
J. H. Ware,
M. Raizenne,
and
F. E. Speizer.
Health effects of acid aerosols on North American children: respiratory symptoms.
Environ. Health Perspect.
104:
500-505,
1996[ISI][Medline].
7.
Dockery, D. W.,
C. A. Pope, III,
X. Xu,
J. D. Spengler,
J. H. Ware,
M. E. Fay,
B. G. Ferris, Jr.,
and
F. E. Speizer.
An association between air pollution and mortality in six U. S. cities.
N. Engl. J. Med.
329:
1753-1759,
1993
8.
Dockery, D. W.,
J. Schwartz,
and
J. D. Spengler.
Air pollution and daily mortality: associations with particulates and acid aerosols.
Environ. Res.
59:
362-373,
1992[ISI][Medline].
9.
Gordon, T.,
L. C. Chen,
J. M. Fine,
R. B. Schlesinger,
W. Y. Su,
T. A. Kimmel,
and
M. O. Amdur.
Pulmonary effects of inhaled zinc oxide in human subjects, guinea pigs, rats, and rabbits.
Am. Ind. Hyg. Assoc. J.
53:
503-509,
1992[ISI][Medline].
10.
Hegg, D. A.,
and
P. V. Hobbs.
Oxidation of sulfur dioxide in aqueous systems with particular reference to the atmosphere.
Atmos. Environ.
12:
241-253,
1978[ISI].
11.
Hemenway, D. R.,
R. W. Clarke,
R. Frank,
and
G. J. Jakab.
Factors governing the mass loading of aerosolized carbon black particles with acid sulfates, inhalation exposure, and alveolar macrophage phagocytic function.
Inhal. Toxicol.
8:
679-694,
1996[ISI].
12.
Hemenway, D. R.,
G. J. Jakab,
R. B. Hmieleski,
T. H. Risby,
S. S. Sehnert,
and
S. Bowes.
A nose-only inhalation exposure chamber system using a fluidized bed generation system for the generation of co-exposures to carbon black and formaldehyde.
Inhal. Toxicol.
2:
69-89,
1989.
13.
Holroyd, K. J.,
S. M. Eleff,
L.-Y. Zhang,
G. J. Jakab,
and
S. R. Kleeberger.
Genetic modeling of susceptibility to nitrogen dioxide-induced lung injury in mice.
Am. J. Physiol. Lung Cell. Mol. Physiol.
273:
L595-L602,
1997
14.
Ichinose, T.,
H. Takano,
Y. Miyabara,
R. Yanagisawa,
and
M. Sagai.
Murine strain differences in allergic airway inflammation and immunoglobulin production by a combination of antigen and diesel exhaust particles.
Toxicology
122:
183-192,
1997[ISI][Medline].
15.
Jakab, G. J.
The relationship between carbon black particulate-bound formaldehyde, pulmonary antibacterial defenses and alveolar macrophage phagocytosis.
Inhal. Toxicol.
4:
349-366,
1992.
16.
Jakab, G. J.,
R. W. Clarke,
D. R. Hemenway,
M. V. Longphre,
S. R. Kleeberger,
and
R. Frank.
Inhalation of acid coated carbon black particles impairs alveolar macrophage phagocytosis.
Toxicol. Lett.
88:
243-248,
1996[ISI][Medline].
17.
Jakab, G. J.,
and
D. R. Hemenway.
Inhalation coexposure to carbon black and acrolein suppresses alveolar macrophage phagocytosis and TNF- release and modulates peritoneal macrophage phagocytosis.
Inhal. Toxicol.
5:
275-289,
1993[ISI].
18.
Jakab, G. J.,
and
D. R. Hemenway.
Concomitant exposure to carbon black particulates enhances ozone-induced lung inflammation and suppression of alveolar macrophage phagocytosis.
J. Toxicol. Environ. Health
41:
221-231,
1994[ISI][Medline].
19.
Kleeberger, S. R.
Genetic susceptibility to ozone exposure.
Toxicol. Lett.
82-83:
295-300,
1995.
20.
Kleeberger, S. R.,
R. C. Levitt,
and
L.-Y. Zhang.
Susceptibility to ozone-induced inflammation. I. Genetic control of the response to subacute exposure.
Am. J. Physiol. Lung Cell. Mol. Physiol.
264:
L15-L20,
1993
21.
Kleeberger, S. R.,
R. C. Levitt,
L.-Y. Zhang,
M. Longphre,
J. Harkema,
A. Jedlicka,
S. M. Eleff,
D. DiSilvestre,
and
K. J. Holroyd.
Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice.
Nat. Genet.
17:
475-478,
1997[ISI][Medline].
22.
Kleeberger, S. R.,
L.-Y. Zhang,
and
G. J. Jakab.
Differential susceptibility to oxidant exposure in inbred strains of mice: nitrogen dioxide versus ozone.
Inhal. Toxicol.
9:
601-621,
1997[ISI].
23.
Lebowitz, M. D.
Population at risk: addressing health effects due to complex mixtures with a focus on respiratory effects.
Environ. Health Perspect.
95:
35-38,
1991[ISI][Medline].
24.
Liberti, A.,
D. Brocco,
and
M. Possanzini.
Adsorption and oxidation of sulfur dioxide on particles.
Atmos. Environ.
12:
255-261,
1978[ISI].
25.
Miyabara, Y.,
R. Yanagisawa,
N. Shimojo,
H. Takano,
H. B. Lim,
T. Ichinose,
and
M. Sagai.
Murine strain differences in airway inflammation caused by diesel exhaust particles.
Eur. Respir. J.
11:
291-298,
1998
26.
Novakov, T.,
S. G. Chang,
and
A. B. Harker.
Sulfates as pollution particulates: catalytic formation on carbon (soot) particles.
Science
184:
259-261,
1974.
27.
Ostro, B. D.
The effects of air pollution on work loss and morbidity.
J. Environ. Econ. Manage.
10:
371-382,
1983[ISI].
28.
Ostro, B. D.,
and
S. Rothchild.
Air pollution and acute respiratory morbidity: an observational study of multiple pollutants.
Environ. Res.
50:
238-247,
1989[ISI][Medline].
29.
Peters, A.,
D. W. Dockery,
J. Heinrich,
and
H. E. Wichmann.
Short-term effects of particulate air pollution on respiratory morbidity in asthmatic children.
Eur. Respir. J.
10:
872-879,
1997
30.
Pope, C. A., III,
M. J. Thun,
M. M. Namboodiri,
D. W. Dockery,
J. S. Evans,
F. E. Speizer,
and
C. W. Heath, Jr.
Particulate air pollution as a predictor of mortality in a prospective study of U. S. adults.
Am. J. Respir. Crit. Care Med.
151:
669-674,
1995[Abstract].
31.
Prows, D. R.,
H. G. Shertzer,
M. J. Daly,
C. L. Sidman,
and
G. D. Leikauf.
Genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice.
Nat. Genet.
17:
471-474,
1997[ISI][Medline].
32.
Qu, Q.-S.,
L. C. Chen,
T. Gordon,
M. Amdur,
and
J. M. Fine.
Alteration of pulmonary macrophage intracellular pH regulation by sulfuric acid aerosol exposures.
Toxicol. Appl Pharmacol.
121:
138-143,
1993[ISI][Medline].
33.
Raizenne, M.,
L. M. Neas,
A. I. Damokosh,
D. W. Dockery,
J. D. Spengler,
P. Koutrakis,
J. H. Ware,
and
F. E. Speizer.
Health effects of acid aerosols on North American children: pulmonary function.
Environ. Health Perspect.
104:
506-514,
1996[ISI][Medline].
34.
Saltini, C.,
A. J. Hance,
V. J. Ferrans,
F. Bassett,
P. B. Bitterman,
and
R. G. Crystal.
Accurate quantitation of cells recovered by bronchoalveolar lavage.
Am. Rev. Respir. Dis.
130:
650-658,
1984[ISI][Medline].
35.
Schlesinger, R. B.,
J. M. Fine,
and
L. C. Chen.
Interspecies differences in the phagocytic activity of pulmonary macrophages subjected to acidic challenge.
Fundam. Appl. Toxicol.
19:
584-589,
1992[ISI][Medline].
36.
Schwartz, J.
Particulate air pollution and chronic respiratory disease.
Environ. Res.
62:
7-13,
1993[ISI][Medline].
37.
Schwartz, J.
What are people dying of on high air pollution days?
Environ. Res.
64:
26-35,
1994[ISI][Medline].
38.
Skornik, L. A.,
and
J. D. Brain.
Effect of sulfur dioxide on pulmonary macrophage endocytosis at rest and during exercise.
Am. Rev. Respir. Dis.
142:
655-659,
1990[ISI][Medline].
39.
Sunyer, J.,
J. Anto,
C. Murillo,
and
M. Saez.
Effects of urban air pollution on emergency room admissions for chronic obstructive pulmonary disease.
Am. J. Epidemiol.
134:
277-286,
1991[Abstract].
40.
Vedal, S.,
J. Petkau,
R. White,
and
J. Blair.
Acute effects of ambient inhalable particles in asthmatic and nonasthmatic children.
Am. J. Respir. Crit. Care Med.
157:
1034-1043,
1998
41.
Warr, G. A.,
and
G. J. Jakab.
Alterations in lung macrophage immune receptor(s) activity associated viral pneumonia.
J. Reticuloendothel. Soc.
26:
357-366,
1979[ISI][Medline].
42.
Wolff, G. T.,
P. J. Globlicki,
S. H. Cadle,
and
R. J. Countess.
Particulate carbon at various locations in the United States.
In: Particulate Carbon: Atmospheric Cycle, edited by G. T. Wolff,
and R. Klimisch. New York: Plenum, 1982, p. 297-314.
43.
Zar, J. H.
Biostatistical Analysis (3rd ed.). Englewood Cliffs, NJ: Prentice-Hall, 1996.
44.
Zelikoff, J. T.,
M. P. Sisco,
Z. Yang,
M. D. Cohen,
and
R. B. Schlesinger.
Immunotoxicity of sulfur acid aerosol: effects on pulmonary effector and functional activities critical for maintaining host resistance against infectious diseases.
Toxicology
92:
269-286,
1994[ISI][Medline].