Platelets: unindicted coconspirators in inflammatory tissue injury.

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, PGF2a), the endoperoxides (eg, PGH2), and thromboxane A2 (TxA2). TxA2 and, to a lesser extent, PGF2a 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 plateletpropagated 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.9–13 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-a (TNF-a) and interleukin-1b.11 L-selectin is constitutively expressed on leukocyte surfaces and also contributes to leukocyte rolling. P-selectin occurs in a-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 ischemiareperfusion 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-leukocyteendothelial interactions in the cerebral microvasculature is addressed. Using the valuable technique of intravital microscopy, the authors found that the inflammatory cytokine TNF-a 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-a. Somewhat surprisingly, however, E-selectin gene-deleted mice also exhibited reduced rolling and adhered leukocytes in response to TNF-a, 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 microcirculaThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. 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 [email protected] (Circ Res. 2000;87:1077-1078.) © 2000 American Heart Association, Inc.