1 National Jewish Medical and Research Center, Denver 80206; and 2 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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Hemorrhage results in excessive
production of superoxide that is associated with severe lung injury. We
examined whether the superoxide dismutase (SOD) mimetic manganese(III)
mesotetrakis (di-N-ethylimidazole) porphyrin (AEOL 10150)
could attenuate this lung injury and whether extracellular
(EC)-SOD-deficient mice would have increased hemorrhage-induced lung
injury. Compared with wild-type mice, EC-SOD-deficient mice had
increased lung neutrophil accumulation, a 3.9-fold increase in
myeloperoxidase activity, a 1.5-fold increase in nuclear factor
(NF)-B activation, and a 1.5-fold increase in lipid peroxidation
1 h after hemorrhage. Pretreatment with AEOL 10150 did not
attenuate neutrophil accumulation but significantly reduced NF-
B
activation and lipid peroxidation in both wild-type and
EC-SOD-deficient mice. The increase in hemorrhage-induced neutrophil
accumulation in the lungs of EC-SOD-deficient mice suggests that EC-SOD
might play a role in mediating neutrophil recruitment to the lung.
catalytic antioxidant; metalloporphyrin
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INTRODUCTION |
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HEMORRHAGE IS OFTEN
ASSOCIATED with severe acute lung injury (35). The
ischemia and reperfusion that occur with hemorrhage result in
production of reactive oxygen species (ROS) that are thought to cause
some of the lung injury that follows hemorrhage (25). ROS
directly injure lung proteins, lipids, and DNA, but may also potentiate
lung injury by recruiting and activating leukocytes. ROS-mediated
recruitment of leukocytes occurs by induction of adhesion molecules
such as P-selectin (4). ROS also cause activation of
transcription factors cyclic adenosine 5'-monophosphate response element binding protein and nuclear factor (NF)-B that potentiate the release of proinflammatory cytokines (1, 20).
Superoxide is one of the reactive oxygen species thought to mediate lung injury after hemorrhage. For instance, inhibition of xanthine oxidase, which produces superoxide, attenuates hemorrhage-induced lung injury (25, 39, 40, 45). The family of superoxide dismutase (SOD) enzymes is a major enzymatic pathway that lowers superoxide concentrations. Exogenously administered, SOD improves blood pressure (42) and survival (36, 45, 46) after hemorrhage. Despite many studies that implicate a role for superoxide in hemorrhage-induced lung injury, the role of extracellular (EC)-SOD has not been defined.
Three observations suggest that EC-SOD may be particularly important in mediating hemorrhage-induced lung injury. First, EC-SOD is abundant in the lung and immunolocalizes to the alveolar septum and blood vessels (13, 30). Second, EC-SOD is upregulated by inflammatory cytokines that are activated during hemorrhagic shock (24, 44). Third, overexpression of EC-SOD can protect the lungs from hemorrhage-induced injury (7). Several questions remain unanswered. For instance, it is not known whether hemorrhage-induced lung injury is worse in EC-SOD-deficient mice, nor is it known whether SOD mimetics are capable of attenuating hemorrhage-induced lung injury.
To answer these questions, we have used two different techniques to manipulate superoxide dismutase activity in a mouse model of hemorrhage. First, the effects of hemorrhage-induced lung injury in EC-SOD knockout mice were studied. Second, the SOD mimetic manganese(III) mesotetrakis (di-N-ethylimidazole) porphyrin (AEOL 10150) was administered to mice before hemorrhage to determine whether this class of antioxidant reduces hemorrhage-induced lung injury. AEOL 10150 has potent in vitro SOD activity and can protect lipids, proteins, and DNA from in vitro oxidative damage (33). Metalloporphyrin SOD mimetics augment natural antioxidant defenses and have been shown to attenuate lung injury in animal models of pulmonary fibrosis (31), paraquat toxicity (11), and stroke-induced brain injury (23). In the present experiments, we found that EC-SOD-deficient mice had increased neutrophil accumulation and hemorrhage-induced lung injury. Although AEOL 10150 pretreatment reduced markers of oxidative stress, it did not appear to effect neutrophil accumulation.
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MATERIALS AND METHODS |
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Reagents.
The SOD mimetic AEOL 10150 [manganese(III) mesotetrakis
(di-N-ethylimidazole) porphyrin] was provided by Incara
Pharmaceuticals (Research Triangle Park, NC). AEOL 10150 (Fig.
1) has a +5 charge with a SOD activity of
~8,500 U/g and catalase activity of ~1% of purified bovine
catalase (wt/wt basis). All other reagents were supplied by Sigma
Chemical (St. Louis, MO) unless otherwise noted.
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Animals. All experiments were conducted in accordance with institutional review board-approved protocols. The derivation of EC-SOD knockout mice has been previously described and has been shown not to result in induction of other SOD or antioxidant enzymes (10). Mice were bred into a C57BL/6 strain (Harlan, Indianapolis, IN) for >10 generations. Max-Bax testing (Charles River Laboratories, Wilmington, MA) revealed 100% homology to the C57BL/6 strain.
Genotyping. Mouse tail DNA was obtained after overnight digestion at 55°C in 400-ug/ml proteinase K. DNA was extracted with phenol/chloroform/isoamyl alcohol (25:24:1 ratio, saturated with Tris buffer, pH 8.0) and then precipitated from the aqueous phase with one volume of 7.5 M ammonium acetate plus two volumes of 100% ethanol. After being centrifuged for 5 min at 9,000 g, the pellet was washed with 70% ethanol and air-dried. DNA was resuspended in sterile H2O and then used for PCR with the primers amplifying both an 805-bp region of the mouse EC-SOD gene (forward CAG CCA TGT TGG CCT TCT TGT TCT A and reverse GGC GCC TGG AGA CAT CTA TGC GT) or a 510-bp amplification product, the knockout neomycin cassette (forward TGC GCA GCT GTG CTC GAC G and reverse TCG GGA GCG GCG ATA CCG TA). Reactions were in 15 mM MgCl2 using Qiagen reagents. The PCRs used a Perkin Elmer 9600 thermocycler set for 94°C for 3 min, then 35 cycles of 94°C for 45 s, 65°C for 30 s, and 72°C for 30 s. PCR products were imaged after 2% agarose electrophoresis. The EC-SOD phenotype was confirmed in the lung by demonstrating the absence of EC-SOD by immunoblotting as previously described (7).
Hemorrhage model. Mice were pretreated with either saline or AEOL 10150 (24 mg/kg) in saline by subcutaneous injection 2 h before hemorrhage. Subcutaneous dosing results in maximum lung and serum concentrations after 2 h (unpublished observations communicated by Dr. Brian Day, Denver, CO). Hemorrhage was performed as previously described (3). Thirty percent of the blood volume, calculated by weight (0.55 ml/20-g mouse), was removed by cardiac puncture. Mice were allowed to recover and were then killed 1 h after hemorrhage.
Histopathology. Mouse lungs were inflation fixed with 10% formaldehyde at 20 cmH20 pressure and embedded in paraffin. Sections (6 µM) were stained with hematoxylin and eosin. With the use of a Nikon light microscope with a × 40 objective, the entire lung was imaged and qualitatively assessed for inflammation by an investigator blinded to the experimental group.
Aconitase and fumarase measurement. The aconitase and fumarase activity of lung homogenates was measured as previously described (34). In brief, the assay measures aconitase activity spectrophotometrically by monitoring the formation of cis-aconitase from isocitrate at 240 nm in 50 mM Tris · HCl (pH 7.4) containing 0.6 mM MnCl2 and 20 mM isocitrate at 25°C. Fumarase activity was measured by monitoring the increase in absorbance at 240 nm at 25°C in a 1-ml reaction mixture containing 30 mM potassium phosphate, 0.1 mM EDTA, and 5 mM L-malate (pH 7.4).
Myeloperoxidase. Myeloperoxidase (MPO) activity was assayed using a modification of Anderson et al. (5) and Parsey et al. (32). A lobe of the lung from each animal was homogenized for 30 s in 1.5 ml of 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 of 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 and corrected to lung weight.
EMSA analysis of NF-B.
Nuclear extracts were prepared as previously described (19,
21). Activation of the transcriptional factor NF-kB was
determined by EMSA analysis (26, 39, 40).
Determination of lipid peroxidation. The lipid fraction was extracted from homogenized tissue using a 1:1 ratio of chloroform and methanol, 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 analysis as described by Waugh and colleagues (48).
AEOL 10150 quantitation.
Serum concentrations of AEOL 10150 were determined using
high-performance liquid chromatography with electrochemical detection (18). For AEOL 10150 lung concentrations, one lobe of the
lung was homogenized in water. Half of the lung homogenate was used for
bicinchoninic acid protein concentration (Pierce), and half was used
for the AEOL 10150 assay with the following modifications: standards
were made by spiking wild-type serum or lung homogenates with known
concentrations of AEOL 10150. Retention time peaks of 13.6 min from the
400-mV electrode were used for calibration curves and unknowns.
Statistical analysis. A one-way analysis of variance was used to determine whether the means were significantly different (P < 0.05). If means were significantly different, a Tukey-Kramer multiple group comparison test was used to compare individual groups. SE of the mean was indicated for each value by a bar. All values were calculated using GraphPad Prism version 3.0 for Windows (GraphPad Software, San Diego, CA).
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RESULTS |
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AEOL 10150 concentrations.
After a single subcutaneous injection, concentrations of AEOL in the
serum and lung were similar for wild-type and EC-SOD lungs (Table
1). There was a significant increase in
AEOL 10150 in the lungs of hemorrhaged mice compared with unhemorrhaged
mice in both the wild-type (4.8 ± 1.5-fold increase;
P < 0.001) and EC-SOD-deficient (3.5 ± 0.5-fold
increase; P < 0.001) mice.
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Hemorrhage-induced lung lipid peroxidation.
Hemorrhage has been shown to cause oxidative damage to lipids as
measured by lipid peroxidation (9). ROS-specific lipid peroxidation can be detected by measuring isoprostanes.
F2-isoprostanes are free radical catalyzed prostaglandin
isomers that increase in tissue during oxidative stress
(6) and have previously been shown to be elevated in
hemorrhage-induced lung injury (7). To determine the role
of EC-SOD in modulating such oxidant-induced lung injury, we measured
lung 8-epi-F2-isoprostanes in wild-type and
EC-SOD-deficient mice before and after hemorrhage (Fig.
2). In the wild-type mice, lung
8-epi-F2-isoprostanes increased from 60 ± 6 ng/g of
protein in unmanipulated mice to 91 ± 5 ng/g of protein after
hemorrhage (P < 0.05). In EC-SOD-deficient mice, there
was a significantly larger increase in lung
8-epi-F2-isoprostanes (from 64 ± 2 ng/g of protein in
unmanipulated mice to 107 ± 3 ng/g of protein after hemorrhage;
P < 0.01).
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Hemorrhage-induced inactivation of aconitase.
On the basis of previous reports describing EC-SOD as a primarily
extracellular antioxidant, we suspected that EC-SOD deficiency would
have minimal impact on hemorrhage-induced intracellular oxidative
stress. Additionally, although the cellular distribution of AEOL 10150 is not known, we suspected that its +5 charge would limit its efficacy
as an in vivo intracellular antioxidant. To assess intracellular
oxidative stress, we measured aconitase activity per gram of protein in
lung homogenates (Fig. 3). Aconitase is an intracellular iron-sulfur-containing dehydratase that is sensitive to superoxide-mediated inactivation (14). Compared with
the control group, hemorrhage resulted in a 45 ± 7% decrease in lung aconitase activity of the wild-type mice (P < 0.01)
and a 58 ± 11% decrease in the EC-SOD-deficient mice
(P < 0.05). The decreases in aconitase activity in
wild-type mice were not statistically different from the decreases in
the EC-SOD-deficient mice. Additionally, the decreases in aconitase
activity after pretreatment with AEOL 10150 were not statistically
different in either wild-type or EC-SOD-deficient mice. This study was
not powered to detect small differences in aconitase activity (<20%),
thus it cannot be excluded that EC-SOD-deficient mice have slightly
more intracellular oxidative stress compared with that of wild-type
mice.
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Neutrophilic inflammation after hemorrhage.
Because hemorrhage-induced neutrophil accumulation mediates much of
hemorrhage-induced lung injury (2), we suspected that EC-SOD-deficient mice would have increased lung neutrophil
accumulation, and mice pretreated with AEOL 10150 would have decreased
neutrophil accumulation. With the use of light microscopy, we found
that hemorrhage results in neutrophil accumulation in both wild-type and EC-SOD-deficient mouse lungs (Fig.
4). One hour after hemorrhage, the
EC-SOD-deficient mouse lungs had qualitatively more neutrophilic infiltration in the lung interstitium compared with wild-type mouse
lungs. Pretreatment with AEOL 10150 did not appear to change histological evidence of neutrophil accumulation in either the wild-type or EC-SOD-deficient mouse lungs (data not shown).
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DISCUSSION |
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Ischemia and reperfusion cause oxidative stress that results in tissue injury in a variety of diseases such as myocardial infarction, stroke, and ischemic bowel. Unlike these organ-specific diseases, hemorrhage results in whole body ischemia with production of systemic ROS (22). Much of the lung injury that occurs after hemorrhage is mediated by superoxide (25, 28, 36, 42, 45, 46). Although it is well established that the lung is sensitive to oxidative stress-mediated injury to proteins, lipids, and DNA (6, 16, 27, 49), the mechanisms by which this injury occurs remain unclear. Previous studies have suggested that decreasing superoxide, either by inhibiting superoxide-generating enzymes such as xanthine oxidase (40) or increasing SOD enzymatic activity (36), can lead to a reduction of hemorrhage-induced lung injury. However, these studies did not distinguish between the types of SODs. The present experiments suggest that EC-SOD deficiency worsens hemorrhage-induced lung injury.
There are two possible mechanisms by which EC-SOD activity might reduce the severity of hemorrhage-induced lung injury. First, EC-SOD could prevent direct ROS-mediated injury through its actions as an antioxidant. Second, EC-SOD could act indirectly by attenuating recruitment or activation of inflammatory cells to the lung. The data presented in these experiments suggest that both mechanisms may be important after hemorrhage.
In the present experiments, hemorrhage resulted in a rapid, moderate
increase in pulmonary lipid peroxidation (F2-isoprostanes) that was significantly increased in EC-SOD-deficient mice. The SOD
mimetic AEOL 10150 also significantly decreased lipid peroxidation in
both the wild-type and EC-SOD-deficient mice.
F2-isoprostanes are prostaglandin-like compounds formed
during ROS-mediated attack of arachidonic acid. Hemorrhage from aortic
rupture results in elevated plasma F2-isoprostanes in
humans (22) and increased F2-isoprostanes in
the lungs of rats (9). Overexpression of EC-SOD in the
lung has previously been shown to reduce increases in
F2-isoprostanes after hemorrhage (7). Although
hemorrhage resulted in an inactivation of lung aconitase, in wild-type
mice the amount of inactivation was not statistically different from either the EC-SOD-deficient mice or mice pretreated with AEOL 10150. This suggests that the protective effect of EC-SOD and AEOL 10150 is
not due to a large reduction in intracellular superoxide concentration;
however, there are alternative explanations that could account for
these findings. First, both EC-SOD and the SOD mimetic AEOL 10150 might
be attenuating the recruitment of cells that produce large amounts of
ROS (e.g., neutrophils). Second, EC-SOD and AEOL 10150 could be
inhibiting the in vivo enzymatic production of ROS by an undescribed
mechanism. Neither EC-SOD nor AEOL 10150 is known to inhibit
ROS-producing enzymes; however, ROS have been implicated in the
recruitment and activation of neutrophils. For instance, ROS are
capable of potentiating neutrophil recruitment to the lung
(47) by increasing neutrophil adhesion to endothelial
cells (29), presumably by enhancing the vascular expression of neutrophil adhesion molecules such as P-selectin (4) and E-selectin (37). Additionally,
superoxide potentiates lung damage by inducing neutrophils to secrete
proinflammatory cytokines such as interleukin-1, macrophage
inflammatory protein-2, and tumor necrosis factor-
(32, 39,
40).
The relationship between hemorrhage-induced superoxide production and
neutrophil-mediated lung injury is complex and likely involves steps
that include both the recruitment and activation of
neutrophils. In the EC-SOD-deficient mice, there was increased recruitment of neutrophils both histologically and by measuring the
activity of the neutrophil enzyme MPO. After hemorrhage, the EC-SOD-deficient mice also had increased NF-B activation in the lungs, suggesting that EC-SOD plays a role in both recruitment and
activation of neutrophils. Although pretreatment with the SOD mimetic
AEOL 10150 attenuated isoprostane formation and NF-
B activity, there
was only a mild decrease in these markers of oxidative stress, and
there was no reduction in neutrophil recruitment to the lungs. This
suggests that AEOL 10150 can attenuate markers of oxidative stress but
may not reduce lung injury as measured by lung neutrophil accumulation.
Several explanations could account for the differences between EC-SOD
and AEOL 10150. First, AEOL 10150, but not EC-SOD, has slight catalase
activity; however, catalase has previously been shown not to effect
neutrophil activation in hemorrhage (41). Second, the
distribution of EC-SOD and AEOL 10150 may be different. For instance,
EC-SOD is highly expressed in pulmonary vasculature and thus may play a
role in superoxide-mediated neutrophil recruitment to the lung. There
are no data regarding the distribution of AEOL 10150; however, in this
study there was a tripling of the lung concentration of AEOL 10150 after hemorrhage.
Although it is well accepted that EC-SOD attenuates lung damage during oxidative stress (7, 8, 10), the duality of EC-SOD as an antioxidant and anti-inflammatory enzyme remains controversial. Overexpression of EC-SOD has previously been shown to blunt the inflammatory response in lung from hyperoxia (12), oil fly ash (15), and influenza (43). EC-SOD-deficient mice show increased neutrophil inflammation after ozone exposure (17) but do not have statistically significant increased lung inflammation after lipopolysaccharide and zymosan exposure (38). Thus the majority of previous reports support the findings in this study that EC-SOD plays a role in the inflammatory response during oxidative stress-mediated lung injury, but further work needs to be done to determine how EC-SOD specifically modulates the inflammatory response.
Many previous studies have demonstrated the importance of superoxide in reperfusion injury (4, 28, 36, 42, 45, 46). The increased injury seen in the EC-SOD-deficient mice confirms these findings and suggests a role for EC-SOD. This is the first study to show that a metalloporphyrin SOD mimetic can attenuate hemorrhage-induced increases in markers of oxidative stress. However, the beneficial effects of AEOL 10150 are mild, and unlike EC-SOD, the mechanism by which AEOL 10150 attenuates markers of oxidative stress does not appear to involve attenuation of neutrophil recruitment. Furthermore, the potential clinical benefit of AEOL 10150 administration after blood loss remains to be proven, since this model used an end point 1 h after hemorrhage, and the pharmacokinetics of AEOL 10150 required it to be dosed 2 h before hemorrhage.
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ACKNOWLEDGEMENTS |
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We thank Mike Nicks and Elysia Min for technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-04407 (R. P. Bowler), HL-62221 (E. Abraham), HL-31992 (J. D. Crapo), and HL-42444 (J. D. Crapo), and by Incara Pharmaceuticals.
Dr. Crapo is a consultant for and holds equity in Incara Pharmaceuticals.
Address for reprint requests and other correspondence: R. P. Bowler, National Jewish Medical and Research Center, K736a, 1400 Jackson St., Denver, CO 80206 (E-mail: BowlerR{at}njc.org).
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.
First published January 10, 2003;10.1152/ajplung.00191.2002
Received 17 June 2002; accepted in final form 16 December 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abraham, E,
Arcaroli J,
and
Shenkar R.
Activation of extracellular signal-regulated kinases, NF-B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia.
J Immunol
166:
522-530,
2001
2.
Abraham, E,
Carmondy A,
Shenkar R,
and
Arcaroli R.
Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury.
Am J Physiol Lung Cell Mol Physiol
279:
L1137-L1146,
2000
3.
Abraham, E,
and
Freitas AA.
Hemorrhage produces abnormalities in lymphocyte function and lymphokine generation.
J Immunol
142:
899-906,
1989
4.
Akgur, FM,
Brown MF,
Zibari GB,
McDonald JC,
Epstein CJ,
Ross CR,
and
Granger DN.
Role of superoxide in hemorrhagic shock-induced P-selectin expression.
Am J Physiol Heart Circ Physiol
279:
H791-H797,
2000
5.
Anderson, BO,
Brown JM,
Shanley PF,
Bensard DD,
and
Harken AH.
Marginating neutrophils are reversibly adherent to normal lung endothelium.
Surgery
109:
51-61,
1991[ISI][Medline].
6.
Becker, PM,
Sanders SP,
Price P,
and
Christman BW.
F2-isoprostane generation in isolated ferret lungs after oxidant injury or ventilated ischemia.
Free Radic Biol Med
25:
703-711,
1998[ISI][Medline].
7.
Bowler, RP,
Arcaroli J,
Crapo JD,
Ross A,
Slot JW,
and
Abraham E.
Extracellular superoxide dismutase attenuates lung injury after hemorrhage.
Am J Respir Crit Care Med
164:
290-294,
2001
8.
Bowler, RP,
Nicks M,
Warnick K,
and
Crapo JD.
Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis.
Am J Physiol Lung Cell Mol Physiol
282:
L719-L726,
2002
9.
Boyd, AJ,
Rubin BB,
Walker PM,
Romaschin A,
Issekutz TB,
and
Lindsay TF.
A CD18 monoclonal antibody reduces multiple organ injury in a model of ruptured abdominal aortic aneurysm.
Am J Physiol Heart Circ Physiol
277:
H172-H182,
1999
10.
Carlsson, LM,
Jonsson J,
Edlund T,
and
Marklund SL.
Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia.
Proc Natl Acad Sci USA
92:
6264-6268,
1995[Abstract].
11.
Day, BJ,
and
Crapo JD.
A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced lung injury in vivo.
Toxicol Appl Pharmacol
140:
94-100,
1996[ISI][Medline].
12.
Folz, RJ,
Abushamaa AM,
and
Suliman HB.
Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia.
J Clin Invest
103:
1055-1066,
1999
13.
Folz, RJ,
Guan J,
Seldin MF,
Oury TD,
Enghild JJ,
and
Crapo JD.
Mouse extracellular superoxide dismutase: primary structure, tissue-specific gene expression, chromosomal localization, and lung in situ hybridization.
Am J Respir Cell Mol Biol
17:
393-403,
1997
14.
Gardner, PR,
Raineri I,
Epstein LB,
and
White CW.
Superoxide radical and iron modulate aconitase activity in mammalian cells.
J Biol Chem
270:
13399-13405,
1995
15.
Ghio, AJ,
Suliman HB,
Carter JD,
Abushamaa AM,
and
Folz RJ.
Overexpression of extracellular superoxide dismutase decreases lung injury after exposure to oil fly ash.
Am J Physiol Lung Cell Mol Physiol
283:
L211-L218,
2002
16.
Ischiropoulos, H,
al-Mehdi AB,
and
Fisher AB.
Reactive species in ischemic rat lung injury: contribution of peroxynitrite.
Am J Physiol Lung Cell Mol Physiol
269:
L158-L164,
1995
17.
Jonsson, LM,
Edlund T,
Marklund SL,
and
Sandstrom T.
Increased ozone-induced airway neutrophilic inflammation in extracellular-superoxide dismutase null mice.
Respir Med
96:
209-214,
2002[ISI][Medline].
18.
Kachadourian, R,
Menzeleev R,
Agha B,
Bocckino SB,
and
Day BJ.
High-performance liquid chromatography with spectrophotometric and electrochemical detection of a series of manganese(III) cationic porphyrins.
J Chromatogr B Analyt Technol Biomed Life Sci
767:
61-67,
2002[ISI][Medline].
19.
Kelley, DM,
Lichtenstein A,
Wang J,
Taylor AN,
and
Dubinett SM.
Corticotropin-releasing factor reduces lipopolysaccharide-induced pulmonary vascular leak.
Immunopharmacol Immunotoxicol
16:
139-148,
1994[ISI][Medline].
20.
Knight, JA.
Review: free radicals, antioxidants, and the immune system.
Ann Clin Lab Sci
30:
145-158,
2000[Abstract].
21.
Kollef, MH,
and
Schuster DP.
The acute respiratory distress syndrome.
N Engl J Med
332:
27-37,
1995
22.
Lindsay, TF,
Luo XP,
Lehotay DC,
Rubin BB,
Anderson M,
Walker PM,
and
Romaschin AD.
Ruptured abdominal aortic aneurysm, a "two-hit" ischemia/reperfusion injury: evidence from an analysis of oxidative products.
J Vasc Surg
30:
219-228,
1999[ISI][Medline].
23.
Mackensen, GB,
Patel M,
Sheng H,
Calvi CL,
Batinic-Haberle I,
Day BJ,
Liang LP,
Fridovich I,
Crapo JD,
Pearlstein RD,
and
Warner DS.
Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant.
J Neurosci
21:
4582-4592,
2001
24.
Marklund, SL.
Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts.
J Biol Chem
267:
6696-6701,
1992
25.
McCord, JM.
Oxygen-derived free radicals in postischemic tissue injury.
N Engl J Med
312:
159-163,
1985[Abstract].
26.
Moine, P,
McIntyre R,
Schwartz MD,
Kaneko D,
Shenkar R,
Le Tulzo Y,
Moore EE,
and
Abraham E.
NF-B regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome.
Shock
13:
85-91,
2000[ISI][Medline].
27.
Mota-Filipe, H,
McDonald MC,
Cuzzocrea S,
and
Thiemermann C.
A membrane-permeable radical scavenger reduces the organ injury in hemorrhagic shock.
Shock
12:
255-261,
1999[ISI][Medline].
28.
Obayashi, H,
Koshi S,
Miyauchi Y,
and
Inoue M.
Inhibition of posthemorrhagic transfusion-induced gastric injury by a long-acting superoxide dismutase derivative.
Proc Soc Exp Biol Med
196:
164-169,
1991[Abstract].
29.
Okayama, N,
Park JH,
Coe L,
Granger DN,
Ma L,
Hisa CJ,
and
Alexander JS.
Polynitroxyl alphaalpha-hemoglobin (PNH) inhibits peroxide and superoxide-mediated neutrophil adherence to human endothelial cells.
Free Radic Res
31:
53-58,
1999[ISI][Medline].
30.
Oury, TD,
Chang LY,
Marklund SL,
Day BJ,
and
Crapo JD.
Immunocytochemical localization of extracellular superoxide dismutase in human lung.
Lab Invest
70:
889-898,
1994[ISI][Medline].
31.
Oury, TD,
Thakker K,
Menache M,
Chang LY,
Crapo JD,
and
Day BJ.
Attenuation of bleomycin-induced pulmonary fibrosis by a catalytic antioxidant metalloporphyrin.
Am J Respir Cell Mol Biol
25:
164-169,
2001
32.
Parsey, MV,
Tuder RM,
and
Abraham E.
Neutrophils are major contributors to intraparenchymal lung IL-1 expression after hemorrhage and endotoxemia.
J Immunol
160:
1007-1013,
1998
33.
Patel, M,
and
Day BJ.
Metalloporphyrin class of therapeutic catalytic antioxidants.
Trends Pharmacol Sci
20:
359-364,
1999[ISI][Medline].
34.
Patel, M,
Day BJ,
Crapo JD,
Fridovich I,
and
McNamara JO.
Requirement for superoxide in excitotoxic cell death.
Neuron
16:
345-355,
1996[ISI][Medline].
35.
Rainer, TH,
Lam PK,
Wong EM,
and
Cocks RA.
Derivation of a prediction rule for post-traumatic acute lung injury.
Resuscitation
42:
187-196,
1999[ISI][Medline].
36.
Rhee, P,
Waxman K,
Clark L,
Tominaga G,
and
Soliman MH.
Superoxide dismutase polyethylene glycol improves survival in hemorrhagic shock.
Am Surg
57:
747-750,
1991[ISI][Medline].
37.
Russell, J,
Epstein CJ,
Grisham MB,
Alexander JS,
Yeh KY,
and
Granger DN.
Regulation of E-selectin expression in postischemic intestinal microvasculature.
Am J Physiol Gastrointest Liver Physiol
278:
G878-G885,
2000
38.
Sentman, ML,
Brannstrom T,
and
Marklund SL.
EC-SOD and the response to inflammatory reactions and aging in mouse lung.
Free Radic Biol Med
32:
975-981,
2002[ISI][Medline].
39.
Shenkar, R,
and
Abraham E.
Hemorrhage induces rapid in vivo activation of CREB and NF-B in murine intraparenchymal lung mononuclear cells.
Am J Respir Cell Mol Biol
16:
145-152,
1997[Abstract].
40.
Shenkar, R,
and
Abraham E.
Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-B, and cyclic AMP response element binding protein.
J Immunol
163:
954-962,
1999
41.
Shenkar, R,
Schwartz MD,
Terada LS,
Repine JE,
McCord J,
and
Abraham E.
Hemorrhage activates NF-B in murine lung mononuclear cells in vivo.
Am J Physiol Lung Cell Mol Physiol
270:
L729-L735,
1996
42.
Simon, HM,
Scalea T,
Paskanik A,
and
Yang B.
Superoxide dismutase (SOD) prevents hypotension after hemorrhagic shock and aortic cross clamping.
Am J Med Sci
312:
155-159,
1996[ISI][Medline].
43.
Suliman, HB,
Ryan LK,
Bishop L,
and
Folz RJ.
Prevention of influenza-induced lung injury in mice overexpressing extracellular superoxide dismutase.
Am J Physiol Lung Cell Mol Physiol
280:
L69-L78,
2001
44.
Tamion, F,
Richard V,
Bonmarchand G,
Leroy J,
Hiron M,
Daveau M,
Thuillez C,
and
Lebreton JP.
Reduced synthesis of inflammatory cytokines by a free radical scavenger after hemorrhagic shock in rats.
Crit Care Med
28:
2522-2527,
2000[ISI][Medline].
45.
Tan, LR,
Waxman K,
Clark L,
Eloi L,
Chhieng N,
Miller B,
and
Young A.
Superoxide dismutase and allopurinol improve survival in an animal model of hemorrhagic shock.
Am Surg
59:
797-800,
1993[ISI][Medline].
46.
Tominaga, GT,
Bailey S,
Daughters K,
Sarfeh IJ,
and
Waxman K.
The effect of polyethylene glycol-superoxide dismutase on gastric mucosa and survival in shock with tissue injury.
Am Surg
61:
925-929,
1995[ISI][Medline].
47.
Wang, Q,
and
Doerschuk CM.
Neutrophil-induced changes in the biomechanical properties of endothelial cells: roles of ICAM-1 and reactive oxygen species.
J Immunol
164:
6487-6494,
2000
48.
Waugh, RJ,
Morrow JD,
Roberts LJ, II,
and
Murphy RC.
Identification and relative quantitation of F2-isoprostane regioisomers formed in vivo in the rat.
Free Radic Biol Med
23:
943-954,
1997[ISI][Medline].
49.
Weitberg, AB,
and
Corvese D.
Oxygen radicals potentiate the genetic toxicity of tobacco-specific nitrosamines.
Clin Genet
43:
88-91,
1993[ISI][Medline].