© 2001 American Heart Association, Inc.
Vascular Biology |
8-Iso-PGF2
Induces ß2-Integrin–Mediated Rapid Adhesion of Human Polymorphonuclear Neutrophils
A Link Between Oxidative Stress and Ischemia/Reperfusion Injury
From the Department of Biomedical and Surgical Sciences (L.F., P.M., A.L.) and the Department of Pathology, Section of General Pathology (C.G., C.L.), University of Verona, Verona, Italy.
Correspondence to Dr Luigi Fontana, Department of Biomedical and Surgical Sciences, Medicina Interna C, Policlinico GB Rossi, Piazzale LA Scuro, 37134 Verona, Italy. E-mail lechi{at}borgoroma.univr.it
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Abstract |
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Abstract—F2-Isoprostanes are generated from a cyclooxygenase-independent oxidative modification of arachidonic acid. They are present in atherosclerotic plaques and are platelet activators as well as potent vasoconstrictors. Polymorphonuclear neutrophils are major players in ischemia/reperfusion injury and in restenosis after PTCA. The effects of 8-isoprostaglandin (PG) F2
on very rapid
ß2-integrin–dependent adhesion was evaluated
in human neutrophils in vitro by use of purified integrin as ligand.
8-Iso-PGF2 (1 nmol/L to 20 µmol/L) triggers
a dose-dependent, very rapid neutrophil adhesion to human fibrinogen
but not to the endothelial ligand intercellular
adhesion molecule-1. Pretreatment with
anti–ß2-integrin subtypes showed activation
of CD11b/CD18 and CD11c/CD18. Adhesion triggering was completely
prevented by pertussis toxin. SQ29,548, a specific
antagonist of thromboxane A2 receptor, also
dose-dependently prevented
8-iso-PGF2–triggered neutrophil adhesion.
8-Iso-PGF2 did not trigger adhesion in human
monocytes and lymphocytes and did not induce neutrophil chemotaxis or
activation of the oxygen free-radical–forming enzyme NADPH-oxidase.
These data highlight the role of 8-iso-PGF2
as a specific activator of rapid neutrophil adhesion and
suggest its involvement in the pathogenesis of
ischemia/reperfusion injury and in restenosis after
PTCA. The effect is transduced via activation of the receptor for
thromboxane A2.
Key Words: neutrophils • adhesion • 8-iso-PGF2 • thromboxane A2 receptor • ß2-integrins
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Introduction |
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F2-Isoprostanes are a series of prostaglandin (PG) F2–like isomers formed primarily by a free-radical mechanism from arachidonic acid on cell membranes and LDL particles. F2-Isoprostanes can be measured in both plasma and urine1 and have been shown to be increased in association with clinical conditions such as coronary ischemia/reperfusion syndrome,2 adult respiratory distress syndrome,3 diabetes mellitus,4 and chronic pulmonary disease.5 They are also increased in association with several risk factors for the development of ischemic vascular disease, including cigarette smoking,6 hypercholesterolemia,7 and hyperhomocysteinemia.8 Thus, analysis of F2-isoprostanes has emerged as a specific and reliable marker of oxidant stress in vivo.1 Although oxygen free-radical reactions have been implicated in chronic diseases, it is important to underline that the relationship between oxidative stress and the onset and progression of such disease processes is not fully established. Nonetheless, one of the F2-isoprostanes formed during lipid peroxidation, 8-iso-PGF2
, has been found to
be a potent vasoconstrictor9
and to modulate several platelet functions via stimulation of
thromboxane A2 receptors
(TP).10 11 Thus
far, however, nothing is known about the effect of isoprostanes on the
biology of inflammatory cells. Proinflammatory reactions rely primarily on the capability of leukocytes to recognize and adhere to the blood vessels. The process leading to leukocyte extravasation is a finely regulated sequence of steps controlled by both adhesion molecules and activating factors. Selective recruitment of various leukocyte subtypes under physiopathological situations depends on the action of different classes of adhesion molecules and activating factors whose combination generates a tissue-specific "area code."12 Activating factors are major players in leukocyte recruitment, because integrins do not mediate firm adhesion unless activated. Signaling events triggered by physiological proadhesive agonists must be very efficient. Indeed, integrin activation needs to be extremely rapid (because arrest often occurs within seconds) and stable to counteract the blood-flow shear stress. Proinflammatory agonists, such as bacterial formyl peptides, complement factors, and lipid-derived products, stimulate integrin-dependent adhesion and chemotaxis in polymorphonuclear leukocytes.13 14 15 16 Notably, integrin activation has emerged as a very active area of investigation, because a complete understanding of the molecular mechanisms leading to the activation of integrin-dependent leukocyte adhesion could open new therapeutic perspectives in inflammatory diseases.
Because an inflammatory response leading to tissue injury
has been demonstrated in the pathogenesis of the atherosclerotic
process, ischemia-reperfusion syndrome, and restenosis
after percutaneous transluminal coronary
angioplasty (PTCA),17 in
which increased isoprostane generation is observed, we set out to
explore the effects of 8-iso-PGF2 on the
proinflammatory activities of human inflammatory cells. Here, we
evaluated the involvement of 8-iso-PGF2 in
rapid integrin-mediated adhesion and chemotaxis triggering in human
polymorphonuclear neutrophils, monocytes, and lymphocytes. We show
that 8-iso-PGF2 is a highly selective
integrin activator of human neutrophils with respect to
rapid adhesion but not chemotaxis triggering, whereas no effect was
found on other leukocyte subtypes.
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Methods |
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Reagents and Antibodies
N-Formyl-Met-Leu-Phe (fMLP) was from Sigma; pertussis toxin (PTx) was from Alexis Biochem; 8-iso-PGF2
,
8-iso-PGF3, PGF2,
the TP agonist U46619, and the TP antagonist SQ29,548 were
from Cayman Chemical; anti-human CD11a blocking monoclonal antibody was
kindly donated by Dr Chilosi (University of Verona, Department of
Pathology); anti-human CD11c blocking monoclonal antibody was from
Santa Cruz Biotech; and anti-human CD11b blocking monoclonal antibody
was from Repligen Corp. Recombinant human intercellular adhesion
molecule (ICAM)-1 was purified as an Ig–ICAM-1 fusion chimera (Ig H
chain 2 and 3) from supernatants of stably transfected Chinese hamster
ovary cell lines. All lipids and peptides were solubilized immediately
before use at 1 mmol/L concentrations in PBS, pH 7.2. Dilutions of
8-iso-PGF2 were in PBS. Stock solution was in
ethanol 2.8 mmol/L and was kept at -20°C. Ethanol was removed
by nitrogen stream evaporation, and solubility in PBS was achieved by
immediate sonication on ice with a batch sonicator (3 bursts of 1
minute each at 400 W).
Isolation of Human Polymorphonuclear Cells,
Monocytes, and Lymphocytes
Blood was collected from healthy donors and
anticoagulated in citrate. Human blood polymorphonuclear
neutrophils were isolated by dextran sedimentation and
centrifugation over Ficoll-Hypaque (Amersham Pharmacia
Biotech) as described
previously.18 Contaminating
erythrocytes were lysed by hypotonic saline, and then neutrophils were
washed with PBS and finally resuspended in RPMI 1640 containing 10%
FCS. Human blood monocytes and lymphocytes were then isolated by
Percoll density
fractionation.19 All of the
above procedures were done under sterile conditions and used reagents
prepared in endotoxin-free water for clinical
use.
Rapid Adhesion Assay
Eighteen-well glass slides were coated for 120
minutes at 37°C with human fibrinogen (Sigma) (20 µg/well in
endotoxin-free PBS) or with purified human ICAM-1. Neutrophils
(5x104/well;
2.5x106/mL in RPMI 1640, containing 10%
heat-inactivated FCS and 20 mmol/L HEPES, pH 7.3) were
added, incubated for 10 minutes at 37°C, stimulated by addition of
the agonists before washing, and fixed on ice in 1.5%
glutaraldehyde for 60 minutes, and computer-assisted
enumeration of cells bound in 0.2 mm2 was
done as
described.20
Chemotaxis Assays
Migration of polymorphonuclear neutrophils,
monocytes, and lymphocytes was assessed in 1-µm or 5-µm pore size
transwells (Bio-Coat, Becton Dickinson). Neutrophils, monocytes,
and lymphocytes were at 2x106/mL in RPMI
1640, without FCS, containing 20 mmol/L HEPES, pH 7.3. Cell
suspension (100 µL) was added to the top well, and 600 µL of medium
containing agonists was added to the bottom well. After fixation with
1.5% glutaraldehyde, migrated cells were counted by
fluorescence-activated cell sorting using polystyrene
beads (Polyscience) as an internal
standard.21
Hydrogen Peroxide Release
H2O2
was measured fluorometrically by conversion of the
nonfluorescent compound 4-hydroxy-3-methoxyphenylacetic acid
(homovanilic acid) to the highly fluorescent
2,2'-dihydroxy-3,3'-dimethoxydiphenyl-5,5'-diacetic acid, catalyzed by
horseradish peroxidase in the presence of
H2O2.22
The conversion of the homovanilic acid was assessed at an excitation
wavelength of 315 nm and an emission wavelength of 425 nm in a
Perkin-Elmer LS-5 Luminescence Spectrometer. The amount of
H2O2 produced was
calculated from a standard curve using known dilutions of
H2O2.
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Results |
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To test the relevance of isoprostanes in rapid integrin-dependent adhesion triggering, we first evaluated the capability of 8-iso-PGF2
to induce rapid
leukocyte binding to purified integrin ligands. As shown in
Figure 1
, 8-iso-PGF2 triggered
rapid neutrophil adhesion to human fibrinogen in a dose-dependent
manner. Notably, 8-iso-PGF2 induced rapid and
consistent adhesion already at 1 nmol/L concentration. At 20
µmol/L concentration, triggered adhesion was 
73% of the maximal
binding induced by fMLP. Thus, 8-iso-PGF2 was
a strong agonist with respect to neutrophil adhesion triggering to
fibrinogen. We also tested 3 structurally related compounds,
8-iso-PGF3,
8-iso-PGF2, and U46619 (10 to 10000 nmol/L).
All of them displayed a similar dose-dependent agonistic activity
toward neutrophil adhesion to fibrinogen, with the maximum effect
observed at 10 µmol/L (with an average induction of adhesion of 2.7
and 2.2 times greater than nonstimulated cells, data not shown).
Pretreatment of neutrophils with the TP antagonist SQ29,548
(5 and 20 µmol/L for 30 minutes at room temperature) blocked both
8-iso-PGF2– and U46619 (0.5
µmol/L)–triggered adhesion, with an average inhibition of
36% and 60%, respectively
(Figure 2). We then evaluated the capability of
8-iso-PGF2 to trigger neutrophil adhesion to
purified human ICAM-1. Surprisingly,
8-iso-PGF2 did not induce neutrophil adhesion
to ICAM-1, even at the highest concentrations
(Figure 3). We investigated whether other leukocyte subtypes
were responsive to 8-iso-PGF2. Interestingly,
8-iso-PGF2 did not induce adhesion to
fibrinogen or to ICAM-1 in either monocytes or lymphocytes (not shown).
We also evaluated other cellular phenomena normally induced by classic
chemoattractants, such as chemotaxis and activation of oxygen
free-radical release. 8-Iso-PGF2 did not
trigger chemotaxis in neutrophils, monocytes, or lymphocytes and did
not directly stimulate the activation of the oxygen
free-radical–forming enzyme NADPH-oxidase, as evaluated by hydrogen
peroxide release (data not shown). To exclude the possibility that
rapid integrin triggering was a consequence of a generic plasma
membrane alteration due to the lipidic nature of
8-iso-PGF2, we evaluated the effect of PTx
pretreatment on adhesion triggering by
8-iso-PGF2. As shown in
Figure 4, PTx pretreatment almost completely abolished
8-iso-PGF2–induced binding of neutrophils to
fibrinogen. The inhibitory effect of PTx was not due to a
generic toxic effect of PTx pretreatment, because neutrophils still
retained the capability to fully adhere upon triggering by phorbol
12-myristate 13-acetate (data not shown). This suggests
that 8-iso-PGF2 induces neutrophil rapid
integrin activation through a signaling pathway dependent on
PTx-sensitive trimeric GTP-binding proteins.
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The previous data suggest that
8-iso-PGF2 is a highly selective neutrophil
agonist with respect to integrin activation and dependent adhesion.
Notably, 8-iso-PGF2 did not trigger binding
to ICAM-1, and this excludes activation of the
ß2-integrin CD11a/CD18 (leukocyte
function-associated antigen, LFA-1). In contrast,
8-iso-PGF2 triggered adhesion to fibrinogen,
thus suggesting the activation of the
ß2-integrins CD11b/CD18 and CD11c/CD18, which
are both receptors for fibrinogen. To investigate the relative
contributions of CD11b/CD18 and CD11c/CD18, we carried out adhesion
assays in the presence of blocking monoclonal antibodies. As shown in
Figure 5, anti-CD11a/CD18 antibody did not block
8-iso-PGF2–triggered adhesion to fibrinogen,
as expected. In contrast, anti-CD11b/CD18 and anti-CD11c/CD18 blocked
triggered adhesion, with an average inhibition of 65% and 45%,
respectively. Thus, CD11b/CD18 and CD11c/CD18 play a cooperative role
in triggering of adhesion to fibrinogen by
8-iso-PGF2. This was further confirmed by the
capability of IB4, an anti-CD18 common chain blocking monoclonal
antibody, to completely prevent induced adhesion (data not shown). The
efficacy of the monoclonal antibodies used was confirmed each time by
their capability to prevent fMLP-triggered rapid adhesion to fibrinogen
as well as to ICAM-1. We conclude that
8-iso-PGF2 stimulates rapid human neutrophil
adhesion to fibrinogen by rapid triggering of both the
ß2-integrins CD11b/CD18 and
CD11c/CD18.
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Discussion |
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Oxidative stress is able to trigger the generation of biologically active substances, such as products of lipid peroxidation, which have been suggested to play a central role in the pathogenesis of many chronic diseases and particularly in atherosclerosis. F2-Isoprostanes are a new family of PGF2
isomers. They are
produced mainly by a cyclooxygenase-independent
oxidative modification of arachidonic acid normally
present in all cell membranes, phospholipids, and plasma LDLs.
8-Iso-PGF2, one of the best known
F2-isoprostanes, was recently shown to be a
specific, chemically stable, and quantitative marker of oxidant stress
in vivo.1 Importantly,
8-iso-PGF2 was shown to be a vasoactive
mediator, a mitogen, and a platelet
activator.9 10 11
Nonetheless, the real significance of
F2-isoprostanes as biological mediators remains
to be established, especially in the context of the highly regulated
multistep process of leukocyte–endothelial cell
interaction, which is critical to the inflammatory response.
Neutrophils are major players in the pathogenesis of
ischemia-reperfusion injury, and their adherence to vascular
endothelium is one of the earliest steps in this
pathogenetic process leading to reperfusion
damage23 and in the
development of restenosis after
angioplasty.24
In the present report, we investigated the potential
relationship between isoprostanes and leukocyte proadhesive activities.
From our results, the following conclusions can be drawn: (1)
8-iso-PGF2 triggers a PTx-sensitive signaling
pathway in human neutrophils leading to rapid integrin activation; (2)
8-iso-PGF2 is likely to exert its effects on
neutrophils via the TP; (3) integrin activation is restricted to the
ß2-integrins CD11b/CD18 (CR3) and CD11c/CD18
(gp150/95) and supports binding to fibrinogen but not to ICAM-1; (4)
8-iso-PGF2 does not trigger integrin
activation in monocytes and lymphocytes; and (5) the signaling
capabilities of 8-iso-PGF2 appear to be
restricted and selective, because it does not induce LFA-1 activation,
chemotaxis, or NADPH-oxidase activity.
This study aimed to investigate the functional activity of
8-iso-PGF2 on leukocytes.
8-Iso-PGF2 appears to have the
characteristics of the classic neutrophil chemoattractant, because it
triggers rapid integrin activation through a PTx-sensitive signaling
pathway, which suggests the involvement of a 7-spanning region
receptor linked to heterotrimeric GTP-binding proteins of the
Gi family. Furthermore, other compounds
structurally related to 8-iso-PGF2, such as
8-iso-PGF3 and PGF2
and U46619, have shown similar capability, thus suggesting that
triggering of rapid neutrophil adhesion may be a common feature of some
eicosanoids and isoeicosanoids. Because in our study the TP
antagonist SQ29,548 was able to inhibit
8-iso-PGF2– and U46619-triggered neutrophil
adhesion in a dose-dependent manner, this indicates that
8-iso-PGF2 may act as a ligand for TP, a
receptor that has been shown to be coupled to G
proteins.25 This is in
agreement with the findings of other authors who recently demonstrated
that 8-iso-PGF2 acts as a vasoconstrictor and
modulator of platelet function via activation of the TP in vivo in
the mouse as well as in
vitro.10 11 25
However, our data do not automatically exclude the existence of
distinct and specific isoprostane receptors.
The functional activity of
8-iso-PGF2, in contrast to other neutrophil
chemoattractants, such as fMLP, leukotriene
B4, C5a, platelet-activating factor, and
interleukin-8, appears to be very selective. Indeed,
8-iso-PGF2 does not direct chemotaxis or
trigger the release of oxygen free radicals. Moreover, and importantly,
8-iso-PGF2 stimulates neutrophil adhesion to
fibrinogen but not to ICAM-1. This last finding is unexpected and of
particular interest. Indeed, if this result excludes, de facto, the
activation of CD11a/CD18, it also should rule out the involvement of
CD11b/CD18, which is also a complementary ICAM-1 receptor able to
mediate adhesion to ICAM-1. CD11b/CD18 activation by
8-iso-PGF2, however, is confirmed by the
capability of anti-CD11b/CD18–blocking monoclonal antibodies to
partially prevent triggered adhesion to fibrinogen. From these data, we
conclude that 8-iso-PGF2 activates a
very restricted signaling pathway that selectively triggers a limited
set of CD11b/CD18 functional modifications that in turn support
interaction with fibrinogen but not with ICAM-1. Although unusual,
these data are not completely surprising. Indeed, other classic
neutrophil chemoattractants, such as leukotriene
B4, platelet-activating factor, C5a,
interleukin-8, and fMLP, also display a high degree of
heterogeneity with respect to adhesion, chemotaxis, and
triggering of free-radical release. This is probably due to
quantitative differences in the signaling pathways, which are modulated
by a combination of still not completely understood mechanisms, such as
receptor affinity, homologous desensitization, agonist stability,
number of receptors, and affinity for intracellular downstream
effectors. All these regulatory factors are, at present, not
defined in the case of 8-iso-PGF2 signaling
capability, and their identification will represent an obvious
major area of investigation.
Notably, 8-iso-PGF2 triggers
activation of ß2-integrin CD11c/CD18, which
has been shown to induce neutrophil respiratory burst on interaction
with immobilized
fibrinogen.26 Thus,
8-iso-PGF2 could amplify oxidative stress by
triggering CD11c/CD18-mediated activation of NADPH-oxidase and the
subsequent release of oxygen free radicals. Interestingly, the
proadhesive activity of 8-iso-PGF2 is
restricted only to neutrophils, because it does not trigger adhesion in
monocytes and lymphocytes. Together, our findings suggest that
8-iso-PGF2 is a peculiar proinflammatory
agonist, being selective at the level of induced phenomenon, integrin
type, integrin ligand, and cell type.
The results of the present study may be of clinical
relevance. F2-Isoprostanes are significantly
elevated in human carotid atherosclerotic plaques and coronary
arteries isolated from patients with coronary heart
disease.27 It has been
demonstrated that during acute coronary reperfusion, there is a
dramatic increase of 8-iso-PGF2 released by
the fissured plaque that peaks at 15 minutes after global myocardial
reperfusion.2 Reperfusion of
ischemic tissue is associated with an acute inflammatory
response that may further exacerbate vascular and tissue damage. This
vascular reperfusion injury is mediated largely by free radicals and
neutrophils through specific interactions between adhesion molecules on
the endothelium, platelets, and neutrophils, an
interaction that precedes myocyte
injury.23 Compelling
evidence from a variety of animal models indicates that blockade of
neutrophil adhesion to endothelium attenuates
ischemia-reperfusion
injury,28 29
further highlighting the importance of these inflammatory cells in this
acute pathogenetic process.
Isoprostanes are also increased in association with such risk factors as hypercholesterolemia7 and diabetes mellitus,4 which are relevant in the development of ischemic vascular disease. Notably, it has been demonstrated that hypercholesterolemia28 and diabetes mellitus,29 well-known risk factors for the progression and destabilization of atherosclerotic plaque, are associated with an inflammatory response that renders the tissues more vulnerable to ischemic episodes. Mounting evidence indicates that metabolic conditions associated with these risk factors may also exacerbate the vulnerability of the microvasculature to the deleterious effects of ischemia and reperfusion.29 30 A common feature of the negative effects of these risk factors on endothelial function during ischemia-reperfusion is the enhanced oxidant stress.
Furthermore, emerging experimental evidence indicates that
neutrophils may also be central to intimal hyperplasia after mechanical
arterial injury, which leads to
restenosis.30
Indeed, in CD11b/CD18-deficient mice, neutrophil recruitment in
vascular repair after PTCA is reduced, thus preventing
neointimal
thickening.31 This further
supports the role of integrin-dependent triggering of neutrophil
adhesion in intimal hyperplasia. Interestingly, despite standard
aspirin and heparin therapy, leukocyte activation and platelet
adherence still occur after coronary
angioplasty.32 In contrast,
experimental data and preliminary clinical studies have suggested that
antioxidants, such as vitamin E, may prevent restenosis after
angioplasty.33 Furthermore,
in a large, double-blind, randomized trial, probucol, a well-known
antioxidant, improved vascular remodeling after
PTCA.34 Notably, it has been
demonstrated that 8-iso-PGF2 is increased
after coronary
angioplasty35 and that
vitamin E is able to suppress 8-iso-PGF2
generation in
vivo.4 36 We
hypothesize that the beneficial effects of antioxidants in the
prevention of restenosis after PTCA may be partly related to
the prevention of isoprostane generation. Furthermore, a second line of
emergent pharmacological therapy in the acute coronary
syndromes, in the ischemia/reperfusion syndromes, and in the
prevention of restenosis after PTCA could be the use of TP
antagonists in association with
cyclooxygenase inhibitors. Notably, it
was recently demonstrated that blockade of TP receptors may inhibit
atherosclerosis via the prevention of cellular events
stimulated by eicosanoids other than thromboxane
A2,37
and that could be even more important in those clinical conditions in
which large amounts of isoprostanes are released into the blood
stream.
In conclusion, our data demonstrate, for the first time,
that 8-iso-PGF2 modulates rapid and selective
proadhesive activity in polymorphonuclear neutrophils. Notably, the
8-iso-PGF2 biological activity that has been
demonstrated here on neutrophils and previously on platelets and
muscle
cells9 10 11
could be shared by the other related families of isoeicosanoids
simultaneously generated by oxidative
stress.1 This is
consistent with the hypothesis of a general role of
isoprostanes as modulators of proinflammatory cells. Inhibition of
F2-isoprostane generation and activity could be
a novel target for drug therapy in clinical conditions in which
oxidative stress and neutrophil activation
coexist.
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Acknowledgments |
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The present study was supported by a grant from Italian Ministry of University and Research (fondi 60%, University of Verona, Italy); by cofinanziamento MURST and University of Verona, Progetto Sanità 1996/97; by Fondazione Cassa di Risparmio; and by Istituto Superiore di Sanità (progetto Sclerosi Multipla).
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Footnotes |
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Reprint requests to Prof Alessandro Lechi, Department of Biomedical and Surgical Sciences, Medicina Interna C, Policlinico GB Rossi, Piazzale LA Scuro, 37134 Verona, Italy.
Received October 19, 2000; accepted October 23, 2000.
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