Departments of 1 Surgery and 3 Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky 40292; and 2 Grand Forks Human Nutrition Research Center, Agricultural Research Service, United States Department of Agriculture, Grand Forks, North Dakota 58202
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ABSTRACT |
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Dietary copper is required for normal
function of >30 mammalian enzyme systems. Copper deficiency causes a
number of cardiovascular defects as well as impaired immune cell
function. Little is known regarding the effects of copper deficiency on
acute inflammatory responses, but this topic is relevant because many
members of the Western population receive less than the recommended
dietary allowance of copper. In the current studies, we investigated
the effects of dietary copper deficiency on acute lung injury induced by intrapulmonary deposition of IgG immune complexes. Weanling male
Long-Evans rats were fed diets either adequate (5.6 µg/g) or
deficient (0.3 µg/g) in copper. IgG immune complex lung injury was
greatly increased in copper-deficient rats as determined by lung
vascular leakage of albumin and histopathology. However, no change was
observed in either the lung content of tumor necrosis factor- or
lung neutrophil accumulation. Lungs from copper-deficient rats had much
higher levels of matrix metalloproteinase (MMP)-2 and MMP-9 than did
copper-adequate control animals. This increased activity was not
attributable to alveolar macrophages or neutrophils. These data suggest
that the augmented lung injury caused by copper deficiency is due to
increased pulmonary MMP-2 and MMP-9 activity and not a generalized
amplification of the inflammatory response.
inflammation; gelatinase; neutrophils; cytokines
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INTRODUCTION |
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COPPER IS A MICRONUTRIENT that is essential for the normal function of a large number of mammalian enzyme systems. Experimental animal models of copper deficiency have demonstrated impaired enzyme activity in association with severe defects in cardiovascular function including altered vascular tone, cardiac hypertrophy, hypotension, and hypercholesterolemia (24). Recent evidence (1, 10) also suggests that adequate intake of copper is necessary for normal immune function. Even marginal copper deficiency, which does not result in cardiovascular defects, causes markedly impaired function of neutrophils and lymphocytes. These studies showed that decreased copper intake reduced lymphocyte proliferation by decreasing the production of interleukin-2 and reduced the ability of neutrophils to generate superoxide anion and kill ingested microorganisms. A subsequent study (14) has shown that copper is essential for the normal maturation of neutrophils.
The current recommended dietary allowance for copper is 900 µg/day, although numerous dietary surveys indicate that many typical Western diets provide less than this amount (16). Although no overt symptoms of copper deficiency have been identified in the general population, compromised immune function in individuals with reduced copper status may increase their susceptibility to infection or inflammatory injury. In neonatal rats, reduced copper intake has been associated with a predisposition to development of acute respiratory distress syndrome (ARDS) (25). However, given the adverse effects of copper deficiency on neutrophil development and function (1, 10, 14) and the known participation of neutrophils in the pathogenesis of ARDS and similar syndromes (29, 33), it might be expected that reduced copper intake would result in a diminished lung inflammatory response.
In the current study, we examined the effects of copper deficiency on
the lung inflammatory response to intrapulmonary deposition of IgG
immune complexes. This model has been well characterized in rats and
bears many similarities to acute lung injury induced by infection or
trauma (11, 20, 34). Central to the development of lung
inflammation in this model is the pulmonary production of tumor
necrosis factor- (TNF-
) (32). This cytokine appears to stimulate other inflammatory pathways that facilitate the
recruitment of neutrophils from the vascular compartment into the lung
parenchyma and airspaces (29). The ensuing lung injury,
characterized by increased vascular permeability and alveolar
hemorrhage, is thought to be mediated by oxidants and proteases
released by neutrophils, lung macrophages, and activated lung
parenchymal cells. Our results demonstrate that copper deficiency
results in greatly augmented lung injury independent of TNF-
production or neutrophil recruitment. We found markedly increased
activity of matrix metalloproteinase (MMP)-2 and MMP-9 in lungs from
copper-deficient rats that could not be attributed to alveolar
macrophages or neutrophils. Based on these data, it appears that
increased lung injury in copper-deficient rats is caused by augmented
MMP activity within the lung compartment.
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MATERIALS AND METHODS |
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Animals and diet. Male weanling Long-Evans rats were purchased from Charles River Laboratories (Wilmington, MA). On arrival, rats were housed individually in stainless steel cages in a temperature- and humidity-controlled room with a 12:12-h light-dark cycle. The rats were given free access to distilled water and to one of two purified diets for 4 wk. The basal diet (13) was a casein-sucrose-cornstarch-based diet (TD 84469, Teklad test diets, Madison, WI) containing all known essential vitamins and minerals except for copper and iron. The copper-adequate (CuA) diet consisted of the basal diet (940 g/kg total diet) along with safflower oil (50 g/kg) and a copper-iron mineral mix that provided 0.22 g ferric citrate (16% Fe) and 24 mg cupric sulfate (monohydrate)/kg diet. The copper-deficient (CuD) diet was the same except for the replacement of copper with cornstarch in the mineral mix. Diet analysis by atomic absorption spectrophotometry indicated that the CuA diet contained 5.56 mg copper/kg diet, and the CuD diet contained 0.33 mg copper/kg diet. Parallel assays of National Institute of Standards and Technology (NIST, Gaithersburg, MD) reference samples (citrus leaves, no. 1572) yielded values within the specified range, which validated our copper assays.
Hepatic copper content.
The median lobe of the liver was removed, weighed, and frozen at
20°C for subsequent copper analysis. Liver samples were lyophilized
and digested in nitric acid and hydrogen peroxide (H2O2) as previously described
(21). Hepatic copper concentrations were assessed by
inductively coupled argon plasma emission spectrometry (Jarrell-Ash
model 1140, Waltham, MA). Parallel assays of reference samples from the
NIST (bovine liver, no. 1477a) yielded mineral contents within the
specified range.
Lung Cu/Zn superoxide dismutase activity. Analysis of lung homogenates for Cu/Zn superoxide dismutase (SOD) activity was initiated by treatment with 0.4 volume of a solution of ethanol and chloroform (25:15) to precipitate Mn SOD (22). This solution was mixed well and centrifuged at 5,000 g for 15 min. Aliquots of clear supernatant were dialyzed against deionized water (4°C, 12,000 md wt exclusion membrane). Cu/Zn SOD activity of the dialysate was measured spectrophotometrically (Beckman Coulter model DU 650, Fullerton, CA) with a kit (OxyScan SOD-525) from OXIS International (Portland, OR). The method is based on the ability of SOD to accelerate autoxidation of a proprietary reagent to a chromophore, with maximum absorbance at 525 nm.
IgG immune complex-induced lung injury. Rats were anesthetized with ketamine hydrochloride (150 mg/kg ip). For measurement of pulmonary vascular permeability, rats received an intratracheal administration of PBS, pH 7.4, or 1.5 mg of rabbit polyclonal IgG anti-BSA (ICN Biomedical, Costa Mesa, CA) in a volume of 0.3 ml of PBS. Immediately thereafter, 10 mg of BSA (<1 ng endotoxin/mg) containing trace amounts of 125I-labeled BSA in 0.5 ml of PBS were injected intravenously. Four hours after IgG immune complex deposition, rats were exsanguinated, the pulmonary circulation was flushed with 10 ml of PBS by pulmonary arterial injection, and the lungs were surgically dissected. The extent of lung injury was quantified by calculating the lung permeability index by dividing the amount of radioactivity (125I-labeled BSA) in the perfused lungs by the amount of radioactivity in 1.0 ml of blood obtained at the time of death.
Lung myeloperoxidase content. Whole lung myeloperoxidase (MPO) activity was quantitated as described previously (30). Briefly, 100 mg of lung tissue were homogenized and diluted in 50 mM potassium phosphate buffer containing 0.5% hexadecyltrimethylammonium bromide, pH 6.0. After sonication and two freeze-thaw cycles, samples were centrifuged at 4,000 g for 30 min. The supernatants were reacted with H2O2 (0.3 mM) in the presence of tetramethylbenzidine (1.6 mM). MPO activity was assessed by measuring the change in absorbance at 655 nm with human MPO used as a standard.
Bronchoalveolar lavage fluid content of TNF-.
Bronchoalveolar lavage (BAL) fluid was collected by instilling and
withdrawing 5 ml of sterile PBS three times from the lungs via an
intratracheal cannula. The TNF-
content of the BAL fluid was
measured with an enzyme-linked immunosorbent assay (ELISA) purchased
from BD PharMingen (San Diego, CA).
Substrate-embedded enzymography. SDS-PAGE gels (7.5%) containing 1 mg/ml of gelatin were prepared. Denatured but nonreduced BAL fluid samples or cell supernatants were electrophoresed into the gels at constant voltage. The gels were then washed twice (20 min/wash) in water containing 2.5% Triton X-100 at room temperature and incubated overnight in activation buffer (10 mM Tris · HCl, pH 7.5, 1.25% Triton X-100, 5 mM CaCl2, and 1 µM ZnCl2) at 37°C. Gels were then stained with Coomassie blue for 3 h and then destained. Regions of negative staining indicated the presence of proteinases with gelatinolytic activity.
Western blot analysis. BAL fluid (35 µl) was separated in a denaturing 10% polyacrylamide gel and transferred to a 0.1-µm-pore nitrocellulose membrane. Nonspecific binding sites were blocked with Tris-buffered saline (TBS; 40 mM Tris, pH 7.6, and 300 mM NaCl) containing 5% nonfat dry milk for 2 h at room temperature. Membranes were then incubated overnight at 4°C in 0.5 µg/ml of polyclonal goat anti-MMP-2 or anti-MMP-9 (Santa Cruz Biotechnology, Santa Cruz, CA) in TBS with 0.1% Tween 20 (TBS-T). After three washes in TBS-T, the membranes were incubated for 2 h in 0.15 µg/ml of horseradish peroxidase-conjugated donkey anti-goat IgG (Santa Cruz Biotechnology) at room temperature. Membranes were washed three times in TBS-T, and immunoreactive proteins were detected by enhanced chemiluminescence.
Isolation and culture of rat alveolar macrophages and peripheral
blood neutrophils.
Rat alveolar macrophages from otherwise normal rats fed either a CuA or
CuD diet were isolated by BAL. Cells were pelleted by centifugation and
plated in DMEM (1 × 106 cells/ml) supplemented with
0.2% BSA. After being allowed to adhere for 1 h, the cells were
washed with fresh medium to remove nonadherent cells. Peripheral blood
neutrophils were isolated by dextran and Percoll separation. The
remaining red blood cells were hypotonically lysed, and the neutrophils
were washed and resuspended in DMEM (1 × 106
cells/ml) supplemented with 0.2% BSA. After isolation, alveolar macrophages or blood neutrophils were cultured for 2 h in the absence and presence of TNF- (10 ng/ml) or lipopolysaccharide (10 µg/ml). Supernatants were then harvested and subjected to substrate-embedded enzymography.
Statistical analysis. All data are expressed as means ± SE. Data were analyzed with a one-way analysis of variance with subsequent Student-Newman-Keuls test. Differences were considered significant when P < 0.05.
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RESULTS |
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Establishment of copper deficiency.
Rats fed a diet deficient in copper for 4 wk had significantly less
hepatic copper and were anemic (Table 1).
These markers are indicative of copper deficiency. In the Long-Evans
rats used for these experiments, the CuD diet slowed weight gain; these rats weighed ~10% less at the time of experimentation than rats fed
a CuA diet (Table 1). Furthermore, CuD rats had significantly less
Cu/Zn SOD activity in lung tissue than rats fed a CuA diet (Table 1),
indicating a potentially altered redox state in the lung.
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Effects of copper deficiency on IgG immune complex-induced lung
injury.
Because lung SOD activity was reduced in rats fed a CuD diet and
because acute inflammatory reactions are often dependent on redox
status, we sought to determine whether the lack of dietary copper
altered the acute lung injury induced by IgG immune complexes. The
extent of lung injury was determined by pulmonary vascular leakage of
125I-albumin. In rats fed the CuA diet, deposition of IgG
immune complexes caused a 130% increase in the lung permeability index compared with that of rats receiving intratracheal PBS (Fig.
1). Interestingly, in rats fed
the CuD diet, IgG immune complex deposition resulted in a 354%
increase in the permeability index compared with similarly fed rats
receiving intratracheal PBS. This augmented lung injury was evident by
a more than twofold increase in the permeability index of CuD rats
versus CuA rats. There was no difference in the lung permeability index
in the PBS control rats fed either diet.
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Effects of copper deficiency on lung production of TNF- and lung
neutrophil accumulation.
The development of the lung inflammatory response induced by IgG immune
complexes requires the pulmonary production of the cytokine TNF-
,
and the ensuing lung injury is heavily dependent on the accumulation of
neutrophils in the lung vasculature and airspaces (32). To
determine how copper deficiency augments the lung inflammatory
response, we examined the pulmonary production of TNF-
and the lung
accumulation of neutrophils in both CuA and CuD rats. BAL fluid levels
of TNF-
were near the lower limit of detection of the ELISA in rats
receiving intratracheal PBS (Fig. 3). IgG immune complex deposition
caused significant increases in BAL fluid levels of TNF-
in both CuA
and CuD rats. However, there was no significant difference between
these groups.
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Effects of copper deficiency on MMP activity and expression.
MMPs are involved in the parenchymal damage that occurs during lung
inflammatory injury (3, 8, 9). Others have shown that
changes in the cellular redox state or in expression of Cu/Zn SOD can
dramatically affect the expression and/or activation of MMPs (4,
5, 19). Because we observed that CuD rats had significantly less
Cu/Zn SOD activity than rats fed a CuA diet (Table 1), we analyzed BAL
fluid for the presence of MMPs with gelatinolytic activity. In CuA rats
receiving intratracheal PBS, no MMP activity was observed (Fig.
5). In contrast, in BAL fluid from CuD
rats, a 72-kDa band was seen, suggesting that copper deficiency may
increase the release of MMP-2 (72-kDa gelatinase A) in the lung in
unstimulated rats. Intrapulmonary deposition of IgG immune complexes
resulted in large amounts of both MMP-2 and a 92-kDa band that likely
represents MMP-9 (92-kDa gelatinase B). Interestingly, there was much
more MMP-2 and MMP-9 activity present in the BAL fluid from CuD rats.
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DISCUSSION |
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IgG immune complex-induced lung inflammation is a
well-characterized model of acute lung injury in which the deposition
of IgG immune complexes in small airways and alveoli causes activation of lung macrophages. Activated alveolar macrophages produce and secrete
proinflammatory cytokines, including TNF- (32). A
primary function of TNF-
is to promote the inflammatory response by
stimulating other lung cells to produce neutrophil-attracting C-X-C
chemokines and cause upregulation of cellular adhesion molecules on the
pulmonary vascular endothelium (29). Through a series of
complex coordinated interactions, chemokines and adhesion molecules
facilitate the adhesion and transmigration of neutrophils from the
vascular lumen into the lung interstitium and airspaces. The products
of these activated neutrophils and lung macrophages, which include
oxidants and proteases, result in damage to lung cells and matrix
components. In the current studies, we used this well-defined model of
lung injury to investigate the effects of copper deficiency on the induction and propagation of the lung inflammatory response.
IgG immune complex lung injury was much more severe in CuD rats as
determined by pulmonary vascular leakage and histopathological analysis. Interestingly, there was no difference in the extent of
neutrophil accumulation in the injured lungs from rats fed either a CuA
or CuD diet. These data suggest that the enhanced lung injury observed
in CuD rats was independent of neutrophils. Consistent with these
findings, when intrapulmonary levels of TNF- protein were measured,
there were no differences between CuA and CuD rats. Thus it appears
that copper deficiency does not amplify the inflammatory response by
increasing TNF-
production or subsequent events leading to the
recruitment of neutrophils.
Copper deficiency did result in reduced activity of Cu/Zn SOD in lung. A previous study (12), however, suggested that there is no direct protective role for SOD in IgG immune complex lung injury. Exogenous administration of SOD had virtually no effect on lung permeability or histopathology in this model. Despite these findings, depressed SOD activity may result in a shift toward a prooxidant environment in the lung. The depression of Cu/Zn SOD activity is representative of a general shift to a prooxidant environment in CuD animals that includes depression of other antioxidant enzymes as well as a change in the metabolism of iron that promotes free radical formation (23). A prooxidant milieu may augment the generation of other factors that contribute to lung injury, such as MMPs. Our current data demonstrate that CuD rats, which have significantly less lung SOD activity, have augmented production or activity of MMP-2 and MMP-9. Both of these enzymes are known to be positively regulated by reactive oxygen species such as H2O2 and superoxide anion (4, 5, 19). Conversely, both MMP-2 and MMP-9 are inhibited by tissue inhibitors of metalloproteinases (TIMPs). However, we found no difference in the mRNA expression of TIMP-1 or TIMP-2 in lungs from rats fed a CuA or CuD diet (unpublished observations).
In the context of acute lung injury, a number of cells may produce MMP-2 and MMP-9, including lung epithelial and endothelial cells, alveolar macrophages, and recruited neutrophils (4, 6, 8, 15). Copper deficiency is known to impair the function of neutrophils, macrophages, and endothelial cells. Neutrophils from CuD rats show diminished respiratory burst and bactericidal activity (1, 10). Similar effects are seen in macrophages from CuD rats (2). Endothelial cell dysfunction induced by copper deficiency appears to be related to suppressed intracellular calcium mobilization (26). In the current studies, no differences in MMP-2 or MMP-9 activity were observed in neutrophils or alveolar macrophages from CuD rats. These findings exclude the possibility that these cells are responsible for the increased MMP-2 and MMP-9 activity found in the BAL fluid of rats fed a CuD diet. Furthermore, by Western blot analysis of BAL fluid, we demonstrated a marked increase in the protein content of MMP-2 and MMP-9. Because this model does not involve lung recruitment of other leukocytes, it is likely that copper deficiency somehow alters lung epithelial and/or endothelial cells to increase their production of MMP-2 and MMP-9. Although our data strongly suggest that copper deficiency results in augmented production of MMPs, an in vitro study (28) showed that copper may also inhibit the activity of MMPs.
A role for MMPs has been established in various animal models of neutrophil-dependent and neutrophil-independent lung injury (3, 8, 9). Clinically, enhanced activity of MMP-2 and MMP-9 is a common observation in patients with ARDS and chronic obstructive pulmonary disease, and it is thought that the enhanced activity of MMP-2 and MMP-9 contributes significantly to the pathogenesis of these syndromes (6, 27, 31). Based on our current data, it is tempting to suggest that individuals who are marginally copper deficient may be predisposed to an exaggerated lung inflammatory response after an insult leading to acute lung injury (i.e., trauma, infection). This concept may also extend to premature infants. It is well documented that premature infants have lower serum copper concentrations than their full-term counterparts (18). Furthermore, premature infants continue to have low serum copper concentrations for up to 6 mo after birth, whereas those of full-term infants quickly reach adult levels (17). Respiratory distress is a major cause of morbidity among premature infants (7), and thus it is inviting to suggest an association between copper status and the risk of pulmonary dysfunction in premature infants.
The current study demonstrates that copper deficiency dramatically
enhances lung injury after intrapulmonary deposition of IgG immune
complexes. This enhanced injury is not due to a generalized amplification of the inflammatory response because production of the
proinflammatory cytokine TNF- and the lung recruitment of
neutrophils were unchanged. The mechanism by which copper deficiency increases lung injury appears to be augmented MMP-2 and MMP-9 activity
in the lung compartment. Likely target cells are lung epithelial and
endothelial cells. A more detailed understanding of the effects of
dietary copper intake on the acute inflammatory response may yield
clues to the factors contributing to pulmonary syndromes such as ARDS.
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ACKNOWLEDGEMENTS |
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We thank Sharon Young and Gwen Dahlen for expert technical assistance.
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FOOTNOTES |
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This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-55030-02.
The US Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer, and all agency services are available without discrimination.
Address for reprint requests and other correspondence: D. A. Schuschke, Dept. of Physiology and Biophysics, HSC-A1103, Louisville, KY 40292 (E-mail: daschu01{at}gwise.louisville.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. Section 1734 solely to indicate this fact.
Received 6 November 2000; accepted in final form 12 March 2001.
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