Editorial [ Cellular and Molecular Mechanisms of Action of Drugs Affecting Inflammatory Leukocyte Function (Guest Editor: P.X. Elsas)]

While it is often repeated that one cannot teach an old dog new tricks, it is likely that one can learn new tricks even from an old dog; and the same is certainly true for old drugs, as abundantly illustrated by the review articles in this special issue of Current Medicinal Chemistry. Even though most of them deal with very timely issues of cellular and molecular mechanism in the context of inflammation, much of the information discussed has been obtained with the help of pharmacological tools that are in some cases more than a century old, like aspirin [1], or which have been in constant use and study for as long as five decades, like the glucocorticoids [2]. In other examples, the field of investigation, rather than the specific pharmacological tool, is time-honored: the study of snake venoms in pharmacology has led to the seminal discovery of bradykinin and the development of a whole class of anti-hypertensive agents, dating back to the studies of brazilian pharmacologist Mauricio Rocha e Silva and his collaborators in the 1940's [3]. The more recent discovery of disintegrins and the development of novel analogues of snake venom disintegrins which have an impact on inflammation, in addition to effects on hemostasis, are among the most striking examples of the enormous potential of venoms as sources of powerful biological probes [4]. Another timehonored field is that of nitric oxide (NO) biology, which largely antedates the identification of NO itself as a central effector in biological processes as different as the control of vascular tone, inhibition of platelet aggregation, killing of intracellular microorganisms by macrophages and wound healing [5-8]: sodium nitroprusside, the effects of which are mediated by NO, was characterized as an anti-hypertensive agent in 1929 and became a standard treatment for acute control of severe hypertension in the 1950's [9] The articles gathered in this special issue follow either one or the other of these patterns. They either concentrate on old drugs that have unexpected effects when tested in novel systems, or they explore novel aspects of mediators that have been intensively studied over a long time, such as NO and snake venoms. Sometimes, they do both. It is clear that important, novel information continues to be generated through both approaches. This suggests that important advances in medicinal chemistry can be made by combining the properties of well-characterized agents available today. The reviews by Riley and colleagues [10] and Gaspar-Elsas and Elsas [11] in this issue provide an example of the first pattern. They review the effects of a number of well-known agents on granulocytes from opposite standpoints: while Riley and colleagues concentrate on the mature granulocytes of the neutrophil and eosinophil lineage, found in peripheral blood and inflammatory sites, Gaspar-Elsas and Elsas analyse the development of eosinophils in bone-marrow and other sites from hemopoietic progenitors and precursors. Even though their reviews address the two extremes of a leukocyte's life cycle, they are closely related by their emphasis in the ubiquitous process of apoptosis. From their contributions, it is clear that apoptosis plays a major role in the regulation of granulocyte numbers, by influencing both production and consumption. The mass of work they summarize also sheds novel life on the actions of inflammatory mediators and anti-inflammatory drugs, which are shown to influence granulocyte survival by acting at key steps in the control of apoptosis. However, such effects are also seen to depend strongly on the developmental stage of the cell being studied, so that certain agents, such as glucocorticoids, may affect apoptosis in strikingly different ways, depending on whether one looks at a mature or an immature cell. This adds a biological dimension to a field in which the response to a drug or mediator is often assumed to be solely determined by the presence of the ligand, its receptor and the corresponding signalling/effector elements. On the other hand, the articles by Shaw et al. [12], Assreuy et al. [13] and Ferreira et al. [14] exemplify the second pattern: they are linked by their common effort to highlight novel aspects of NO, which is as physiologically versatile as it is structurally simple. According to Shaw et al., adequate manipulation of NO in atherosclerotic lesions may provide a muchneeded means of controlling the progression of life-threatening atherosclerotic plaques. This view is linked to the increasing................