(Circulation. 1995;91:1872-1885.)
© 1995 American Heart Association, Inc.
Articles |
Role of Neutrophils in Myocardial Ischemia and Reperfusion
From the Department of Medicine B2142, Division of Cardiology, Rigshospitalet, University of Copenhagen (Denmark).
Correspondence to Peter Riis Hansen, MD, PhD, Department of Medicine B2142, Division of Cardiology, Rigshopitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Abstract |
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 Top Abstract IntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
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Abstract In the intact organism, ischemic myocardial injury initiates an acute inflammatory response in which polymorphonuclear leukocytes (PMNs) are major participants. Evidence indicates that the interplaying inflammatory reactions are augmented by reperfusion and that accumulating PMNs can contribute to myocardial damage, eg, by release of oxygen-derived free radicals, proteases, and leukotrienes. In experimental models, interventions aimed at PMN inhibition can exert cardioprotective effects, and some of these strategies raise hope for future clinical applications. A greater understanding of the mechanisms involved in PMN-mediated myocardial damage is necessary for designing a rational approach to reduce the putative detrimental effects of PMNs without antagonizing their favorable consequences in tissue healing.
Key Words: leukocytes • heart diseases • reperfusion • free radicals
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Introduction |
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TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
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The association of inflammation with acute myocardial infarction (AMI) was recognized more than 50 years ago,1 and the appearance of inflammatory lesions in the injured myocardial region traditionally has been taken to represent a pathophysiological healing response to tissue injury. In the mid-1970s, the beneficial effect of this healing process was clearly demonstrated in a clinical trial in which anti-inflammatory treatment with a high dose of prednisone in patients with AMI resulted in several cases of ventricular aneurysm and cardiac rupture.2 At about the same time, it was recognized that myocardial ischemia leads to a time-dependent loss in myocyte viability and that early reperfusion conveyed tissue salvage, ie, reduction in infarct size and improvement in left ventricular function. In 1980, formation of an occlusive thrombus in the atherosclerotic coronary artery was shown to be the key event in the evolution of an AMI,3 and thrombolytic therapy has presently made early myocardial reperfusion an obtainable goal for many patients with AMI. In the late 1970s, however, it was suggested that reperfusion itself may contribute to myocardial injury, and within the past decade, the concept of myocardial reperfusion injury has profoundly changed the experimental and clinical view of myocardial damage resulting from ischemia and reperfusion. Accumulating evidence has indicated that myocardial ischemia elicits an acute inflammatory response that is greatly augmented by reperfusion and that a significant part of total myocardial injury after ischemia and reperfusion is attributable to these effects.4 5 6
Polymorphonuclear leukocytes (PMNs) are integrated into the acute inflammatory response to tissue injury7 and possess the capacity to produce oxygen-derived free radicals (OFRs) when activated by appropriate stimuli.8 9 PMNs are thus a first-line defense of the organism against invading pathogens, but since the beginning of the 1980s, increasing attention has been directed toward the role of PMNs as mediators of tissue destruction in inflammatory diseases. PMNs accumulate in ischemic and reperfused myocardium under the influence of chemoattractants, and a growing body of evidence has proposed that PMNs participate in myocardial injury after ischemia and reperfusion.10 11 12 13 14 15 Understanding of these mechanisms is critical to designing new therapeutic interventions capable of reducing the putative deleterious effects of PMNs without influencing favorable actions of these cells in tissue healing.
PMN myelopoiesis, maturation, and mobilization from the bone marrow and marginating pool during the acute-phase response will not be considered here. The first part of the present review provides an overview of the mechanisms by which activated PMNs can directly exert cardiotoxic effects in vitro. This discussion is succeeded by a presentation of available experimental data concerning factors involved in PMN adhesion and myocardial accumulation and the results of PMN inhibition on expressions of myocardial reperfusion injury. The last section summarizes epidemiological and clinical data implicating PMNs in the pathophysiology of ischemic heart disease.
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Cardiotoxic Potential of PMNs |
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TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
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PMNs as a Source of OFRs
PMNs contain an extensive cytotoxic armamentarium, and their potential to destroy tissue is realized by concerted and synergistic effects of exocytosed granule constituents and generation of OFRs (Fig 1
).8 9 16 Activation of
the PMN
membrane–associated NADPH oxidase system by various soluble and
particulate stimuli initiates a respiratory burst characterized by a
marked increase in cellular oxygen consumption and generation of
superoxide anions.9 The superoxide anions apparently
dismutate quantitatively to hydrogen peroxide, although it is possible
that hydrogen peroxide and superoxide anions may react in the
metal-catalyzed modified Haber-Weiss reaction to form highly reactive
hydroxyl radicals. However, most stimuli that induce superoxide
generation by PMNs also cause the release of myeloperoxidase from the
azurophil granules, and this enzyme efficiently removes hydrogen
peroxide by catalyzing the interaction of hydrogen peroxide with
Cl- to form hypochlorous acid. Hypochlorous acid is a
powerful oxidant that may chlorinate or oxidize a variety of target
molecules, and reactions of hypochlorous acid with primary amines or
ammonia can give rise to chloramines, which are also energetic
oxidants. By these mechanisms, hypochlorous acid is considered to be
primarily responsible for the OFR-dependent cytotoxicity of
PMNs.8 9
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The experimental cardiotoxicity of chemically and photochemically generated OFRs is extensively documented,17 18 19 20 and the cytotoxicity of PMN-derived OFRs has been amply demonstrated in cultured endothelial cells.21 22 23 24 25 Furthermore, PMNs exacerbate cellular damage in anoxia-reoxygenated cultured myocytes by mechanisms that depend, in part, on OFRs.26 27 In isolated arteries, PMN-derived OFRs can induce vascular contraction, and in isolated perfused hearts, they aggravate postischemic coronary endothelial dysfunction28 and decrease left ventricular mechanical performance.29 30 One mechanism behind the vasoconstricting properties of activated PMNs may be inactivation of endothelial nitric oxide (NO) by PMN-derived superoxide.31 32 However, PMNs also can release NO,33 34 although evidence indicates that PMN stimulation results in progressive inactivation of PMN-derived NO by concomitant release of OFRs.34 NO may directly inhibit PMN NADPH oxidase activity,35 and the mechanisms underlying modulation of vasomotor tone by PMNs are therefore likely to be complex. Oxidants from activated PMNs can also cause depression of calcium transport in isolated cardiac myocyte sarcoplasmic reticulum,36 and PMN-derived hydrogen peroxide may promote release of proinflammatory arachidonic acid metabolites (ie, prostacyclin) from cultured endothelial cells.37 Furthermore, chemically generated superoxide anions can generate potent chemotactic activity in plasma38 or after incubation with arachidonic acid,39 and it is conceivable that PMN-derived superoxide anions can have similar effects. Interestingly, PMN-derived OFRs can oxidize LDL in vitro,40 and the multiple proatherogenic properties of oxidized LDL41 may therefore provide an additional link between PMNs and human ischemic heart disease, although PMNs are usually not thought to play a role in atherogenesis.42
To eliminate interference from other mechanisms, studies of direct PMN-dependent cellular damage generally have been conducted in static in vitro systems, and the absence of a complete pathophysiological milieu represents an inherent limitation to these studies.16 Importantly, PMNs integrate the signals from agonist receptors and adherence receptors before committing to secretion. For example, several soluble stimuli (eg, N-formylated peptides, the complement component C5a, platelet-activating factor [PAF], and inflammatory cytokines) in concentrations that are likely to be generated in vivo elicit little or no release of OFRs from PMNs in suspension. However, this response can be greatly increased after PMN adherence to biological surfaces,43 44 priming of PMNs by various inflammatory mediators (eg, tumor necrosis factor [TNF]45 46 and interleukin-6 [IL-6]47 ), or pharmacological inhibition of phagosome formation with cytochalasin B.48 Under pathophysiological conditions, other endogenous mediators (eg, platelet-derived growth factor49 ) may inhibit PMN respiratory burst activity, and naturally occurring antioxidants can attenuate OFR-mediated tissue injury (eg, erythrocytes are excellent scavengers of PMN-derived OFRs50 ). These mechanisms are likely to modulate PMN-mediated cellular damage in vivo, and caution must be exercised when extrapolating in vitro effects of PMNs to direct pathophysiological actions.
PMN-Derived Proteinases
Although interest has focused on the
cytotoxic potential of PMN
oxidants, PMN degranulation also releases several proteolytic enzymes
into the extracellular milieu.8 16 The serine
proteinase
elastase has been implicated most consistently in PMN-mediated tissue
damage.8 51 Several PMN-derived proteinases
(including
elastase) are highly positively charged, and their cationic nature may
contribute to tissue damage by direct alterations in target cell
surface charge or by enhancing binding to cell membranes and
extracellular matrix components.16 Elastase can hydrolyze
a host of proteins in the extracellular matrix (eg, elastin,
fibronectin, and collagen types III and IV) and plasma (eg, complement
proteins and clotting factors),51 52 and although
they are
generally resistant to proteinases, most tissue collagens are readily
cleaved by PMN collagenase (albeit with different substrate specificity
for individual collagen types).53 In addition, elastase
may inhibit platelet function by proteolysis of platelet membrane
glycoproteins.54 A synergism is thought to exist between
PMN elastase and PMN-generated OFRs in vivo, since PMN oxidants (ie,
hypochlorous acid) can inactivate the powerful antiproteinases
present in plasma and extracellular fluid (eg,
1-proteinase
inhibitor).8 16 55
Furthermore, PMN-generated OFRs can promote activation of latent
metalloproteinases (eg, collagenase and gelatinase) released by
PMNs.8 53
In cultured endothelial cells, elastase can enhance cell detachment and destruction of monolayer integrity without evidence of cytolysis,56 57 58 and postischemic migration of PMNs through the vascular endothelium may be dependent on elastase.59 Evidence also indicates that PMN-mediated damage to cultured endothelium is dependent on a synergistic interaction of proteases and OFRs,25 60 and elastase plays a role in PMN-dependent increased anoxia-reoxygenation injury in cultured endothelial cells57 or cardiac myocytes.26 27 Cleavage of interstitial matrix molecules by collagenase and elastase may generate peptide fragments that are chemotactic for monocytes,61 62 and it is possible that this mechanism can promote recruitment of monocytes to the postischemic myocardial inflammatory zone.
Arachidonic Acid Metabolites and PAF
In addition to OFRs and
proteinases, activated PMNs release
several other proinflammatory mediators with a wide range of biological
activities. Stimulation of phospholipase A2 after PMN
activation mobilizes membrane lipids and results in generation of
5-lipoxygenase products (eg, leukotriene B463 )
and the phospholipid PAF.64 Arachidonic acid metabolism
may proceed through differing pathways in PMNs from different
species,65 and cyclooxygenase (present in small
amounts in human PMNs) may convert arachidonic acid to cyclic
endoperoxides, for example, thromboxane A2.66
Furthermore, activated PMNs can release phospholipase A2
into the external environment,67 thereby enhancing
production of eicosanoids and PAF by other cells, and PMNs can transfer
eicosanoids for processing in endothelial cells68 and
platelets.69 Thromboxane-B2 concentration in
cardiac lymph is elevated after reperfusion subsequent to 1 hour of
myocardial ischemia,70 and enhanced PMN-dependent
myocardial generation of eicosanoid metabolites (eg, leukotriene
B4 and thromboxane B2) has been demonstrated ex
vivo after experimental myocardial infarction.71 In
addition, leukotrienes72 and PAF73 can be
generated in buffer-perfused hearts after ischemia and reperfusion, and
cultured human endothelial cells produce PAF upon stimulation with
inflammatory cytokines (eg, TNF),74 hydrogen
peroxide,75 or thrombin.76 Interestingly,
endothelial PAF synthesis is also increased by plasmin, streptokinase,
or recombinant tissue-plasminogen activator
(rTPA).77 78
Leukotriene B4 and PAF are potent stimulants of PMN chemotaxis, adhesion to endothelial cells, and oxydative metabolism and degranulation79 80 and may serve to amplify PMN-mediated tissue injury and vascular permeability.81 Leukotrienes C4, D4, and E4 and thromboxane A2 and PAF can cause coronary vasoconstriction and depression of left ventricular function.82 83 In addition to stimulation of PMNs, PAF produces aggregation and degranulation of platelets, and the decrease in coronary flow and cardiac function by PAF is likely to be dependent on platelet products.73
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PMN Adhesion and Migration |
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TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
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Cellular Adhesion Molecules
Extravasation of PMNs in postcapillary venules is mediated by at least three sequential steps: (1) initial rolling of PMNs along the endothelium; (2) PMN activation, strengthening of PMN adhesion, and cessation of rolling; and (3) transendothelial migration (Fig 2
).84 85 86 PMN rolling is
mediated by the
selectin family of adhesion molecules: E-selectin, L-selectin, and
P-selectin.87 Selectins bind to sialylated carbohydrate
determinants related to sialyl Lewisx and sialyl
Lewisa, although the exact identities of specific
ligands of individual selectins have not been completely
defined.87 88 L-selectin is constitutively expressed
on
the surface of PMNs but is rapidly shed after PMN
activation.89 E-selectin is expressed on endothelial cells
after stimulation by inflammatory cytokines (eg, TNF).90
P-selectin is stored in platelets and Weibel-Palade bodies of
endothelial cells and is rapidly mobilized to the endothelial cell
surface in response to various inflammatory stimuli, eg, thrombin,
histamine, and OFRs.91 92 A rapid but transient
translocation of P-selectin to the endothelial cell membrane in the
myocardial microvasculature is also observed after myocardial ischemia
and reperfusion.93 In this manner, selectins initiate
rolling and tethering of circulating PMNs to the endothelial
surface and facilitate exposure to various PMN activators (eg,
PAF75 76 91 94 95
and IL-896 97 ). At
physiological flow rates, these events promote PMN recruitment by the
local microenvironment and provide the basis of activation-induced
adhesion strengthening through ß2
integrins.84 85 86 98 99 100
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Firm attachment of PMNs to the endothelial cell and direction of PMN
transendothelial migration are mediated by PMN ß2 integrins. These
phylogenetically ancient surface-associated heterodimeric glycoproteins
possess a common ß2 chain (CD18) and one of three separate chains
(CD11a, CD11b, or CD11c).101 PMNs constitutively express
ß2 integrins, and chemotactic stimulation results in a rapid but
transient upregulation of CD11b/CD18, which is a prerequisite for firm
PMN attachment to the endothelium and subsequent
diapedesis.15 84 85 86
Integrins bind to endothelial cell
immunoglobulin-like counterreceptors, namely, intercellular adhesion
molecule 1 (ICAM-1), which constitutes the principal ligand for PMN
CD11b/CD18 (Mac-1 or Mo1).102 CD11b/CD18 is also the
receptor for C3bi (CR3), one of the breakdown components of the third
component of complement C3.101 ICAM-1 is upregulated by
cytokine stimulation,103 and the increased PMN adherence
to endothelial cells after endothelial exposure to OFRs104
or anoxia-reoxygenation105 is dependent on ICAM-1. In
addition, interaction of CD11b/CD18 with biological surfaces mediates
the massive and prolonged OFR production by adherent PMNs in response
to physiological concentrations of chemotactic ligands, which are very
weak agonists when tested with PMNs in
suspension.43 44 106 107
Interestingly, soluble isoforms
of cell adhesion molecules (eg, ICAM-1, L-selectin, and E-selectin)
have been detected in blood and tissue fluids, and by retaining
biological activity, these molecules may potentially modulate
inflammatory reactions.108 109
Cardiac Myocyte Expression of ICAM-1: A Possible Controller of
PMN-Dependent Injury
Isolated adult cardiac myocytes express ICAM-1
after
stimulation with cytokines110 or postischemic cardiac
lymph,111 and adhesion of PMNs to these cells is dependent
on ICAM-1 and CD11b/CD18.106 110 111
Adherence of PMNs to
cytokine-stimulated cardiac myocytes activates the respiratory burst,
resulting in highly compartmentalized oxidative myocyte
injury,112 and in anoxia-reoxygenated isolated myocytes,
PMN-mediated augmentation of cellular damage also appears to
be dependent on ICAM-1.27 ICAM-1–dependent PMN
adherence may therefore be an obligatory step for direct target cell
damage by PMNs, possibly by mediating the adherence-dependent
potentiation of PMN OFR
production.44 106 107 112 In
addition to these in vitro data, induction of ICAM-1 mRNA has recently
been found in the postischemic heart during early
reperfusion,113 and rapid reperfusion-induced expression
of ICAM-1 mRNA in the border zone of viable myocytes surrounding
necrotic myocardial regions (in association with intense PMN
infiltration) strongly indicates that inflammatory tissue injury by
these mechanisms plays an important role in myocardial reperfusion
injury in vivo.114
Autocrine Effects of NO
Diminished basal NO release from
coronary endothelial cells after
myocardial ischemia and reperfusion promotes adherence of PMNs in vitro
through a CD11b/CD18-dependent mechanism.115 In addition,
in the feline mesenterial preparation, ischemia-reperfusion and
pharmacological NO synthesis inhibition increase PMN adherence and
microvascular albumin leakage, respectively, by mechanisms dependent on
ICAM-1 and CD11b/CD18.116 117 NO may also attenuate
thrombin-induced PAF synthesis in endothelial cells,118
and recent data have suggested that inhibition of NO synthesis in
cultured endothelial cells increases intracellular oxidative stress and
is associated with ICAM-1–mediated PMN adherence.119 It
is therefore conceivable that NO from endothelial cells may act in an
autocrine fashion to regulate various endothelial cell adhesive
mechanisms. Constitutive120 and
cytokine-inducible121 NO synthases are present in
cardiac myocytes, and it is tempting to speculate that NO can also
regulate expression of adhesion molecules in these cells.
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Myocardial PMN Accumulation |
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TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
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In experimental models, PMN accumulation is accelerated by reperfusion,122 123 and in dogs, the greatest rate of PMN localization after 1 hour of myocardial ischemia is observed in the first hour of reperfusion.124 During reperfusion after sustained myocardial ischemia, PMN accumulation occurs preferentially in the subendocardial region124 125 and may correlate with infarct size.126 Interestingly, reperfusion after brief (eg, 12-minute) periods of myocardial ischemia apparently is not associated with PMN accumulation.125 PMNs migrate into the walls of epicardial coronary arteries,127 and evidence suggests that the presence of an experimental coronary stenosis (ie, with elimination of the reactive hyperemic response) does not significantly inhibit PMN accumulation during early reperfusion.128
Microvascular PMN Plugging
PMNs are larger and much stiffer
than erythrocytes, and the
cytoskeletal assembly after PMN activation is associated with
additional decreases in cellular deformability.129 These
hemorheological properties can promote physical trapping of PMNs in
myocardial capillaries after ischemia and reperfusion, and thus PMNs
may contribute to the no-reflow phenomenon.123 130 In
addition, regional plugging of the myocardial microvasculature by PMNs
is likely to be enhanced by various other postischemic microvascular
alterations, eg, PMN aggregation, reduced myocardial perfusion
pressure, and upregulation of PMN–endothelial cell adhesive activities
(eg, in association with reduced endothelial NO
production).10 84 116 131
Complement, Chemokines, and Other Chemotactic Factors
During
myocardial ischemia and reperfusion, the complement cascade
may be activated after complement proteolysis by myocardial
proteases51 132 or by interaction between complement
component C1 and heart mitochondrial membranes released from disrupted
myocytes.133 In addition, PMNs can directly activate
complement by actions of proteases134 or
OFRs.135 Complement fixation has been demonstrated in
ischemic myocardium136 and appears to correlate with the
localization of PMN accumulation.137 Evidence indicates
that experimental myocardial ischemia rapidly induces complement
activation,133 138 139 and ability of
postischemic cardiac
lymph to stimulate isolated PMNs is neutralized by anti-C5a
antiserum.138 139
The role of the complement system in myocardial ischemia and reperfusion has recently been reviewed.140 C5a is a strong PMN chemoattractant, and generation of C3bi on the endothelial cell surface in vitro elicits rapid CD11b/CD18-dependent PMN adhesion.141 In pigs, intracoronary administration of C5a reduces coronary blood flow and myocardial contractile function by mechanisms dependent on myocardial PMN accumulation and production of thromboxane A2 and leukotrienes.142 The canine coronary vasculature may be less responsive to thromboxanes, and C5a appears to dilate canine coronary arteries in vivo and in vitro.143 In addition to recruitment and activation of PMNs within the ischemia-reperfused myocardium, complement-derived products can directly contribute to myocardial injury by PMN-independent mechanisms. C3a can decrease left ventricular contraction and coronary flow in isolated guinea pig hearts,144 and similar alterations, myocardial edema, and release of creatine kinase, have been observed in isolated rabbit hearts perfused with human plasma (a situation eliciting complement activation).145 In a recent study, reperfusion with PMNs and plasma or PMNs and C5a reduced ventricular function and coronary flow after global ischemia in an isolated rat heart model, whereas reperfusion with only plasma, PMNs, complement-activated plasma, or C5a failed to induce significant alterations.146 In addition, electron paramagnetic resonance spectroscopy measurements indicated that reperfusion with PMNs and plasma resulted in marked prolongation in the duration of OFR generation.146
Although the
complement system is believed to be one of the most
important sources of inflammatory mediators after myocardial ischemia
and reperfusion, a novel superfamily of low-molecular-weight
chemotactic cytokines known as chemokines has recently been defined;
chemokines are secreted by several types of cells in response to
inflammatory stimuli in vitro.147 148 Chemokines are
subdivided into and ß subfamilies on the basis of the presence or
absence of an intervening amino acid between the first two of four
conserved cysteines, and the two subfamilies differ in their target
cell selectivity, ie, or C-X-C chemokines primarily stimulate PMNs,
whereas ß or C-C chemokines predominantly act on monocytes,
basophils, eosinophils, and T
cells.147 148 149 Specifically,
IL-8 synthesized by endothelial cells after stimulation with TNF or
IL-1 is a strong PMN chemoattractant.150 Chemokines
possess proteoglycan-binding sites, and IL-8 can induce
transendothelial PMN migration, rapid shedding of L-selectin, and
upregulation of PMN integrins, possibly by generation of a chemotactic
gradient of immobilized matrix-associated IL-8.96 97
Various other PMN chemotactic agents are released from the postischemic
myocardium, eg, leukotrienes71 72 and
PAF,73
and PMN chemoattraction and activation after myocardial ischemia and
reperfusion are therefore likely to be the result of amplification by
numerous interacting proinflammatory mechanisms, with several of the
involved mediators playing the role of initiator and
product.15
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Cardioprotection by PMN Inhibition In Vivo |
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TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
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The cardioprotective potential of PMN inhibition in intact animals subjected to myocardial ischemia and reperfusion has been widely used to indirectly assess the role of PMNs. Several methodological considerations are relevant to these experimental models and may contribute to conflicting results, eg, the selection of animal species, duration of myocardial ischemia and reperfusion, presence of a critical coronary stenosis during reperfusion, characteristics of the intervention (eg, time of administration, duration, and dosage), and control of independent predictors of myocardial infarct size (ie, myocardial area at risk, collateral blood flow, and oxygen demand). In addition, few if any interventions are exclusively specific for the anticipated mechanism during the highly complex myocardial and systemic reactions after myocardial ischemia and reperfusion. The favorable effects on myocardial reperfusion injury of "anti-PMN interventions" discussed below (Table
) are therefore
likely to result, in part, from a combination of direct and indirect
effects on PMNs. However, even in the face of these methodological
problems, most evidence showing a favorable effect of PMN inhibition on
myocardial reperfusion injury raises hope for future clinical
application.
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Antioxidants
OFRs have been implicated in all manifestations
of myocardial
reperfusion injury. The available evidence indicates that antioxidants
can ameliorate myocardial stunning and reperfusion arrhythmias, whereas
the capacity for antioxidants to improve coronary vascular and
microvascular reperfusion injury is less substantiated, and the ability
of antioxidants to reduce reperfusion-induced acceleration or
precipitation of myocyte death is even more
controversial.6 151 In addition to PMNs, a host of
potential sources of OFRs has been suggested during myocardial ischemia
and reperfusion (eg, the xanthine oxidase pathway, arachidonate
metabolism, and "leaky" mitochondria).152 Although
cardioprotective effects have been demonstrated in studies with
antioxidant inhibitors of PMN oxidative
metabolism,153 154 155
these agents are not specific for PMN-derived OFRs, and the precise
role of these species per se in myocardial reperfusion injury has not
been clearly defined.
PMN Depletion
Experimental PMN depletion has been achieved by
several methods,
eg, chemotherapy,71 156 157
administration of PMN
antibodies,122 158 159 160 161 162 163
or coronary perfusion through
leukocyte-depleting
filters.157 164 165 166 167
These methods have
limitations: they may depress other blood cell lines in addition to
PMNs; PMN antiserum may activate complement and cause alterations of
the immunological network, which can potentially influence reperfusion
injury; and leukocyte filters require complex instrumentation, activate
complement, release adenosine and other mediators from blood cells, and
imply a nonphysiological (roller-pump) coronary perfusion
pattern.157 165 168 From these studies,
however, there is
now a general agreement that PMNs do not play a role in myocardial
stunning after brief ischemic periods.157 168 Some
reports, although they are not unchallenged, have indicated that PMN
depletion can decrease reperfusion
arrhythmias,161 166
ameliorate postischemic no-reflow,164 165 and reduce
the
increase in microvascular permeability163 167 after
myocardial ischemia and reperfusion of medium duration (ie, <3 hours)
in the dog model. With regard to the contribution of PMNs to lethal
myocardial injury, results from studies that use PMN depletion are
controversial. Some reports have indicated that PMN depletion reduces
myocardial infarct size when administered
before158 160 161 162 or at
the time165 of
reperfusion. However, negative results have been
obtained,122 and evidence suggests that PMN depletion does
not reduce infarct size after prolonged coronary occlusion periods (ie,
>3 hours in dogs).159 Furthermore, a recent study in a
rat model demonstrated that initial benefits in myocardial contractile
function by PMN depletion may be lost after prolonged reperfusion, and
in this model, mechanical recovery required a minimal period of 10
minutes of PMN-depleted reperfusion.156 The protection
offered by PMN depletion (or any other anti-PMN intervention) may
therefore not be sustained, and studies with long-term follow-up
periods are warranted.162
Inhibition of Intercellular Adhesion
Administration of a
monoclonal antibody (MAb 904) to CD11b/CD18
before reperfusion may induce sustained reduction in myocardial infarct
size and PMN accumulation in the dog model.169 Similar
beneficial effects have been observed in cats subjected to myocardial
ischemia and reperfusion by treatment with monoclonal antibodies to the
common ß2 chain (CD18) of PMN integrins (MAb
R15.7),170 L-selectin,171
ICAM-1,172 or P-selectin,93 and in these
studies, depressed endothelium-dependent vasorelaxant
responses in ischemic-reperfused epicardial coronary arteries were
improved by antibody treatment. In addition, amelioration of
PMN-mediated reductions in contractile function and coronary flow has
been demonstrated by MAb R15.7 in an isolated rat heart
model173 and in isolated neonatal lamb hearts subjected to
hypothermic global ischemia followed by reperfusion.174
Another monoclonal antibody to CD18 (MAb IB4) failed to reduce
myocardial infarct size in dogs.175 Soluble ligands to
adhesion molecules (or soluble adhesion molecules per se) may also have
the potential to attenuate postischemic PMN-endothelial interactions.
Indeed, a sialyl Lewisx–containing oligosaccharide was
recently shown to attenuate myocardial injury and preserve global
cardiac performance after myocardial ischemia and reperfusion in a
feline model.176 Furthermore, inhibition of
PMN-endothelial interactions can contribute to the reduction of
myocardial reperfusion damage observed with transforming growth
factor-ß177 178 and osteogenic protein
1,179 respectively. Interestingly, a member of the new
group of anti-inflammatory agents ("leumedins"), which inhibit
PMN upregulation of CD11b/CD18, was recently shown to decrease
myocardial PMN accumulation, protect against mechanical dysfunction,
and attenuate the increase in myocardial vascular resistance after
reperfusion of in situ neonatal piglet hearts subjected to hypothermic
global ischemia.180
Inhibition of Complement Activation
Complement depletion by
administration of cobra venom factor
(which activates the alternative pathway) can reduce myocardial
complement localization, PMN accumulation, and tissue necrosis in
models of myocardial infarction that use permanent coronary
occlusion.132 136 181 182
Recently, a recombinant soluble
complement receptor type 1 has been synthesized, which, in nanomolar
concentrations, blocks complement activation in human
serum.183 This agent induced sustained reductions in
myocardial infarct size in rats183 and reduced
PMN-dependent contractile dysfunction and OFR generation in isolated
rat hearts subjected to global ischemia followed by
reperfusion.184
Inhibition of Arachidonic Acid Metabolism or PAF
Lipoxygenase
inhibitors (many of which are potent
antioxidants185 ) may inhibit PMN function in vitro and
reduce myocardial infarct size and PMN accumulation in experimental
models of myocardial infarction,186 187 and the
5-lipoxygenase inhibitor 5-aminosalicylic acid can attenuate myocardial
microvascular damage after a reversible ischemic
episode.155 Furthermore, BW755C, a mixed
cyclooxygenase-lipoxygenase inhibitor, may exert cardioprotective
effects.188 189 Coincident reduction in myocardial
PMN
accumulation by BW755C has been suggested,71 190
although
treatment with this agent in a recent study reduced myocardial infarct
size without significantly attenuating myocardial PMN accumulation, as
indicated by tissue myeloperoxidase activity.189 In
agreement with this finding, in vitro experiments showed that BW755C
inhibited PMN oxidative metabolism, degranulation, and leukotriene
B4 production, but had only a minimal influence on PMN
chemotaxis.189
The effect of cyclooxygenase inhibitors in experimental models of myocardial infarction is unclear. Ibuprofen can reduce myocardial infarct size and PMN accumulation,191 but treatment with other cyclooxygenase inhibitors has not shown beneficial effects,192 193 although some of these agents may inhibit PMN function in vitro.194 One explanation is simultaneous inhibition of vascular endothelial cell synthesis of prostaglandin I2 (which may be a cardioprotective agent195 ), since selective thromboxane A2 synthetase inhibitors appear to attenuate PMN function and reduce myocardial infarct size and PMN accumulation.196 197 Furthermore, prostacyclin, stable prostacyclin analogues (eg, iloprost or taprostene), and prostaglandin E1 can inhibit PMN function and exert cardioprotective effects.162 198 199 200 201 A therapeutic time window has been indicated for iloprost, and treatment with this agent for up to 48 hours after reperfusion may be required to achieve sustained limitation of myocardial infarct size.162
Recent evidence has demonstrated that PAF antagonists can reduce myocardial necrosis and other manifestations of myocardial injury after ischemia and reperfusion,202 203 whereas these agents do not appear to attenuate myocardial stunning after brief periods of coronary occlusion.202
Inhibition of Proteases
In rats subjected to permanent
coronary occlusion, myocardial
proteolysis is apparently primarily mediated by cathepsins and
calcium-activated neutral proteases (enzymes present in PMNs and
other cells), but proteolysis is not significantly increased during the
first 24 hours of occlusion.204 In this model, myocardial
infarct size was not reduced by a combination of protease inhibitors
that almost completely suppressed proteolysis.205
Preliminary results have indicated that administration of a PMN
elastase inhibitor as an adjunct to rTPA can reduce PMN infiltration
and tissue necrosis in a canine model of coronary
thrombolysis,206 but the potential for protease inhibitors
to inhibit myocardial injury after ischemia and reperfusion is
otherwise unknown.
Enhancement of Endogenous NO Availability
Administration of
NO donors207 208 209 or
L-arginine210 211 was recently shown to
reduce tissue damage and PMN accumulation after experimental myocardial
ischemia and reperfusion. One mechanism of this protection is the
preservation of postischemic coronary endothelial production of NO, and
this effect is likely to attenuate PMN-endothelial interactions.
Perfluorochemicals
Perfluorocarbons have a high
oxygen-carrying capacity, low
viscosity, and small particle size, and these substances (ie, Fluosol)
can inhibit PMN adherence to anoxic endothelial cells212
and influence other PMN effector functions.212 213 In
the
canine model, Fluosol has been shown to inhibit myocardial PMN
accumulation and manifestations of myocardial reperfusion
injury.213 214 215
Adenosine
In addition to its well-known cardiovascular
effects,216 adenosine is a strong inhibitor of PMN
respiratory burst217 and prevents PMN adherence and
cytotoxicity to endothelial cells in vitro.218 Myocardial
adenosine release increases in response to ischemia,216
and adenosine thus may act as an endogenous modulator of the
inflammatory process.219 In agreement with this
hypothesis, administration of adenosine can reduce myocardial infarct
size, postischemic PMN accumulation, coronary endothelial damage, and
contractile dysfunction,220 221 and AICA-riboside, an
agent that increases adenosine release from energy-deprived cells, may
decrease PMN accumulation and increase collateral blood flow to
ischemic myocardium.222 223
Pentoxifylline
Pentoxifylline, a methylxanthine used in the
treatment of
peripheral occlusive disease, inhibits PMN activation (eg, superoxide
anion production and cytoskeletal polymerization) in
vitro224 225 226 and reduces
PMN-dependent vascular injury in
experimental models of sepsis.227 228 PMN inhibition
by
pentoxifylline may be mediated by phosphodiesterase inhibition with
increased intracellular levels of cAMP,229 and,
interestingly, pentoxifylline and adenosine synergistically decrease
PMN superoxide anion production.230 Recent evidence has
indicated that pentoxifylline can decrease myocardial PMN accumulation
and coronary endothelial injury after experimental ischemia and
reperfusion.231
|
Epidemiological and Clinical Evidence |
|---|
|
TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
|---|
Despite the vast body of experimental evidence suggesting a role for PMNs in myocardial ischemia and reperfusion, limited clinical data are available. This discrepancy is readily explained by the relative easiness to define and manipulate experimental systems as opposed to the complexity of the clinical situation. However, the association between the white blood cell count (which is mainly represented by PMNs) and the risk of AMI was recognized two decades ago, and with the advent of thrombolytic therapy, coronary bypass surgery, coronary angioplasty, and cardiac allograft transplantation, the evolving experimental concept of myocardial reperfusion injury has formed the background for a growing number of studies examining the role of PMNs in patients with ischemic heart disease.
PMNs as a Risk Factor for Ischemic Heart Disease
Epidemiological studies have demonstrated the total white blood
cell count to be an independent risk factor for ischemic heart
disease.232 233 234 235
Furthermore, the leukocyte count may be
positively correlated to the extent of coronary artery
disease236 and risk of coronary recurrence after
myocardial infarction.237 Clearly, this does not establish
a cause-effect relation, and in some studies, the association has not
been significant in smokers.234 236 Smoking is known
to
increase the leukocyte count and prime PMNs for enhanced oxidative
metabolism.238 With regard to the correlation between PMNs
and other risk factors for ischemic heart disease, it is notable that
unstimulated PMNs from patients with insulin-dependent diabetes
mellitus may demonstrate elevated superoxide
production,239 whereas abnormalities in the regulation of
PMN superoxide formation in hypertensive patients are not
apparent.240
Chemoattractants and PMN Activation in Ischemic Heart Disease
In patients with AMI, the white blood cell count increases within
a few hours after the onset of chest pain, peaks 2 to 4 days after
infarction, and returns to normal in 1 week.241 Treatment
with streptokinase in patients with AMI was recently shown to be
associated with abrupt complement activation and a transient decrease
in the white blood cell count followed by a rebound increase in the
number of circulating cells.242 After a permanent coronary
occlusion, PMNs accumulate in infarcted human myocardium within 24
hours; their presence reaches a peak within 24 hours and diminishes
after 1 week.1 Myocardial PMN accumulation in patients
with AMI has been observed in vivo by uptake of
111In-labeled PMNs,243 and these studies have
indicated decreased PMN accumulation in patients receiving
thrombolysis.244
Products of complement activation may be demonstrated in plasma from nonthrombolyzed patients with AMI245 246 (although this observation was recently challenged242 ), and immunocytochemical studies have shown deposition of the terminal C5b-9 complement complex in infarcted human myocardium.247 Marked complement activation has been observed in patients with AMI after administration of streptokinase242 or rTPA,248 and in vitro experiments have demonstrated that addition of streptokinase to human plasma may result in generation of chemotactic activity and activity capable of priming PMNs for enhanced OFR generation.249 A recent report has also indicated that treatment with streptokinase stimulates the release of PAF into the circulation in patients with AMI,77 and this may be the mechanism underlying the systemic hypotension and platelet activation induced by streptokinase.78 250 Furthermore, increased urinary excretion of leukotriene E4 (the major urinary metabolite of peptide leukotrienes in humans) has been demonstrated in patients with AMI,251 and elevated plasma levels of TNF252 and IL-6253 in these patients can contribute to PMN-mediated myocardial damage.
Increased chemotactic activity and increased capacity for leukotriene B4 generation have been observed in peripheral PMNs from patients with stable angina pectoris, and it is possible that the decrease in these parameters in patients with unstable angina pectoris or AMI indicates PMN exhaustion after previous in vivo activation.254 Peripheral venous blood PMNs from patients with AMI demonstrate increased aggregability,254 255 and increased aggregability of PMNs from the coronary sinus compared with the aorta has been reported in patients with angina pectoris.256 In these patients, a decreased capacity to release leukotriene C4 in PMNs from the aorta compared with PMNs from the coronary sinus was also apparent, suggesting cellular leukotriene C4 release during passage of the diseased coronary tree.257 Plasma elastase and Bß 30-43 fibrin(ogen)-derived peptide (derived from fibrin that has been broken down specifically by elastase) are increased in patients with unstable angina and AMI.244 258 259 260 Furthermore, evidence indicates that PMN activation is induced by thrombolytic treatment, and in patients with AMI, treatment with streptokinase is associated with an abrupt peak in plasma elastase and circulating Bß 30-43 fibrin(ogen)-derived peptide244 260 compared with patients with contraindications to thrombolytic treatment. Thrombolytic agents may promote PMN activation through several mechanisms (eg, enhanced generation of complement fragments242 248 249 and PAF78 ), and this property can potentially modulate their therapeutic effect. A PMN activation-exhaustion sequence of events may also be initiated by myocardial ischemia and reperfusion per se, since plasma elastase levels increase after coronary angioplasty, and subsequent transcardiac PMN activation is indicated by a decreased capacity for elastase release and superoxide production in coronary sinus PMNs as compared to PMNs from the aorta.261
Cardiopulmonary Bypass: Activation of Complement and PMNs
Cardiopulmonary bypass elicits complement
activation,262 263 264 265
OFR generation,263 266
sequestration of PMNs in the pulmonary circulation,265 and
a transient decrease (followed by a rebound increase) in the
peripheral-blood PMN counts.264 267 These effects may
be
related to the presence of endotoxin (a well-known activator of the
complement system) in the blood of patients after cardiopulmonary
bypass.268 269 270 Furthermore,
cardiopulmonary bypass is
associated with increased plasma concentrations of PMN granule
constituents (eg, elastase)264 267 and priming of
circulating PMNs for increased OFR production.266 270
Activation of PMNs and enhanced release of OFRs may therefore
contribute to the postoperative cardiac dysfunction, which still plays
an important role in patients undergoing cardiac surgery.
Clinical Effects of PMN Inhibition in Myocardial Ischemia and
Reperfusion
The capacity for inhibitors of PMN function to ameliorate
myocardial damage after ischemia and reperfusion in the clinical
setting has not been explored in detail. Intracoronary infusion of a
perfluorochemical emulsion (Fluosol) may reduce regional ventricular
dysfunction and tissue necrosis in patients with AMI undergoing
emergency coronary angioplasty.271 In contrast, recent
evidence indicates that intravenous superoxide dismutase does not
ameliorate global or regional left ventricular function in these
patients.272 During cardiopulmonary bypass, the iron
chelator deferoxamine may counteract PMN priming273 and
the calcium antagonist nifedipine can decrease PMN
degranulation.264 Several drugs used in the treatment of
patients with myocardial ischemia (eg, calcium
antagonists,274 lidocaine,275
heparin,276 and captopril277 ) inhibit PMN
function in addition to their other pharmacological effects, but the
contribution of PMN inhibition to the overall efficacy of these agents
is unknown.
|
Conclusions |
|---|
|
TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
|---|
The acute-phase response elicited in vivo by tissue injury is characterized by a pathophysiological cascade of proinflammatory reactions, eg, cytokine production, fever, complement activation, leukocytosis, acute-phase protein synthesis, and tissue PMN infiltration. Although in patients with AMI, early reperfusion enhances structural and functional recovery of the myocardium and improves survival, accumulating experimental evidence has indicated that myocardial reperfusion can promote potentially cardiotoxic inflammatory reactions. PMNs are among the cellular mediators implicated in myocardial reperfusion injury, primarily since PMNs may be an important biological source of OFRs. This hypothesis fits well with the other evolving concepts of myocardial reperfusion damage, and it is strengthened by observations that PMNs accumulate in ischemic-reperfused myocardium and can have cardiotoxic effects in vitro and in vivo and that inhibition of PMNs can reduce myocardial damage after experimental ischemia and reperfusion. Further work is required to define the precise role of PMNs and their relative importance in the pathophysiological processes occuring at various times during myocardial ischemia and reperfusion. These studies should provide a rationale for designing clinically applicable interventions directed at inhibiting PMN-mediated myocardial damage.
|
Acknowledgments |
|---|
This work was supported in part by the Alfred Benzon Foundation, the Danish Heart Foundation, and the Novo Foundation.
Received August 22, 1994; accepted October 26, 1994.
|
References |
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TopAbstractIntroductionCardiotoxic Potential of PMNs...PMN Adhesion and Migration...Myocardial PMN Accumulation Cardioprotection by PMN...Epidemiological and Clinical...Conclusions References |
|---|
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Y. Ikeda, L. H Young, R. Scalia, C. R Ross, and A. M Lefer PR-39, a proline/arginine-rich antimicrobial peptide, exerts cardioprotective effects in myocardial ischemia-reperfusion Cardiovasc Res, January 1, 2001; 49(1): 69 - 77. [Abstract] [Full Text] [PDF]
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M. R. Hoffmeyer, R. Scalia, C. R. Ross, S. P. Jones, and D. J. Lefer PR-39, a potent neutrophil inhibitor, attenuates myocardial ischemia-reperfusion injury in mice Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2824 - H2828. [Abstract] [Full Text] [PDF]
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A. Rahman, B. Ustunda, O. Burma, I. H. Ozercan, A. Cekirdekci, and M. K. Bayar Does aprotinin reduce lung reperfusion damage after cardiopulmonary bypass? Eur. J. Cardiothorac. Surg., November 1, 2000; 18(5): 583 - 588. [Abstract] [Full Text] [PDF]
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L. H. Young, Y. Ikeda, R. Scalia, and A. M. Lefer Wortmannin, a Potent Antineutrophil Agent, Exerts Cardioprotective Effects in Myocardial Ischemia/Reperfusion J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 37 - 43. [Abstract] [Full Text]
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Y. Okazaki, Z.-L. Cao, S. Ohtsubo, M. Hamada, K. Naito, K. Rikitake, M. Natsuaki, and T. Itoh Leukocyte-depleted reperfusion after long cardioplegic arrest attenuates ischemia-reperfusion injury of the coronary endothelium and myocardium in rabbit hearts Eur. J. Cardiothorac. Surg., July 1, 2000; 18(1): 90 - 97. [Abstract] [Full Text] [PDF]
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A. Szekely, B. Heindl, S. Zahler, P. F. Conzen, and B. F. Becker Nonuniform Behavior of Intravenous Anesthetics on Postischemic Adhesion of Neutrophils in the Guinea Pig Heart Anesth. Analg., June 1, 2000; 90(6): 1293 - 1300. [Abstract] [Full Text] [PDF]
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Z.-L. Cao, Y. Okazaki, K. Naito, T. Ueno, M. Natsuaki, and T. Itoh Ulinastatin attenuates reperfusion injury in the isolated blood-perfused rabbit heart Ann. Thorac. Surg., April 1, 2000; 69(4): 1121 - 1126. [Abstract] [Full Text] [PDF]
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A. Buffon, S. A. Santini, V. Ramazzotti, S. Rigattieri, G. Liuzzo, L. M. Biasucci, F. Crea, B. Giardina, and A. Maseri Large, sustained cardiac lipid peroxidation and reduced antioxidant capacity in the coronary circulation after brief episodes of myocardial ischemia J. Am. Coll. Cardiol., March 1, 2000; 35(3): 633 - 639. [Abstract] [Full Text] [PDF]
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G. Liuzzo, L. M. Biasucci, J. R. Gallimore, G. Caligiuri, A. Buffon, A. G. Rebuzzi, M. B. Pepys, and A. Maseri Enhanced inflammatory response in patients with preinfarction unstable angina J. Am. Coll. Cardiol., November 15, 1999; 34(6): 1696 - 1703. [Abstract] [Full Text] [PDF]
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J. K. Kirklin and D. C. McGiffin Control of the inflammatory response in extended myocardial preservation of the donor heart Ann. Thorac. Surg., November 1, 1999; 68(5): 1978 - 1982. [Abstract] [Full Text] [PDF]
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P G Browning, M Pullan, M Jackson, and A Rashid Leucocyte-depleted cardioplegia does not reduce reperfusion injury in hypothermic coronary artery bypass surgery Perfusion, September 1, 1999; 14(5): 371 - 377. [Abstract] [PDF]
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S. M. Wildhirt, S. Weismueller, C. Schulze, N. Conrad, A. Kornberg, and B. Reichart Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury Cardiovasc Res, August 15, 1999; 43(3): 698 - 711. [Abstract] [Full Text] [PDF]
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A. E. Vento, J. Aittomaki, K. A. Verkkala, L. J. Heikkila, J. A. Salo, J. Sipponen, and O. J. Ramo Nitecapone as an additive to crystalloid cardioplegia in patients who had coronary artery bypass grafting Ann. Thorac. Surg., August 1, 1999; 68(2): 413 - 420. [Abstract] [Full Text] [PDF]
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S. P. Jones, W. G. Girod, D. N. Granger, A. J. Palazzo, and D. J. Lefer Reperfusion injury is not affected by blockade of P-selectin in the diabetic mouse heart Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H763 - H769. [Abstract] [Full Text] [PDF]
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L. C. Becker, R. W. Jeremy, J. Schaper, and W. Schaper Ultrastructural assessment of myocardial necrosis occurring during ischemia and 3-h reperfusion in the dog Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H243 - H252. [Abstract] [Full Text] [PDF]
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I. Tritto and G. Ambrosio Spotlight on microcirculation: an update Cardiovasc Res, June 1, 1999; 42(3): 600 - 606. [Full Text] [PDF]
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S. Zahler, P. Massoudy, H. Hartl, C. Hahnel, H. Meisner, and B. F Becker Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass Cardiovasc Res, March 1, 1999; 41(3): 722 - 730. [Abstract] [Full Text] [PDF]
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T. Takeuchi, T. Ueki, H. Nishimatsu, T. Kajiwara, T. Ishida, K.-i. Jishage, O. Ueda, H. Suzuki, B. Li, N. Moriyama, et al. Accelerated Rejection of FAS Ligand-Expressing Heart Grafts J. Immunol., January 1, 1999; 162(1): 518 - 522. [Abstract] [Full Text] [PDF]
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G.-L. Liu, T. A. Christopher, B. L. Lopez, F. Gao, Y. Guo, E. Gao, K. Knuettel, M. Feelisch, and X. L. Ma SP/W-5186, A Cysteine-Containing Nitric Oxide Donor, Attenuates Postischemic Myocardial Injury J. Pharmacol. Exp. Ther., November 1, 1998; 287(2): 527 - 537. [Abstract] [Full Text]
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M. L. Myers, P. Farhangkhoee, and M. Karmazyn Hydrogen peroxide induced impairment of post-ischemic ventricular function is prevented by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide) Cardiovasc Res, November 1, 1998; 40(2): 290 - 296. [Abstract] [Full Text] [PDF]
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P. F. Lennon, C. T. Taylor, G. L. Stahl, and S. P. Colgan Neutrophil-derived 5'-Adenosine Monophosphate Promotes Endothelial Barrier Function via CD73-mediated Conversion to Adenosine and Endothelial A2B Receptor Activation J. Exp. Med., October 19, 1998; 188(8): 1433 - 1443. [Abstract] [Full Text] [PDF]
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N. Aoki and H. Tomoda Plasma Soluble P-Selectin in Acute Myocardial Infarction: Effects of Coronary Recanalization Therapy Angiology, September 1, 1998; 49(9): 807 - 813. [Abstract] [PDF]
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A. T Gonon, Q.-D. Wang, and J. Pernow The endothelin A receptor antagonist LU 135252 protects the myocardium from neutrophil injury during ischaemia/reperfusion Cardiovasc Res, September 1, 1998; 39(3): 674 - 682. [Abstract] [Full Text] [PDF]
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Th. Hauet, G. Bauza, J. M. Goujon, J. C. Caritez, M. Carretier, M. Eugene, and J. P. Tillement Effects of Trimetazidine on Lipid Peroxidation and Phosphorus Metabolites during Cold Storage and Reperfusion of Isolated Perfused Rat Kidneys J. Pharmacol. Exp. Ther., June 1, 1998; 285(3): 1061 - 1067. [Abstract] [Full Text]
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M. Riera, J. Torras, I. Herrero, J. Valles, M. Paubert-Braquet, J. M. Cruzado, J. Alsina, and J. M. Grinyo Neutrophils Accentuate Renal Cold Ischemia-Reperfusion Injury. Dose-Dependent Protective Effect of a Platelet-Activating Factor Receptor Antagonist J. Pharmacol. Exp. Ther., February 1, 1997; 280(2): 786 - 794. [Abstract] [Full Text]
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G. Liuzzo, L. M. Biasucci, A. G. Rebuzzi, J. R. Gallimore, G. Caligiuri, G. A. Lanza, G. Quaranta, C. Monaco, M. B. Pepys, and A. Maseri Plasma Protein Acute-Phase Response in Unstable Angina Is Not Induced by Ischemic Injury Circulation, November 15, 1996; 94(10): 2373 - 2380. [Abstract] [Full Text]
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A. Lopez-Farre, A. Riesco, E. Digiuni, J. R. Mosquera, C. Caramelo, L. S. de Miguel, I. Millas, T. de Frutos, M. R. Cernadas, M. Monton, et al. Aspirin-Stimulated Nitric Oxide Production by Neutrophils After Acute Myocardial Ischemia in Rabbits Circulation, July 1, 1996; 94(1): 83 - 87. [Abstract] [Full Text]
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