© 2000 American Heart Association, Inc.
Editorial |
Platelets
Unindicted Coconspirators in Inflammatory Tissue Injury
From the Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Allan M. Lefer, Department of Physiology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107-6799. E-mail Allan.M.Lefer{at}mail.tju.edu
Key Words: platelets • leukocytes • endothelium • inflammation
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Introduction |
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 Top Introduction References |
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In the 1970s, during the peak of eicosanoid research, platelets were generally considered to play a major role in mediating the cell and tissue injury known to occur in cerebral ischemia/stroke, myocardial ischemia/infarction, and traumatic injury to other organs or regions. Foremost among the platelet-derived humoral mediators of this type of tissue injury were the prostaglandins (eg, PGF2
), the endoperoxides (eg,
PGH2), and thromboxane A2
(TxA2). TxA2 and, to a
lesser extent, PGF2 and
PGH2 are potent vasoconstrictors and thus can
reduce blood flow to vital vascular
beds.1 2 Moreover,
these agents are also prothrombotic by virtue of potently stimulating
platelet
aggregation.1 2
These two effects can, of course, work together to constrict and
obstruct microvessels. In fact, a popular and useful research protocol
of that era was the intravenous injection of arachidonic acid, the
precursor of the eicosanoids, into rabbits, resulting in a severe
pulmonary thrombosis/vasoconstriction and sudden cardiopulmonary
death.3 Because platelets are
the primary source of TxA2, release of
TxA2 aggregates other platelets and stimulates
their release of additional TxA2, thus
propagating this response. Platelets also release serotonin, ADP, and
catecholamines, which are contained within storage granules. These
platelet-propagated processes are all considered to be major factors
contributing to direct ischemic injury as occurs in myocardial and
cerebral ischemia. With the discovery of the mechanism of action of
aspirin,4 5 this
area of pathophysiology was addressed in a very practical way.
Presently, aspirin is widely used in transient ischemic attacks, which
often are precursors of strokes, and in patients experiencing a
myocardial infarction to limit the spread of ischemic injury and thus
prevent a full transmural
infarct.6 Recent analysis of
patients at our university hospital having a myocardial infarct
indicate that 98.5% receive aspirin before discharge. The major effect
of the aspirin is thought to be prevention of platelet-induced
exacerbation of the ischemic processes.
With the advent of thrombolytic agents (eg, streptokinase
and tissue plasminogen activator) and coronary angioplasty, reperfusion
became a common practice, additionally complicating the ischemic
process.7 The late 1980s and
the 1990s were a period of intense investigation into the mechanisms of
reperfusion injury, the component of the ischemic process that
exacerbates ischemic injury and occurs on rapid and abrupt restoration
of blood flow to a previously ischemic vascular bed. Paramount among
the many factors thought to be involved in mediating reperfusion injury
are leukocytes,8 primarily
polymorphonuclear leukocytes. About this time, major discoveries were
made elucidating the role of several families of cell adhesion
molecules located on either the leukocyte or the endothelial cell
surface.9 10 11 12 13
These families of adhesion molecules regulate leukocyte-endothelial
cell interaction in a well-orchestrated sequence. The first phase of
leukocyte-endothelial interaction, which triggers the subsequent
adherence and transmigration, is leukocyte rolling (ie, a slowing of
leukocytes involving a process of surface bonds attached and detached
in a periodic manner), and this allows capture of
leukocytes.13 14
The phenomenon of leukocyte rolling is regulated by the selectin family
of adhesion glycoproteins consisting of P-selectin, E-selectin, and
L-selectin.15 E-selectin is
upregulated on the endothelial cell surface by cytokines, including
tumor necrosis factor- (TNF-) and
interleukin-1ß.11
L-selectin is constitutively expressed on leukocyte surfaces and also
contributes to leukocyte rolling. P-selectin occurs in -granules of
platelets as well as in Weibel-Palade bodies of endothelial
cells10 and can be
translocated to the cell surface of these cells in 10 to 20 minutes by
inflammatory stimuli, including thrombin, histamine, and
peroxides.14 Moreover,
P-selectin is coexpressed along with platelet-activating factor. Both
are translocated to the endothelial cell surface, which contributes to
leukocyte adhesion to the
endothelium.14 P-selectin
has been shown to play a major role in propagating myocardial
ischemia-reperfusion
injury,16 mesenteric
ischemia-reperfusion
injury,17 and other
inflammatory
states.18
In the study by Carvalho-Tavares et
al19 in this issue of
Circulation Research, the issue
of platelet-leukocyte-endothelial interactions in the cerebral
microvasculature is addressed. Using the valuable technique of
intravital microscopy, the authors found that the inflammatory cytokine
TNF- induced a significant degree of platelet adherence to the
microvascular endothelium along with leukocytes. Furthermore,
antibodies directed against platelets markedly attenuated leukocyte
rolling and adherence to the endothelium, as did aspirin. Using
P-selectin gene-deleted mice, the leukocyte rolling and adherence were
markedly diminished in response to TNF-. Somewhat surprisingly,
however, E-selectin gene-deleted mice also exhibited reduced rolling
and adhered leukocytes in response to TNF-, suggesting that both
endothelial selectins participate in the response. Both selectins share
the same ligand.20 A major
finding of this study was that platelets, in addition to
polymorphonuclear leukocytes, were also recruited to the cerebral
microcirculation. In fact, platelets covered 13.5% of the venules
studied. The platelets appeared to act as bridges in linking some of
the leukocytes to the endothelium. In a clever investigative maneuver
using chimeric mice, these workers determined that the P-selectin of
the endothelium was the major factor in attracting leukocytes rather
than P-selectin expressed on the platelet surface.
This cooperativity among platelets, leukocytes, and the microvascular endothelium has been investigated previously, and preliminary evidence for it has been obtained in the systemic circulation,21 mesenteric microcirculation,22 and coronary microvasculature,23 the latter two studies during ischemia-reperfusion of these vasculatures.
It should be stated that it is very difficult to quantify leukocyte-platelet interactions and describe the precise spatial interaction between these cell types because of the dynamic nature of these interactions, disparity in their cell sizes, and host of granular-secreted inflammatory mediators generated by both cell types. Carvalho-Tavares et al19 have made an important contribution to elucidating the key role of the vascular selectins (ie, P-selectin and E-selectin) in these processes, providing strong evidence of this interaction in vivo and following up on this concept postulated earlier in the development of the selectin regulation of platelet-leukocyte cooperativity.21 22 23
Additional work characterizing the time course of this
platelet-leukocyte cooperativity, the role of P-selectin glycoprotein
ligand-1 (PSGL-1) to this
interaction,24 and the
applicability of these phenomena in other microvascular beds and to
inflammatory stimuli other than TNF- will be of great value.
However, this study clearly advances the concept of platelet-leukocyte
cooperativity in inflammatory states.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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3.
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