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1 Department of Pediatric Surgery, School of Medicine, Dokuz Eylül University, Izmir, Turkey 35340; Departments of 2 Surgery and 3 Molecular and Cellular Physiology, School of Medicine, Louisiana State University, Shreveport, Louisiana 71130; 4 Department of Pediatrics, University of California, San Francisco, California 94143; and 5 Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Superoxide has been implicated in the regulation of endothelial
cell adhesion molecule expression and the subsequent initiation of
leukocyte-endothelial cell adhesion in different experimental models of
inflammation. The objective of this study was to assess the
contribution of oxygen radicals to P-selectin expression in a murine
model of whole body ischemia-reperfusion, i.e.,
hemorrhage-resuscitation (H/R), with the use of different strategies
that interfere with either the production (allopurinol,
CD11/CD18-deficient or p47phox
/ mice) or accumulation
[intravenous superoxide dismutase (SOD), mutant mice that overexpress
SOD] of oxygen radicals. P-selectin expression was quantified in
different regional vascular beds by use of the dual-radiolabeled
monoclonal antibody technique. H/R elicited a significant increase in
P-selectin expression in all vascular beds. This response was blunted
in SOD transgenic mice and in wild-type mice receiving either
intravenous SOD or the xanthine oxidase inhibitor allopurinol. Mice
genetically deficient in either a subunit of NADPH oxidase or the
leukocyte adhesion molecule CD11/CD18 also exhibited a reduced
P-selectin expression. These results implicate superoxide, derived from
both xanthine oxidase and NADPH oxidase, as mediators of the increased
P-selectin expression observed in different regional vascular beds
exposed to hemorrhage and retransfusion.
ischemia-reperfusion; leukocyte-endothelial cell adhesion; xanthine
oxidase; 
2-integrins
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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BOTH OXYGEN RADICALS AND LEUKOCYTES have been implicated in the pathogenesis of ischemia-reperfusion (I/R) injury (10, 11, 31). Evidence supporting a role for oxygen radicals is provided by studies demonstrating diminished I/R injury in animals treated with agents that either blunt the production of or scavenge oxygen radicals or in mutant mice that overexpress an oxygen radical-scavenging enzyme, such as superoxide dismutase (SOD) (8, 10, 11, 14, 31). Multiple experimental strategies have also been used to invoke a role for leukocytes in I/R injury. Animals rendered neutropenic or that receive monoclonal antibodies that prevent leukocyte-endothelial cell adhesion (LECA) (5, 10, 12, 23) as well as mice that are genetically deficient in adhesion molecules that mediate LECA (5, 12, 23) all exhibit a diminished injury response to I/R. Although the ability of both oxygen radical- and leukocyte-directed interventions to blunt I/R injury suggests that at least two distinct mechanisms are involved in the injury process, there is evidence supporting a link between the two mediators (oxygen radicals and leukocytes) of I/R injury (10, 11, 31). Published reports describing the attenuation of I/R-induced LECA in animals treated with radical-scavenging enzymes (14, 19, 29) or peptide inhibitors of neutrophilic NADPH oxidase (17) or in mutant mice that overexpress SOD (6, 14) suggest that oxygen radicals contribute to reperfusion injury by initiating the recruitment and activation of adherent leukocytes.
LECA is regulated by a number of factors, including cell adhesion molecules (CAMs) expressed on the surfaces of leukocytes and endothelial cells (5, 12, 23). Although it has been shown that both leukocyte and endothelial CAMs are upregulated in tissues exposed to I/R, the mechanisms that contribute to this increased expression of adhesion glycoproteins remain poorly defined. P-selectin, which is the first endothelial CAM that is upregulated after I/R (5, 12, 23), appears to be under the control of oxygen radicals. Both in vitro (25) and in vivo (4, 9) experiments have revealed that superoxide and hydrogen peroxide are potent stimuli for the rapid upregulation of P-selectin on vascular endothelial cells. However, the relevance of these observations to the condition of I/R, wherein oxygen radical production is linked to LECA, remains uncertain. It is conceivable that I/R-induced oxygen radical production, resulting from either the activation of endothelial xanthine oxidase or neutrophilic NADPH oxidase, elicits the expression of P-selectin. The objective of this study was to test this possibility in a murine model of whole body I/R, i.e., hemorrhage-resuscitation (H/R), with the use of both oxygen radical- and leukocyte-directed strategies to interfere with either the production or accumulation of oxygen radicals.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Monoclonal antibodies. The monoclonal antibodies (MAbs) used for the in vivo assessment of P-selectin were RB40.34, a rat immunoglobulin G1 (IgG1) against mouse P-selectin (Pharmigen, San Diego, CA), and P-23, a nonbinding murine IgG1 directed against human P-selectin.
Radioiodination of monoclonal antibodies. RB40.34 and P-23 were labeled with 125I and 131I (NEN Life Sciences Products, Boston, MA), respectively, with the use of the iodogen method (6). In brief, 250 µg of protein were incubated with 250 µCi of sodium iodine-125 (or sodium iodine-131) and 125 µg of sodium iodogen at 4°C for 5 min. Phosphate-buffered saline (PBS) (pH = 7.4) was added to bring the volume to 2.5 ml. Thereafter, the radiolabeled MAb was separated from free 125I or 131I by gel filtration on a Sephadex PD-10 column (Pharmacia & Upjohn, Uppsala, Sweden). The column was equilibrated and then eluted with PBS containing 1% bovine serum albumin. Two fractions of 2.5 ml were collected, the second of which contained the radiolabeled MAb. Absence of free 125I or 131I was ensured by extensive dialysis of the protein-containing fraction. Radiolabeled MAbs were stored at 4°C until use.
Animal procedures.
All experimental protocols were applied to either C57BL/6 (wild-type)
mice (Jackson Laboratory, Bar Harbor, ME) or transgenic mice with the
human gene for CuZn-SOD [TgN(SOD1)3Cje], which express approximately
three times the wild-type level of CuZn-SOD as hemizygotes and five
times the wild-type level as homozygotes (8). These CuZn-SOD transgenic mice, developed on a C57BL/6 background, were bred
by our animal care facility. Both hemizygous positive (SOD-Tg) and
negative (SOD-nonTg) mice were used in this study. Some experiments were also performed with the use of CD11/CD18-deficient mice (Jackson Laboratory) developed on a C57BL/6 background. An additional series of
experiments was performed with the use of NADPH oxidase-deficient (p47phox/) mice that were developed on a
C57BL/6 background (16) (provided by Dr. Christopher Ross,
Kansas State Univ.).
Calculation of P-selectin expression. The 125I (binding MAb) and 131I (nonbinding MAb) activities in different organs and a 50-µl plasma sample were counted in a 14800 Wizard 3 gamma-counter (Wallac, Turku, Finland), with automatic correction for background activity and spillover. A 4-µl aliquot of the preinjection mixture of labeled MAbs was assayed to determine total injected activity of each labeled MAb. The tube used to mix the MAbs and the infusion syringe were likewise counted, and their activities were subtracted from the total levels. P-selectin expression was determined by subtracting the accumulated activity of the nonbinding MAb from that of the binding MAb activity and was expressed as nanograms of MAb per gram of tissue.
Experimental protocols.
Mice were anesthetized with intraperitoneal ketamine (150 mg/kg) and
xylazine (7.5 mg/kg). The left femoral artery was catheterized through
an inguinal incision by use of a PE-50 catheter with a PE-10 tip. The
catheter was connected to a transducer attached to a pressure monitor
(BP-1; World Precision Instruments, Saratosa, FL) for blood pressure
measurements. The catheter and transducer were primed with normal
saline containing 10 U/ml heparin. The maximum amount of heparin
introduced by the end of the experiments with infusion of shed blood to
the animal was 3 U (0.1-0.15 U/g). Blood withdrawal and arterial
pressure measurements were performed through the same arterial line.
The mice were bled by withdrawing blood into the 1-ml syringe over a
5-min period until a predetermined mean arterial pressure (MAP) of 30 mmHg was reached. MAP was maintained at 30 mmHg for 45 min by the
withdrawal or reinfusion of shed blood. Body temperature was monitored
through a rectal thermistor and was maintained at 37°C with the aid
of a heating pad. At the end of the 45-min hemorrhagic shock period,
animals were resuscitated by infusion of lactated Ringer solution with
a volume corresponding to 50% of the shed blood volume. Thereafter,
shed blood was infused. Resuscitation with lactated Ringer solution
plus shed blood was performed over a 10-min period. In wild-type
(control) mice, the bleed-out volume (in ml/100 g body wt) was
2.62 ± 0.12. The mean values for bleed-out volume in all other
experimental groups did not differ significantly from the control
group. The initial (prehemorrhage) arterial blood pressure in wild-type
mice was 76.3 ± 4.2 mmHg, and the postresuscitation (5 min) blood
pressure was 77.5 ± 2.1 mmHg. These values were not significantly
different in the other experimental groups, except in the
p47phox/ mice, which had initial and postresuscitation
blood pressures of 97.8 ± 4.8 and 104.4 ± 4.9 mmHg, respectively.
/) mice (n = 8). SOD (Sigma,
St. Louis, MO) was infused during resuscitation with the lactated
Ringer solution (8,000 U/kg) (14). Allopurinol (Sigma) was
administered orally (50 mg/kg) for 2 days before surgery. An additional
dose of allopurinol (50 mg/kg) was administered 1 h before
hemorrhagic shock (19).
Statistics. Data among groups were compared with the use of an analysis of variance. The Tukey's test was used for multiple comparisons. Significance was set at P < 0.01.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Figure 1, A and
B, summarizes the changes in P-selectin
expression induced by H/R in different organs of untreated and
SOD-treated (iv) wild-type (WT) mice as well as in
SOD-overexpressing mutants (SOD-Tg) or their normal littermates
(SOD-nonTg). In all organs studied, H/R elicited a profound increase in
P-selectin expression. Treatment of WT mice with intravenous SOD
significantly attenuated the H/R-induced P-selectin expression. A
similar attenuation of P-selectin expression after H/R was noted in
SOD-Tg but not in SOD-nonTg mice. These findings indicate that either
administration of exogenous SOD to WT mice or genetic overexpression of
SOD results in a significant attenuation of H/R-induced P-selectin
expression.
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Figure 2, A and B,
illustrates the H/R-induced changes in P-selectin expression observed
in different vascular beds of untreated and allopurinol-treated WT mice
and in mice that are genetically deficient in the leukocyte adhesion
molecule CD11/CD18 (CD18 deficient). The xanthine oxidase inhibitor
allopurinol significantly attenuated the H/R-induced expression of
P-selectin. Mutant mice that are genetically deficient in CD11/CD18
also exhibited a profound attenuation of the H/R-induced P-selectin
response. The attenuation of P-selectin expression was significantly
greater for CD18-deficient mice than for allopurinol-treated mice.
These findings indicate that both xanthine oxidase and activated
neutrophils may contribute to the upregulation of P-selectin that is
elicited by H/R.
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Figure 3 illustrates the
H/R-induced changes in P-selectin expression observed in the
intestinal vasculature of WT mice and in mice that are genetically
deficient in the p47phox-subunit of NADPH oxidase. The
H/R-induced increment in P-selectin expression was significantly lower
in the intestines of p47phox/ mice compared with their
WT counterparts. These experiments indicate that NADPH oxidase
contributes to ~35% of the P-selectin expression elicited by H/R in
the small intestine. Although some other tissues (e.g., mesentery and
colon) also exhibited a significantly lower expression of P-selectin in
p47phox/ mice, most tissues studied did not.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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There is a large body of evidence that implicates activated neutrophils in the pathogenesis of H/R injury (1-3, 13, 21). Compelling evidence for the contribution of neutrophils in this disease process is provided by studies showing attenuated injury in animals that are treated with CAM MAbs (20, 26, 30). These findings suggest that an increased expression of adhesion molecules on leukocytes and/or endothelial cells is a critical component of the pathological process. Although several studies have demonstrated upregulation of soluble CAMs in humans with H/R (27, 28), it remains uncertain which endothelial CAM is expressed (and by how much) after H/R and what mechanism(s) accounts for this response. In the present study, we demonstrate that P-selectin, an endothelial receptor for rolling leukocytes, is expressed more intensely in different vascular beds after exposure to H/R. Furthermore, evidence is provided that implicates superoxide as an important mediator of the H/R-induced P-selectin expression.
The magnitude of the increased P-selectin expression induced by H/R varied between vascular beds, with the kidneys and liver exhibiting the smallest and largest relative changes, respectively (1.5× and 200× control, respectively). Most vascular beds exhibited three- to fivefold increases in P-selectin expression over constitutive (basal) levels. P-selectin expression in the intestinal vasculature increased approximately fivefold after H/R. This response is comparable with the approximately fourfold increase observed in murine small intestine exposed to 20 min of local ischemia (complete occlusion of the superior mesenteric artery) and 5 h of reperfusion (6). However, the P-selectin responses of all vascular beds to H/R are significantly lower than the 15- to 75-fold increases in P-selectin expression measured in murine tissues after high-dose endotoxin treatment (7). Thus it appears that although the P-selectin upregulation elicited by H/R is substantial, it represents only a fraction of the maximal capacity of endothelial cells to express this adhesion molecule.
Superoxide has been implicated in the regulation of endothelial CAM expression and the subsequent initiation of LECA (12). Exogenously generated superoxide has been shown to promote P-selectin expression on monolayers of cultured endothelial cells (25) and to elicit P-selectin-dependent rolling in intact postcapillary venules (4, 9). Furthermore, it has been shown that intravascular administration of either CuZn-SOD or Mn-SOD significantly attenuates the LECA that is elicited in venules by I/R (15, 19, 29) or exogenous platelet-activating factor (PAF) (18, 32), both of which cause an oxidant stress in venules (7, 11). Similarly, it has been shown that the LECA induced by I/R in the hepatic microvasculature is significantly lower in mutant mice that overexpress CuZn-SOD compared with their WT counterparts (14). The results of the present study provide the first direct support for a role of superoxide in the induction of endothelial CAM expression after H/R. Using two different experimental strategies, i.e., transgenic mice that overexpress CuZn-SOD and WT mice receiving intravenous CuZn-SOD, we demonstrated that scavenging the superoxide anions generated in response to H/R significantly attenuates the accompanying enhancement of P-selectin expression. In the tissues studied, the inhibition of H/R-induced P-selectin expression was similar for CuZn-SOD transgenics and WT mice receiving exogenous SOD. This observation suggests that increased extracellular SOD is as effective as increased intracellular SOD in preventing the P-selectin upregulation, possibly reflecting a source of superoxide that is at, or near, the endothelial cell surface.
Studies on endothelial cell monolayers exposed to anoxia-reoxygenation (A/R) and postcapillary venules subjected to I/R have revealed a role for xanthine oxidase in producing the superoxide detected in postischemic (hypoxic) endothelial cells (15). The possibility that xanthine oxidase-derived superoxide mediates A/R- or I/R-induced LECA is supported by studies demonstrating an inhibitory effect of allopurinol on LECA that is comparable with that observed with SOD treatment (15). Our finding that allopurinol reduced H/R-induced P-selectin expression supports the possibility that xanthine oxidase contributes to the superoxide-mediated response. Xanthine oxidase could contribute to this response in two ways: 1) by directly generating the superoxide that elicits P-selectin biosynthesis and cell surface mobilization in postischemic endothelium and/or 2) by eliciting superoxide-mediated recruitment of leukocytes, which, in turn, generate superoxide fluxes (from NADPH oxidase) that result in the increased expression of P-selectin.
A role for leukocytes in mediating H/R-induced P-selectin
expression is supported by our observation that mice that are
genetically deficient in CD11/CD18 also exhibit an attenuated
P-selectin response to H/R. The leukocyte adhesion molecule CD11/CD18
mediates the firm adhesion of neutrophils to postischemic vascular
endothelium and is required for neutrophils to generate maximal levels
of superoxide (15). Our findings in CD11/CD18-deficient
mice suggest that adherent leukocytes may be the major source of
superoxide that elicits the increased P-selectin expression after H/R.
However, this possibility is not supported by experiments performed in NADPH oxidase-deficient (p47phox/) mice
(16), which exhibited a smaller decrement in H/R-induced P-selectin expression than either allopurinol-treated WT mice or
CD11/CD18-deficient mice. Moreover, the attenuated P-selectin responses
observed in p47phox/ mice were limited to only a few
vascular beds in the splanchnic circulation.
Our observation that both xanthine oxidase inhibition and prevention of
LECA are effective in blunting the H/R-induced P-selectin response
suggests that these two sources contribute to the response via a common
pathway. It is possible, therefore, that the two sources are linked by
a mechanism wherein superoxide generated from xanthine oxidase (and
other sources) promotes the formation of mediators (e.g., PAF) that
upregulate CD11/CD18 on leukocytes. The adherent leukocytes then
generate substances (e.g., proteases) onto the surface of endothelial
cells, which respond by synthesizing and expressing P-selectin. The
novel data derived from the p47phox/ mice indicate that
adherent leukocytes are not a major source of the superoxide that
modulates P-selectin after H/R. These findings suggest that therapeutic
interventions directed toward prevention of the systemic inflammatory
response to H/R should focus on scavenging superoxide or preventing
LECA rather than on inhibiting the production of oxygen radicals.
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ACKNOWLEDGEMENTS |
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This work was supported in part by Grants P01-DK-43785 (to D. N. Granger) and P01-AG-08938 and R01-AG-16998 (both to C. J. Epstein) from the National Institutes of Health.
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FOOTNOTES |
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F. M. Akgür is the recipient of a Fulbright Fellowship from the National Institutes of Health.
Address for reprint requests and other correspondence: D. N. Granger, Dept. of Molecular and Cellular Physiology, Louisiana State Univ. Medical Center, 1501 Kings Highway, Shreveport, LA 71130-3932 (E-mail: dgrang{at}lsumc.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 22 February 1999; accepted in final form 24 February 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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 M. Lehnert, T. Uehara, B. U. Bradford, H. Lind, Z. Zhong, D. A. Brenner, I. Marzi, and J. J. Lemasters Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation Am J Physiol Gastrointest Liver Physiol, September 1, 2006; 291(3): G456 - G463. [Abstract] [Full Text] [PDF]
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 N. Li, G. Zhang, F.-X. Yi, A.-P. Zou, and P.-L. Li Activation of NAD(P)H oxidase by outward movements of H+ ions in renal medullary thick ascending limb of Henle Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1048 - F1056. [Abstract] [Full Text] [PDF]
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 A. M. Condliffe, K. Davidson, K. E. Anderson, C. D. Ellson, T. Crabbe, K. Okkenhaug, B. Vanhaesebroeck, M. Turner, L. Webb, M. P. Wymann, et al. Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils Blood, August 15, 2005; 106(4): 1432 - 1440. [Abstract] [Full Text] [PDF]
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 A. Nakatani-Okuda, H. Ueda, S.-i. Kashiwamura, A. Sekiyama, A. Kubota, Y. Fujita, S. Adachi, Y. Tsuji, T. Tanizawa, and H. Okamura Protection against bleomycin-induced lung injury by IL-18 in mice Am J Physiol Lung Cell Mol Physiol, August 1, 2005; 289(2): L280 - L287. [Abstract] [Full Text] [PDF]
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 R. P. Bowler, M. Nicks, K. Tran, G. Tanner, L.-Y. Chang, S. K. Young, and G. S. Worthen Extracellular Superoxide Dismutase Attenuates Lipopolysaccharide-Induced Neutrophilic Inflammation Am. J. Respir. Cell Mol. Biol., October 1, 2004; 31(4): 432 - 439. [Abstract] [Full Text] [PDF]
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 D. K. Kaul, X.-d. Liu, S. Choong, J. D. Belcher, G. M. Vercellotti, and R. P. Hebbel Anti-inflammatory therapy ameliorates leukocyte adhesion and microvascular flow abnormalities in transgenic sickle mice Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H293 - H301. [Abstract] [Full Text] [PDF]
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 D. N. Granger, T. Vowinkel, and T. Petnehazy Modulation of the Inflammatory Response in Cardiovascular Disease Hypertension, May 1, 2004; 43(5): 924 - 931. [Abstract] [Full Text] [PDF]
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 J. Vinten-Johansen Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 481 - 497. [Abstract] [Full Text] [PDF]
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 H. Setiadi and R. P. McEver Signal-dependent distribution of cell surface P-selectin in clathrin-coated pits affects leukocyte rolling under flow J. Cell Biol., December 22, 2003; 163(6): 1385 - 1395. [Abstract] [Full Text] [PDF]
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B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]
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Z.-Q. Zhao, J. S. Corvera, M. E. Halkos, F. Kerendi, N.-P. Wang, R. A. Guyton, and J. Vinten-Johansen Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning Am J Physiol Heart Circ Physiol, August 1, 2003; 285(2): H579 - H588. [Abstract] [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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W. H. Cerwinka, D. Cooper, C. F. Krieglstein, C. R. Ross, J. M. McCord, and D. N. Granger Superoxide mediates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H535 - H541. [Abstract] [Full Text] [PDF]
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S. Shigematsu, S. Ishida, D. C. Gute, and R. J. Korthuis Bradykinin-induced proinflammatory signaling mechanisms Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2676 - H2686. [Abstract] [Full Text] [PDF]
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P. Kubes, D. Payne, and R. C. Woodman Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation Am J Physiol Gastrointest Liver Physiol, July 1, 2002; 283(1): G139 - G147. [Abstract] [Full Text] [PDF]
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R. Shenkar, H.-K. Yum, J. Arcaroli, J. Kupfner, and E. Abraham Interactions between CBP, NF-{kappa}B, and CREB in the lungs after hemorrhage and endotoxemia Am J Physiol Lung Cell Mol Physiol, August 1, 2001; 281(2): L418 - L426. [Abstract] [Full Text] [PDF]
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 R. P. BOWLER, J. ARCAROLI, J. D. CRAPO, A. ROSS, J. W. SLOT, and E. ABRAHAM Extracellular Superoxide Dismutase Attenuates Lung Injury after Hemorrhage Am. J. Respir. Crit. Care Med., July 15, 2001; 164(2): 290 - 294. [Abstract] [Full Text] [PDF]
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R. P. Bowler, M. Nicks, K. Warnick, and J. D. Crapo Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L719 - L726. [Abstract] [Full Text] [PDF]
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H. D. Wang, D. G. Johns, S. Xu, and R. A. Cohen Role of superoxide anion in regulating pressor and vascular hypertrophic response to angiotensin II Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1697 - H1702. [Abstract] [Full Text] [PDF]
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P < 0.001 relative to
H/R alone; no. of mice (n) = 5 in each group. MAb,
monoclonal antibody.
