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ABSTRACT |
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INTRODUCTION
METHODS
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DISCUSSION
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Reperfusion of the lung after hemorrhage generates free radicals
such as superoxide (O2·) that may injure the lung; however, the
relative importance of intracellular versus extracellular free radicals is unclear. The superoxide dismutases (SOD) are the primary
enzymatic method to reduce superoxide. We examined whether
lung-specific overexpression of extracellular superoxide dismutase
(EC-SOD) would attenuate hemorrhage-induced lung injury. Wild-type mice and mice overexpressing the human EC-SOD gene with
a lung-specific promoter were hemorrhaged by removing 30% of
blood volume. After hemorrhage, the lung wet to dry weight ratios increased from 5.4 ± 0.11 in unmanipulated control mice to
6.3 ± 0.16 in wild-type mice, but to only 5.60 ± 0.17 in the EC-SOD transgenic mice (p < 0.05 compared with hemorrhaged wild-type). Hemorrhage-induced lipid peroxidation, as assessed by lung
F2 isoprostanes, was lower in the EC-SOD transgenic mice (3.4 ± 0.3 µg/lung) compared with wild-type mice (1.9 ± 0.2 µg/lung; p < 0.05). Compared with wild-type, EC-SOD transgenic mice had attenuated the hemorrhage-induced increase in both pulmonary nuclear factor kappa B (NK-
B) activation (relative absorbance 1.1 ± 0.2 for EC-SOD transgenic versus 2.5 ± 0.1 for wild-type; p < 0.05) and myeloperoxidase activity (5.1 ± 0.87 units/g for EC-SOD
transgenic versus 11.3 ± 1.8 units/g for wild-type; p < 0.01). Thus,
overexpression of pulmonary EC-SOD in the mouse lung attenuates lung injury after hemorrhage.
Keywords: hemorrhage; extracellular superoxide dismutase; NF-B;
myeloperoxidase
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Acute lung injury (ALI) frequently occurs after blood loss (1). Reactive oxygen species (ROS) generated as a result of ischemia-reperfusion associated with hemorrhage have been postulated to contribute to the development of ALI in this setting (2). Both an activation of membrane oxidases (3) and the uncoupling of the respiratory chain in mitochondria (4) contribute to ROS production after reperfusion. Superoxide is one of the ROS that mediate this injury.
The superoxide dismutase (SOD) family catalyzes the dismutation of superoxide into hydrogen peroxide and oxygen at
an extremely rapid rate (k > 109 M
1s1) (5). Three SOD enzymes (intracellular [CuZnSOD or SOD1], mitochondrial
[MnSOD or SOD2], and extracellular [EC-SOD or SOD3]) have been identified in mammals. Superoxide is likely to be
especially important in the extracellular space of the lung because lung tissue has one of the highest concentrations of EC-SOD (5). The distribution of EC-SOD in normal lung suggests
that control of superoxide is important in specific extracellular
compartments. In normal lung, EC-SOD immunolocalizes to
the alveolar interstitium and extracellular space, but not pulmonary endothelial cells (6). Furthermore, EC-SOD is unique
among SOD enzymes in that it has a carboxyterminus with
high affinity for the extracellular matrix (ECM). Thus, extracellular superoxide would seem to be particularly important in
controlling superoxide in the alveolar interstitium.
Although others have investigated the role of superoxide in hemorrhage, their focus has been on vascular or intracellular compartments. For instance, hemorrhage-induced superoxide has recently been found to play a role in both the intracellular space and on the endothelial surface (7), and exogenously administered SOD, which sticks to endothelium, can ameliorate a hemorrhage-induced decrease in blood pressure (8) and survival (9). However, the role of ROS in the ECM of the alveolar interstitium, particularly for superoxide, has not been fully elucidated.
Our laboratory has constructed an EC-SOD transgenic mouse that specifically overexpresses EC-SOD in the lung in order to study the relationship between superoxide, the extracellular space, and lung injury. In the present investigation, we examined the ability of EC-SOD to attenuate hemorrhage- induced lung injury during oxidative stress. Using a mouse that overexpressed human EC-SOD under the control of the surfactant protein C (SPC) promoter, the effect of selectively increasing EC-SOD in the lung on the development of ALI was evaluated.
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METHODS |
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METHODS
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Experiments were conducted in accordance with institutional review board-approved protocols. Sixteen mice overexpressing full-length human EC-SOD complementary DNA (cDNA) using a SPC promoter that directs transgene expression to alveolar type II and nonciliated distal bronchial epithelial cells (12) and 33 negative (wild-type) littermates 8 to 12 wk of age were included in the hemorrhaged and untreated control groups.
Hemorrhage was performed as previously described (13). Thirty percent of the blood volume calculated by weight (0.55 ml per 20 g mouse) was removed by cardiac puncture. Mice were killed after 1 h.
EC-SOD Quantitation
A lobe of the lung was homogenized in lysis buffer (Tris-Cl 25 mM,
pH 7.5; NaCl 500; ethylenediaminetetraacetic acid [EDTA] 5 mM; triton 0.5%). A volume of 10 µg was used for a Western blot (rabbit
polyclonal 
-EC-SOD antibody) that was quantitated using ECL Plus
(Amersham Pharmacia Biotech, Piscataway, NJ) and a Molecular Dynamics Imaging system (Amersham Pharmacia Biotech).
Immunocytochemistry
Multiple EC-SOD transgenic mouse lungs were inflation fixed in a mixture of 2% formaldehyde and 0.2% glutaraldehyde in 0.05 M phosphate-buffered saline (PBS) for 1 h followed by overnight fixation in 4% paraformaldehyde at 4° C (14). After fixation, the tissues were equilibrated in 30% sucrose overnight at 4° C. Ultrathin cryosections of EC-SOD transgenic mouse lung tissue were immunolabeled with rabbit antirecombinant human-EC-SOD and 10 nm protein A-gold (6). After immunolabeling, the sections were stained and embedded in mixtures of uranyl acetate and methylcellulose (15).
Wet-to-Dry Lung Weight Ratios
Lungs were excised, rinsed briefly in PBS, blotted, then weighed to obtain the "wet" weight. Lungs were dried in an oven at 80° C for 7 d to obtain the "dry" weight.
Myeloperoxidase (MPO)
Using a modification from Anderson and coworkers (16, 17), a lobe of the lung from each animal was homogenized for 30 s in 1.5 ml 20 mM potassium phosphate, pH 7.4, and centrifuged at 4° C for 30 min at 40,000 × g. The pellet was resuspended in 1.5 ml 40 mM potassium phosphate, pH 6.0, containing 0.5% hexacetyltrimethyl ammonium bromide, sonicated for 90 s, incubated at 60° C for 2 h, and centrifuged. The supernatant was assayed for peroxidase activity corrected to lung weight.
Electrophoretic Mobility Shift Assay (EMSA) Analysis of
Nuclear Factor Kappa B (NK-B)
Nuclear extracts were prepared as previously described (18, 19). Activation of NF-B was determined by EMSA analysis (2, 20, 21).
Determination of Lipid Peroxidation
The lipid fraction was extracted from homogenized tissue, partially purified by solid-phase extraction and then derivatized to the pentafluorobenzyl ester trimethylsilyl ethers. F2-isoprostanes were measured by negative ion chemical ionization gas chromatography/mass spectrometry (GC/MS) analysis (22).
Statistical Analysis
A Tukey-Kramer multiple group comparison test was used to compare individual groups. All values were calculated using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego, CA).
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RESULTS |
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DISCUSSION
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Characterization of the EC-SOD Transgenic Mice
Compared with wild-type mice, mice overexpressing the EC-SOD transgene have a threefold increase in lung tissue EC-SOD (Figure 1), yet have been previously shown to have no difference in SOD1, SOD2, glutathione peroxidase, glutathione, and catalase (12).
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The distribution of EC-SOD within the alveolar septum was evaluated from multiple EC-SOD transgenic mouse lungs using immunocytochemistry (Figure 2). The antibody was specific for human EC-SOD and did not label wild-type lungs. This micrograph clearly demonstrates that the transgene product is mainly associated with ECM elements in the interstitial space of the alveoli. There was little intracellular labeling. The luminal endothelial cell surface, which is rich in heparin proteoglycans, did not have significant EC-SOD labeling. The procedure did not preserve airspace surfactant, so we were not able to assess the level of EC-SOD transgene product on the surface of alveolar epithelial cells. Thus, the transgenic mice have a threefold increase in EC-SOD that immunolocalizes primarily in the alveolar interstitium and is associated with the ECM.
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Reduction of Lung Injury with Lung EC-SOD Overexpression
Lung wet-to-dry weight ratios were 5.5 ± 0.11 in unmanipulated mice and increased to 6.3 ± 0.16 after hemorrhage (Figure 3). However, in EC-SOD transgenic mice, the wet-dry ratios were 5.60 ± 0.17 after hemorrhage (p < 0.05 comparing wild-type to EC-SOD transgenic).
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Hemorrhage-induced neutrophil accumulation in the lungs was also reduced in EC-SOD transgenic mice compared with wild-type mice (Figure 4). Lung MPO was 1.1 ± 0.1 units/g in unmanipulated mouse lungs, 11.3 ± 1.8 units/g after hemorrhage in the wild-type lungs, and 5.1 ± 0.87 units/g after hemorrhage in the EC-SOD transgenic mouse lungs (p < 0.01 comparing hemorrhaged wild-type with EC-SOD transgenic; p < 0.001 comparing unmanipulated mice with hemorrhaged wild-type).
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Overexpression of EC-SOD Decreases Lipid Peroxidation
Hemorrhage has previously been shown to increase lipid peroxidation in the lungs (23). F2-isoprostanes are free radical catalyzed prostaglandin isomers that increase in tissue during oxidative stress (24). To determine the role of EC-SOD in modulating such oxidant-induced lung injury, we measured lung F2-isoprostanes in EC-SOD transgenic and wild-type mice before and after blood loss (Figure 5).
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F2-isoprostanes in lung increased from 2.3 ± 0.2 µg/lung in unmanipulated mice to 3.4 ± 0.3 µg/lung after hemorrhage in the wild-type (p < 0.05 compared with unmanipulated mice). In the EC-SOD transgene positive mice, there was a smaller increase in isoprostanes after hemorrhage (2.0 ± 0.2 µg/lung; p < 0.05 comparing hemorrhaged wild-type with EC-SOD transgenic; p < 0.05 comparing unmanipulated mice with hemorrhaged wild-type).
Overexpression of EC-SOD Decreases NF-B Activation
Hemorrhage results in activation of the transcriptional regulatory factor NF-B in the lungs (2) through pathways involving ROS (25, 26). To examine the role of EC-SOD in modulating hemorrhage-induced NF-B activation, we measured lung NF-B activity in wild-type and EC-SOD transgenic mice after
blood loss (Figure 6). After quantitation of NF-B activity using
densitometry, values were normalized to unmanipulated wild-type mice. Overexpression of EC-SOD attenuated hemorrhage-induced NF-B activation compared with wild-type mouse lungs
(relative absorbance 1.3 ± 0.1 versus 2.5 ± 0.3; p < 0.05).
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EC-SOD Protein in Hemorrhaged Mice
Proinflammatory cytokines, including interleukin-1
, tumor
necrosis factor-, and macrophage inflammatory protein-2 are
increased in the lungs after hemorrhage (2, 13, 17). The cytokines interleukin-1, tumor necrosis factor-, and interferon-
increase EC-SOD protein in cell culture (27, 28). As shown in
Figure 1, EC-SOD transgenic mice have a threefold increase
in lung tissue EC-SOD protein. To see if hemorrhage induced
a potentiating effect on EC-SOD expression in vivo, we examined lung EC-SOD protein after blood loss. Hemorrhage did
not significantly increase total lung EC-SOD protein in either
the wild-type (6 ± 10% increase) or EC-SOD transgenic mice
(15 ± 25% increase).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Hemorrhage causes whole body ischemia with resultant generation of ROS when reperfusion occurs (29). In the lung, ROS are capable not only of potentiating neutrophil recruitment (30), but also are associated with injury to proteins, lipids, and DNA (24, 31). Superoxide production is increased after blood loss and contributes to oxidant-induced tissue injury in this setting (8, 34, 35). SODs are the primary defense against excess superoxide.
The consequences of the superoxide/SOD interaction are likely to be highly dependent on the domain in which they occur because superoxide is impermeable to membranes and the three mammalian SODs are fixed within their subcellular localization. The specific lung domains likely to be relevant to reperfusion injury include: the endothelial membrane and the vascular space; the cytoplasm of endothelial cells, smooth muscle cells, or alveolar epithelial cells; mitochondria; the alveolar interstitium and its ECM; and the alveolar epithelial membrane and the alveolar airspace. Multiple published reports address the role of the first two domains, but we are unaware of any reports specifically examining the role of superoxide in the alveolar interstitium and ECM after hemorrhage.
The role of superoxide in activating the endothelial membrane and initiating neutrophil adhesion is well established (36). For instance, exogenous SOD1 blunts the vascular expression of P-selectin, an adhesion molecule crucial for recruitment of activated leukocytes to the lung (7). Other adhesion molecules, such as E-selectin, can also be inhibited in vitro by adding SOD1 (37). These pharmacologic experiments used SOD1, an enzyme that is normally found in the cytoplasm. However, in these experiments it is likely that most of the added SOD activity remained extracellularly. Additionally, SOD1 has a net negative charge, unlike EC-SOD, whose carboxyterminus gives it a strong positive charge that determines distribution. Finally, because there is normally scant SOD found on the surface of pulmonary vessels (6), it is unclear how much SOD modulates hemorrhage-induced superoxide production in vivo. Thus, the distribution of EC-SOD activity in our EC-SOD transgenic animals is likely very different from that in the pharmacologic experiments. The cytoplasm, on the other hand, has high levels of superoxide activity. Overexpression of cytoplasmic SOD has been shown to blunt activation of endothelium after hemorrhage (7), but these experiments did not elucidate in which cells overexpression was important.
This is the first report to specifically address the role of superoxide in the alveolar interstitium and ECM. We found that overexpression of EC-SOD could attenuate several markers of lung injury after hemorrhage: lung edema, lipid peroxidation, and MPO activity. Lung edema has been previously shown to increase after lung injury and likely represents increased microvascular permeability (24, 38). Lipid peroxidation, as assessed by F2-isoprostanes, has also been demonstrated to increase after hemorrhage. For example, blood loss due to aortic rupture produces elevated plasma F2-isoprostanes in humans (29) and increased F2-isoprostanes in the lungs of rats (23). MPO causes much of the lung damage associated with hemorrhage (38). Thus, a reduction of all of these markers in the EC-SOD transgenic mouse implies that superoxide activity in the alveolar interstitium and ECM is an important mediator in hemorrhage-induced lung injury.
EC-SOD probably reduces lung injury by decreasing superoxide in the alveolar interstitium and ECM. This may lead
to decreased recruitment of activated neutrophils to the lung
by an unclear mechanism. Our data suggest that it may be mediated by reducing activity of NF-B. We have recently reported that neutrophils are responsible for most of the increased activity of NF-B in the lungs after hemorrhage (41).
Thus, the attenuated increase in lung NF-B activity in the
EC-SOD transgenic mouse lung is most likely to a decrease in
activated lung neutrophils. Whether neutrophils have a direct
or indirect interaction with alveolar interstitial superoxide is
currently the subject of investigation in our laboratory.
The link between activation of inflammatory cells and EC-SOD is strengthened by the observation that NF-B controls
transcriptional regulation of EC-SOD in alveolar type II cells
(27). Because hemorrhage results in rapid activation of NF-B
in the lungs, we expected to find increased EC-SOD in this
setting. However, no hemorrhage-induced alteration in lung
EC-SOD was found in the present experiments. It is possible
that the time elapsed posthemorrhage was too short to permit
increased expression of EC-SOD. In vitro, maximal transcription of the EC-SOD gene only occurs 6 h after NF-B activation is induced (27) and optimal EC-SOD protein secretion
only occurs after 3 d of continuous cytokine stimulation (28).
This study has potentially important implications in the prevention and treatment of acute respiratory distress syndrome after hemorrhagic shock. Although previous studies have demonstrated the importance of superoxide in reperfusion injury (7, 34), this is the first study to show that EC-SOD can attenuate hemorrhage-induced lung injury and suggests that the alveolar interstitial space and ECM play a role in superoxide-mediated lung injury. Our data suggest that elevated alveolar interstitial SOD activity may decrease the likelihood of developing acute inflammatory lung injury after hemorrhage. However, because the present experiments used a model where increased lung concentrations of EC-SOD were present before hemorrhage, the potential clinical benefit of EC-SOD administration after blood loss remains to be proven.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Russell P. Bowler, M.D., National Jewish Medical and Research Center, K707, 1400 Jackson Street, Denver, CO 80206. E-mail: BowlerR{at}njc.org
(Received in original form November 13, 2000 and in revised form March 30, 2001).
Acknowledgments:
Supported by Grants NIH HL-04407, HL-62221, HL31992, HL 42444, and the
Andrew Goodman Fellowship in Medicine at National Jewish Medical and Research Center.
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 J.D. Crapo Oxidative stress as an initiator of cytokine release and cell damage Eur. Respir. J., September 20, 2003; 22(44_suppl): 4s - 6s. [Full Text] [PDF]
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R. P. Bowler, J. Arcaroli, E. Abraham, M. Patel, L.-Y. Chang, and J. D. Crapo Evidence for extracellular superoxide dismutase as a mediator of hemorrhage-induced lung injury Am J Physiol Lung Cell Mol Physiol, April 1, 2003; 284(4): L680 - L687. [Abstract] [Full Text] [PDF]
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R. P. Bowler and J. D. Crapo Oxidative Stress in Airways: Is There a Role for Extracellular Superoxide Dismutase? Am. J. Respir. Crit. Care Med., December 15, 2002; 166(12): S38 - 43. [Abstract] [Full Text] [PDF]
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 R. P. Bowler, M. Nicks, D. Aa. Olsen, I. B. Thogersen, Z. Valnickova, P. Hojrup, A. Franzusoff, J. J. Enghild, and J. D. Crapo Furin Proteolytically Processes the Heparin-binding Region of Extracellular Superoxide Dismutase J. Biol. Chem., May 3, 2002; 277(19): 16505 - 16511. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Critical Care Medicine in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 565 - 583. [Full Text] [PDF]
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R. Bowler ERRATUM: EXTRACELLULAR SUPEROXIDE DISMUTASE ATTENUATES LUNG INJURY AFTER HEMORRHAGE Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 730 - 730. [Full Text] [PDF]
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