Eicosanoids include the prostanoid, leukotriene and epoxygenase metabolites of arachidonic acid. The pharmacological regulation of prostanoid synthesis with nonsteroidal anti- inflammatory drugs and the newer cyclooxygenase-2 (COX-2)-inhibitors (e.g. Celebra and Vioxx) and the inhibition of leukotriene actions with leukotriene receptor antagonists (e.g. Singular) have important clinical consequences in the treatment of various chronic diseases. Currently, the two major questions in the prostanoid area are: 1) why are there two COX isozymes, and 2) how do these isozymes operate independently when co-expressed in the same cell? Research on these topics focuses on defining how COX-1 and -2 couple biochemically to upstream phospholipase A2 and downstream prostaglandin H2 (PGH2) metabolizing enzymes and on how different prostanoid receptors are involved in the actions of the COX isoforms. Major unresolved issues in the leukotriene area include defining the role of these products in host defense responses, the structural biology of leukotriene biosynthetic enzymes, and the biochemical bases for the mediator actions of leukotrienes. The long-term outcome of these studies is likely to extend the usage of available cyclooxygenase and lipoxygenase inhibitors and leukotriene receptor antagonists and the development of prostanoid receptor antagonists. The epoxygenase area is not as well developed. Epoxygenase metabolites include epoxy, monohydroxy, and dihydroxy polyunsaturated fatty acids that are formed via the actions of P450s. These compounds may play key roles in regulating blood pressure and in local inflammatory responses, and thus, offer potentially important therapeutic targets. Key questions in the epoxygenase field involve defining the P450s relevant to epoxygenase metabolite formation and defining the specific epoxygenase metabolites that are of biological importance. Bringing together investigators studying a broad range of topics in the eicosanoid area will lead to a more comprehensive understanding of the regulation of the biosynthesis and mechanisms of actions of these lipid mediators. Importantly, the Keystone Symposium format provides an open, congenial setting for graduate students and postdoctoral fellows to interact with senior researchers in the eicosanoid area.
