Sol Sherry Lecture in Thrombosis

Abstract

Abstract-The inflammatory response is characterized by a multistep molecular interaction between "signaling" cells, such as endothelial cells, and "responding" cells, such as neutrophils and monocytes. In the first step, selectins produced by signaling cells mediate the tethering of responding cells at sites of inflammation. Subsequently, an additional mediator expressed by signaling cells activates the tethered responding cells. Under pathological conditions, the same mechanism is invoked in inappropriate ways: (1) by prolonged presentation of selectins on the cell surface and (2) by the unregulated production of oxidized phospholipids that mimic the normal secondary signaling molecule, platelet-activating factor (PAF). The enzyme PAF acetylhydrolase (PAF-AH) inactivates PAF and oxidized phospholipids and constitutes an "off" switch that suppresses inflammation. Inhibition of normal PAF-AH function or inactivating mutations of the PAF-AH gene can lead to increased susceptibility to inflammatory disease. These studies have relevance to atherosclerosis and thrombosis, because inflammation is a central feature of both. (Arterioscler Thromb Vasc Biol. 2002;22:727-733.)Key Words: inflammation Ⅲ selectins Ⅲ platelet-activating factor Ⅲ chemokines Ⅲ oxidized phospholipids T his article is a summary of the Sol Sherry lecture of the Council on Arteriosclerosis, Thrombosis, and Vascular Biology, which was presented at the 73rd Scientific Sessions of the American Heart Association, New Orleans, La, November 12-15, 2000. It highlights work from our laboratory addressing the molecular basis of inflammation, particularly early events at the vascular wall. For this lecture, we have focused on our own work and have not attempted to provide a general review of this topic.In response to infection and other tissue damage, leukocytes emigrate from the bloodstream to the tissues. The adhesion of leukocytes to endothelial cells is a crucial first step in this process. When appropriately regulated, the inflammatory response is physiological and homeostatic. However, when the stimulus is spatially, temporally, or quantitatively inappropriate, adhesion and activation of leukocytes can have pathological effects (Figure 1). We have focused on the molecular changes responsible for these early steps. We have described a mechanism by which cells react to inflammatory signals to permit a spatially specific response and a high-fidelity reaction (Figure 2). Several different types of circulating cells use this same molecular mechanism."Signaling" cell/"responding" cell pairs of a number of different types are involved in inflammatory events, eg, endothelial cells and polymorphonuclear neutrophils (PMNs), endothelial cells and monocytes, and platelets and monocytes. We and others (see review 1 ) have shown that in all of these cases, the signaling cell communicates with the responding target cell in a multistep fashion. First, it tethers the target cell at the site of inflammation, and then it sends a signal to it through a molecule recognized ...

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“…The inflammatory actions of PAF include activation of polymorphonuclear leukocytes and increased vascular permeability (Prescott et al, 2002). The concentration of PAF in plasma and tissues is tightly regulated by the balance of synthesis and degradation (Snyder, 1995).…”

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“…1, 2 The LDL oxidation reportedly involves a platelet-activating factor (PAF), a potent lipid mediator implicated in inflammatory reactions. 3,4 Local inflammation in the vascular wall immediately triggers the production of chemical mediators, and at the same time induces leukocyte adhesion to the endothelium mainly through P-selectin. 3 Chemical mediators such as thrombin and bradykinin increase the expression of PAF on the endothelial surface and activate leukocytes.…”

“…3,4 Local inflammation in the vascular wall immediately triggers the production of chemical mediators, and at the same time induces leukocyte adhesion to the endothelium mainly through P-selectin. 3 Chemical mediators such as thrombin and bradykinin increase the expression of PAF on the endothelial surface and activate leukocytes. Activated leukocytes further stimulate the formation of oxidized lipid.…”

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