Inhibition of Leukotriene D₄ Mediated Release of Prostacyclin Using Antisense DNA

Abstract

We have chosen to study the response of endothelial cells during agonist stimulation as a model system for understanding the biochemical mechanisms of siglnal transduction because of the central role played by the endothelium in mediating inflammation and other important biological phenomenon. The response of the endothelium to inflamntatory stimuli has recently received a great deal of attention due, at least in part, to the realization that it is not just a passive, vascular tissue, but an active cellular component of the inflarmnatory response. Inflammatory stimuli may directly effect the endothelium causing increased vascular permeability and enhanced adhesiveness of polymorphonuclear leukocytes and macrophages. A variety of inflammatory stimuli effect the endothelium by direct induction of the synthesis of several autocoids by endothelial cells (Clark, 1986a; Clark, 1986b; Clark, 1987a). Some of these stimuli cause the endothelium to develop large gaps between adjacent cells leading to plasma exudation and margination of lymphocytes, macrophages and polymorphonuclear leukocytes (PMN) into the extravascular space. Many of the aforementioned endothelial responses are regulated by the synthesis of oxygenated ecoisanoids which is demonstrated by the salulatory effect of anti-inflammatory drugs which attenuate ecoisanoids synthesis and prevent these endothelial cell responses.