Departments of Environmental Health, Molecular and Cellular Physiology, Medicine, and Civil and Environmental Engineering, University of Cincinnati, Cincinnati, Ohio 45267
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ABSTRACT |
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Recent studies suggest that genetic variability can influence
irritant-induced lung injury and inflammation. To begin identifying genes controlling susceptibility to inhaled irritants, seven inbred mouse strains were continuously exposed to nickel sulfate
(NiSO4), polytetrafluoroethylene, or ozone
(O3), and survival time was recorded. The A/J (A) mouse
strain was sensitive, the C3H/He (C3) strain was intermediate, and the
C57BL/6 (B6) strain was resistant to NiSO4-induced acute
lung injury. The B6AF1 offspring were also resistant. The
strain sensitivity pattern for NiSO4 exposure was similar
to that of polytetrafluoroethylene or ozone (O3). Pulmonary pathology was comparable for A and B6 mice. In the A strain, 15 µg/m3 of NiSO4 produced 20% mortality. The
strain sensitivity patterns for lavage fluid proteins (B6 > C3 > A) and neutrophils (A B6 > C3) differed from
those for acute lung injury. This phenotype discordance suggests that
these traits are not causally linked (i.e., controlled by independent
arrays of genes). As in acute lung injury, B6C3F1 offspring
exhibited phenotypes (lavage fluid proteins and neutrophils) resembling
those of the resistant parental strain. Agreement of acute lung injury
strain sensitivity patterns among irritants suggested a common
mechanism, possibly oxidative stress, and offspring resistance
suggested that sensitivity is inherited as a recessive trait.
acute respiratory distress syndrome; particulate matter; asthma; bronchitis; oxidant; ozone; air pollution; environmental genetics; nickel
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INTRODUCTION |
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EPIDEMIOLOGICAL
STUDIES have associated air pollution with respiratory morbidity
and mortality (32, 50). Of the specific criteria
pollutants measured, fine particulate matter (particle diameter 2.5 µm) is often of the greatest concern, with mortality estimated to
increase ~1% per 10 µg/m3 (7, 14, 42,
49). Because the levels of pollution associated with adverse
effects are low compared with existing animal and clinical data, we
reasoned that individual susceptibility must play a major role in these
responses (30, 45). Previous studies have suggested that
individuals vary in their responses to ozone (O3), a common
respiratory oxidant. A clinical study (34) indicated varied responses to O3-induced bronchoconstriction.
Similarly, inbred mouse strains varied in sensitivity to
O3-induced acute lung injury, pulmonary inflammation, and
increased protein in lavage fluid (17-20, 23-27, 36,
44, 45, 47, 54).
Less is currently known about the susceptibility to fine particulate matter, but one possible mechanism involves the induction of oxidative stress (43, 46, 53). For example, ultrafine particulate, such as that generated from polytetrafluoroethylene (PTFE), can induce oxidative injury in the lung (22, 39, 46). Fine particulate matter is enriched in water-soluble transition metals that also may induce oxidative stress. Recent studies (6, 8, 11) of a particulate matter surrogate, residual oil fly ash, indicate that the water-soluble metals (vanadium, chromium, nickel, and iron) released from this material were responsible for the observed acute lung injury and inflammation. Subsequent in vitro studies (29, 43) reported that the active components of this mixture were vanadium, chromium, and nickel, with vanadium being the most active. However, in vivo studies (6, 29, 43) found that the converse was true and that nickel may be the most biologically active of the metals found in surrogate particulate matter. An additional in vivo study (28) with intratracheal instillation of residual oil fly ash found differences in rat strains, suggesting that genetic susceptibility may play a role in individual responsiveness to inhaled particulate matter.
Of the transition metals enriched in the fine fraction of the ambient aerosol and the workplace, nickel is acutely toxic to the lung (21, 43). Nickel enters the environment via high-temperature combustion, electroplating, and smelting processes (21, 35, 38, 51) and exists primarily in soluble [e.g., nickel sulfate (NiSO4)] and insoluble (e.g., nickel oxide and elemental nickel) forms. Ambient concentrations of nickel in particulate matter have ranged from 1 to 328 ng/m3 in urban areas and 0.6 to 78 ng/m3 in rural areas in the US (35, 48). Concentrations of nickel in stack effluent are significantly higher, ranging from 0 to 260 ng/m3 (municipal solid waste incinerators), 200 to 510 ng/m3 (oil combustors), and 2,000 to 5,182 ng/m3 (coal combustors) (3). Previous NiSO4 inhalation studies have noted acute (inflammation, macrophage cytotoxicity, alveolar proteinosis, and epithelial cell injury) and chronic (chronic interstitial infiltrates and fibrosis) respiratory effects in Fischer 344 rats and B6C3F1 mice (2, 9, 10, 38). Exposure to 1,600 µg Ni/m3 (6 h/day, 5 days/wk) produced 100% mortality within 12 days in B6C3F1 mice. Chronic occupational exposures have been associated with an increased incidence of deaths from respiratory disease and asthma when concentrations exceeded the current standard (100 µg/m3 for soluble nickel) (5, 37, 41, 52).
The purpose of this study was to determine whether host (genetic) factors contribute to increased individual susceptibility to respiratory irritants. Interstrain differences in pulmonary responses were compared by measuring acute lung injury, protein content of lavage fluid, and pulmonary inflammation with selected strains of inbred mice exposed continuously to fine NiSO4 aerosol. Strain phenotype patterns were also assessed for acute lung injury produced by exposure to two known oxidants, ultrafine PTFE and O3. After the identification of resistant and sensitive strains, the mode of inheritance was assessed by exposing offspring of the respective polar strains.
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MATERIALS AND METHODS |
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Experimental design. To investigate genetic determinants of irritant-induced acute lung injury, seven inbred mouse strains were continuously exposed to NiSO4, PTFE, or O3. Two strains with polar responses to acute lung injury, a sensitive A/J (A) strain and a resistant C57BL/6J (B6) strain, were identified. To investigate the mode of inheritance of NiSO4-induced acute lung injury, the survival times of the offspring from a cross of the resistant and sensitive inbred mouse strains (B6AF1) were determined. To investigate the pathology associated with NiSO4-induced acute lung injury, A and B6 mouse strains were exposed, histological sections were microscopically examined, and lung wet and dry weights were determined. To evaluate whether lower doses of NiSO4 produce acute lung injury, groups of the sensitive A strain mice were exposed to concentrations ranging from 15 to 150 µg Ni/m3. Previously, Kleeberger and colleagues (23, 26) reported that pulmonary protein and inflammatory cells present in lavage fluid varied between B6 (sensitive) and C3H/He (C3; resistant) mice exposed to ozone for 48 h. Protein and polymorphonuclear neutrophil (PMN) levels were therefore measured in the lavage fluid of B6, C3, A, and the F1 cross of the B6 and C3 mice after 48 h of NiSO4 exposure.
Atmosphere generation and characterization. Continuous irritant exposures (up to 2 wk) of inbred mice included fine NiSO4 (particle alone), ultrafine PTFE (particle and gas mixture), and O3 (gas alone). Mice were exposed to NiSO4 or O3 in stainless steel cages placed inside a 0.32-m3 stainless steel inhalation chamber. NiSO4 aerosol [mass median aerodynamic diameter (MMAD) = 0.22 µm; geometric SD = 1.9] was generated from a solution of nickel sulfate hexahydrate (NiSO4 · 6H2O; Sigma, St. Louis, MO) with a modified Collison three-jet nebulizer (3.5 l/min; BGI, Waltham, MA) placed inside a glass tube (24-mm ID). The particle number concentration and particle size were determined with a differential mobility analyzer consisting of an electrostatic classifier [model 3071A, Thermo-Systems (TSI), St. Paul, MN], a condensation nucleus counter (model 3022A, TSI), and scanning mobility particle sizer fast-scanning software (TSI). The chamber nickel concentration was determined with the dimethylglyoxime method (15). Samples of the chamber atmosphere were collected with 2 midget impingers (Ace Glass) in series, each containing 10 ml of distilled water (flow rate 11.3 l/min). Collected samples were mixed with a solution containing 1 M HCl, 0.2 M bromine, 12 M NH4OH (Fisher Scientific, Fair Lawn, NJ), 1% dimethylglyoxime (Sigma), and 95% ethanol. Absorbance was measured at 445 nm (model DU-64, Beckman, Fullerton, CA). During nickel exposures, mice were supplied with food and water. For initial assessment of acute lung injury, mice were exposed to 150 ± 15 µg Ni/m3. O3 [10.0 ± 0.2 parts/million (ppm)] was generated from 100% ultradry oxygen (Matheson, Columbus, OH) with a model V1-0 ultraviolet ozonator (OREC, Phoenix, AZ) and analyzed continuously with an ozone detector (Dasibi model 1008-PC, Glendale, CA). This instrument was calibrated against a US Environmental Protection Agency transfer standard.
For PTFE exposures, mice were placed in stainless steel cages inside a 0.05-m3 Plexiglas chamber and were continuously exposed to 107 PTFE particles/cm3 (30 l/min). PTFE powder (0.75 g; Fluon, ICI Chemicals and Polymers, Bayonne, NJ) was placed in a ceramic furnace tube (2.5-cm ID) and heated to 420 ± 5°C with a Lindberg Hevi-Duty furnace (Sola Basics Industries, Watertown, WI). At this temperature, ultrafine particles (0.02-µm MMAD) and hydrofluoride gas are released (39). Airflow through the heated tube was 5.0 l/min, and diluting airflow was 25 l/min. Particle size and concentration were determined with an electrical aerosol analyzer (model 3030, TSI).Strain selection and tissue preparation. All inbred mouse strains (A, AKR, C3, B6, CBA, DBA/2, FVB/N, and specific F1 crosses) were purchased from Jackson Laboratory (Bar Harbor, ME). To examine lung pathology, NiSO4-exposed mice were obtained at death, and control mice were injected with pentobarbital sodium (50 mg/kg; Nembutal, Abbott Laboratories, North Chicago, IL) and exsanguinated. A cannula (0.58-mm ID) was inserted into the trachea, and the lungs were instilled in situ (30 cmH2O, 850 µl) with phosphate-buffered formaldehyde (pH 7.1), removed, and immersed in fixative (24 h). The left lung was washed with PBS, dehydrated through a series of graded ethanol solutions (30-70%), and processed into paraffin blocks (Hypercenter XP, Shandon Scientific). Paraffin-embedded tissues were sagittally sectioned (5 µm) and stained with hematoxylin and eosin.
To obtain tissue for determination of lung wet weight, lung dry weight, and wet-to-dry weight ratio, the chest cavity was opened and the heart-lung block was removed. The lungs were rinsed with PBS, trimmed (heart, connective tissue, and esophagus), and blotted dry with gauze, and the wet weight was recorded. The lungs were then dried in a plastic desiccator containing silica gel (Sargent-Welch, Skokie, IL) for 2 wk before dry weights were recorded.Bronchoalveolar lavage. Mice were exposed to NiSO4 aerosol for 48 h and killed (50 mg/kg of pentobarbital sodium intraperitoneally with exsanguination). The lungs were lavaged three times with 1 ml of Hanks' balanced salt solution (GIBCO BRL, Life Technologies, Grand Island, NY) without Ca2+ and Mg2+ and containing D-glucose (pH 7.2). Individual lavage samples were pooled and immediately placed on ice (4°C). Aliquots (250 µl) of lavage fluid were centrifuged (Cytospin 3, Shandon Scientific), and the cells were stained with Diff-Quik (Baxter Diagnostics, McGaw Park, IL) for differential cell analysis. Differential cell counts were performed by identifying at least 300 cells. The pooled lavage fluid was then centrifuged (500 g for 4 min at 4°C), and the supernatant was decanted. The cell pellet from each lavage was resuspended in 1 ml of Hanks' balanced salt solution. Total cell counts were determined with a hemocytometer. The total protein concentration in the supernatant was measured with the Bradford (4) method (bovine serum albumin standard, 595 nm; Bio-Rad Laboratories, Hercules, CA).
Data analysis. To evaluate resistance to NiSO4-, PTFE-, or O3-induced acute lung injury, survival times are presented as means ± SE, and the differences between means were assessed with ANOVA followed by a Student-Newman-Keuls multiple comparison test of significance. To assess NiSO4-induced changes in lung wet-to-dry weight ratios and protein and PMNs in lavage fluid, values are presented as means ± SE. Statistical analysis was performed with a two-way ANOVA followed by a Student-Newman-Keuls test of significance. The factors for each analysis were strain (A vs. C3 vs. B6C3F1 vs. B6) and exposure (exposed vs. control). Significance for all comparisons of means was accepted at P < 0.05.
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RESULTS |
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Strain phenotype pattern.
The survival time of seven inbred mouse strains was used to assess
acute lung injury induced by continuous exposures. After exposure to
NiSO4, the A strain was sensitive and the B6 strain was
resistant (Fig. 1). Other strains, FVB/N,
CBA, AKR, DBA/2, and C3, varied in sensitivity. The strain phenotype
pattern observed with NiSO4 was similar to that of the
other two oxidants tested, ultrafine PTFE and O3
(Fig. 1). The survival times decreased with each irritant
(NiSO4 > PTFE > O3); nonetheless,
the patterns of the sensitive A strain and the resistant B6 strain were
consistent across the agonists. Of the three more common strains, the
relative susceptibility for this trait followed the order A > C3 > B6.
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Mode of inheritance.
To determine whether resistance or sensitivity is recessive or
dominant, the offspring of a cross of the resistant B6 strain with the
sensitive A strain (B6AF1) were exposed to
NiSO4. These mice were resistant, resembling the survival
time of the resistant B6 parental strain (Fig.
2). Exposure to the two oxidants,
ultrafine PTFE and O3, each resulted in the same effect,
with the B6AF1 mice having survival times resembling the B6
parental strain (Fig. 2). For each irritant, the response of the A
strain was significantly less than that of the B6 strain, which was not
significantly different from response of the B6AF1 mice.
These findings suggest that resistance is inherited as a dominant trait
or that susceptibility is recessive.
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Pulmonary histopathology induced by NiSO4.
Acute lung injury in the sensitive A and resistant B6 strains was
evaluated by light-microscopic observations and by measuring lung
wet-to-dry weight ratios. The exposure-induced changes in pulmonary
histology were comparable between the sensitive A and resistant B6
strains. Compared with corresponding control mice (Fig.
3, A and B),
exposed mice had greater perivascular distension (Fig. 3, C
and D) and focal loss of epithelial integrity, alveolar congestion, and alveolar hemorrhage (with luminal erythrocytes; Fig. 3,
E and F). No strain difference was observed
between A and B6 mice. At the time of death (survival times = 61 ± 3 and 118 ± 5 h for A and B6 mice, respectively),
lung wet-to-dry weight ratios increased significantly over their
respective control values (Fig. 4). No
statistical difference was observed between control A and B6 mice or
between exposed A and B6 mice, indicating that the amount of lung edema
at death was comparable between the two strains. Together with the
results of lung histopathology, these findings indicate that both
strains succumbed to comparable acute lung injury.
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Dose-response relationship.
Having found that A mice were sensitive, dose-response information was
then obtained for this strain. Groups of 10 mice (5 males and 5 females) were continuously exposed for up to 14 days, and 100%
mortality was observed at 150 and 60 µg Ni/m3 (Fig.
5). At lower doses of 30 and 15 µg Ni/m3, the A mice exhibited 60 and 20% mortality,
respectively. The lethal dose producing 50% mortality was estimated to
be 27 µg Ni/m3 (Fig. 5).
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Pulmonary protein and leukocyte infiltration in lavage fluid.
Compared with nonexposed control mice, A, B6, and C3 mice had greater
levels of protein recovered in lavage fluid after a 48-h exposure to
fine NiSO4 aerosol. The amount of protein induced by
exposure varied between strains. The response of the B6 strain was
greatest, with a mean value higher than that of the C3 or A strains
(Fig. 6). Of the three strains tested,
susceptibility to lavage fluid protein followed the order B6 > C3 A. The cross of the sensitive B6 with the resistant C3
strain produced offspring (B6C3F1) with a resistant
phenotype, resembling the resistant C3 parental strain.
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DISCUSSION |
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We found that nickel, a transition metal released from particulate matter, can induce acute lung injury in mice. Susceptibility varied more between than within inbred mouse strains. The A strain was found to be sensitive, and the B6 strain was found to be resistant. The cross of these strains produced offspring with a resistant phenotype, indicating that sensitivity is inherited as a recessive trait. The strain phenotype pattern for NiSO4, ultrafine PTFE, or O3 exposure was similar, suggesting that the trait of sensitivity to acute lung injury could be independent of the agent producing injury. Histopathological findings indicated comparable injury in both strains at the time of death. Acute lung injury was observed in the A strain at the lowest dose tested (15 µg Ni/m3). In contrast, the strain phenotype patterns of protein in lavage fluid, PMNs in lavage fluid, and acute lung injury differed, suggesting each trait is inherited independently.
One possibility for a consistent strain phenotype pattern for fine NiSO4, ultrafine PTFE, or O3 exposure is that each agent is capable of producing oxidant lung injury. All three agonists can penetrate to the distal regions of the lung (1, 2, 39, 46, 54). Of the three agonists, O3 is the best studied and is known to readily oxidize surface proteins (e.g., surfactant) and phospholipids (e.g., unsaturated fatty acids) (31). Recently, ultrafine PTFE has also been found to deplete sulfhydryls and to activate compensatory antioxidant pathways (increasing transcript levels of several antioxidant enzymes in the lung) (22, 39, 46). In this study, we selected a fine nickel aerosol as a surrogate for particulate matter because it is a transition metal also capable of initiating oxidant injury through a Fenton reaction (53). In addition, instillation of soluble nickel can produce effects similar to residual oil fly ash, a material used as a surrogate for particulate matter (6, 29). Histopathology after nickel exposure was comparable in both the A and B6 strains at the time of death, suggesting that resistance is an ability to forestall injury. Such a response would be consistent with a gradual loss of the lung metabolic capability to handle oxidants (18, 22, 31, 33). Thus our findings that the strain phenotype pattern is similar with the three agonists tested implies that a common mechanism, possibly oxidant injury, is responsible for acute lung injury.
Acute lung injury was observed after continuous low-level nickel exposure, which contrasts with existing literature. In this study with A strain mice, 20% mortality (2 of 10 mice died at 148 and 173 h) occurred with continuous exposure to 15 µg Ni/m3. In past studies (2, 21, 38) with Fischer 344 rats and B6C3F1 mice, 100% mortality (10 of 10 mice within 288 h) occurred with intermittent exposure to a higher concentration (1,600 µg Ni/m3). Our findings that B6 mice impart resistance to their offspring for acute lung injury and C3 mice impart resistance for protein and PMNs in lavage fluid suggest that B6C3F1 mice represent a resistant model for these responses to inhaled NiSO4. In addition, the previous studies with B6C3F1 mice (2, 38) differed in other ways from the exposure protocol used in this study. In the previous study, exposures were intermittent (6 h/day, 5 days/wk; 6 h of exposure separated by 18 h of recovery) and to a larger diameter (>2.0-µm MMAD) aerosol, whereas in this study, exposures were continuous and to an aerosol with a smaller particle diameter (0.2-µm MMAD). The latter may influence lung dosimetry because regional deposition in the mouse respiratory tract may vary due to the high collection efficiency of the murine nasal passage for >1.0-µm particles.
Previously, Prows and colleagues (44, 45) reported that ozone-induced acute lung injury is an oligogenetic trait with linkage to at least two major quantitative trait loci. One major locus, Ali1 (now Aliq1), was isolated to a region on mouse chromosome 11 with marked synteny with human chromosome 17. Interesting candidate genes in this region include inducible nitric oxide synthase, a cluster of the small inducible cytokines, and myeloperoxidase, each having properties that could mediate oxidant injury and inflammation. Independently, Kleeberger et al. (26) have identified a locus for O3-induced lung inflammation on mouse chromosome 17 (with synteny to human chromosome 6). The NiSO4 findings presented here are consistent with the strain phenotype patterns and mode of inheritance observed with O3. The strain patterns with O3 or NiSO4 differ with each phenotype, acute lung injury, or inflammation, but with either irritant, the same strains are sensitive and resistant, and sensitivity is inherited as a recessive trait. In addition, increases in NiSO4-induced PMNs in lavage fluid did not correlate with protein in lavage fluid. This conclusion is limited in that these variables were measured at only one time (48 h), which was selected based on findings of Kleeberger et al. with O3. Nonetheless, the consistency of interstrain differences with NiSO4 and O3 across these studies (and sustaining evidence with another oxidant, PTFE) supports this hypothesis.
The discordance of the strain patterns for the three NiSO4-induced phenotypes (acute lung injury, lavage fluid protein, or lavage fluid PMNs) suggests that all three traits are controlled by different genes that can be inherited in different arrays. As mentioned above, recent studies with O3 (23-26, 44, 45) support independent genetic determinants for susceptibility to acute lung injury or PMN inflammation. This leads to an important possibility: increases in protein or PMNs in lavage fluid are not related causally to acute lung injury. This possibility implies that measures of protein or PMNs by bronchoalveolar lavage may have little value in predicting the survival time of patients with acute lung injury, a finding consistent with previous animal studies (12, 13, 24) and clinical observations (16, 40, 55).
In summary, mice vary in their susceptibility to acute lung injury, protein content in lavage fluid, and inflammation in response to a surrogate particulate matter, NiSO4. Each phenotype is inherited as an independent recessive trait. The NiSO4 concentrations used to produce acute lung injury were as low as 15 µg Ni/m3. Finally, the strain phenotype patterns are shared by three irritants, fine NiSO4, ultrafine PTFE, and O3, suggesting that this is a conserved response mechanism possibly related to oxidant injury.
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ACKNOWLEDGEMENTS |
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We thank Gunter Oberdörster, Kevin Driscoll, Raymond Suskind, Howard Shertzer, Marian Miller, Michael Borchers, Steven Weldert, Albert Senft, and John Leikauf for helpful advice and technical assistance.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant R01-HL-58275; National Institute of Environmental Health Sciences Grant P30-ES-06096; and the Health Effects Institute.
The Health Effects Institute is an organization jointly funded by the US Environmental Protection Agency, Assistance Agreement X-812059, and automotive manufacturers. The contents of this article do not necessarily reflect the views of the Health Effects Institute or the policies of the US Environmental Protection Agency or automotive manufacturers.
S. Wesselkamper received a J. Stara Fellowship and a University of Cincinnati Graduate Assistantship, and this work is in partial fulfillment of the degree requirements at the University of Cincinnati.
Address for reprint requests and other correspondence: G. D. Leikauf, Dept. of Environmental Health, Univ. of Cincinnati, PO Box 670056, Cincinnati, OH 45267-0056 (E-mail: leikaugd{at}ucmail.uc.edu).
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.
Received 24 March 1999; accepted in final form 1 June 2000.
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