SPECIFICITY OF EXPRESSION AND EFFECTS OF EICOSANOID MEDIATORS IN NORMAL PHYSIOLOGY AND HUMAN-DISEASES

The eicosanoids are a family of oxygenated arachidonic acid derivatives that potently mediate diverse physiological and pathophysiological processes. Recent research on eicosanoids has revealed novel pathways of synthesis, a family of related cell membrane receptors, and distinctive roles in cellular functions. There are two cyclooxygenases that convert arachidonic acid to thromboxane and prostaglandins, one of which is localized in the endoplasmic reticulum and the other in the nuclear envelope. The cyclooxygenases differ in their susceptibility to inhibition by nonsteroidal antiinflammatory drugs. The leukotriene-generating pathway consists of a cytosolic perinuclear 5-lipoxygenase, two integral nuclear envelope proteins, termed 5-lipoxygenase-activating protein and LTC4 synthase, and a cytosolic LTA4 hydrolase. Each protein of the leukotriene synthetic pathway is a target for specific pharmacological intervention. Cellular recognition and effects of eicosanoids are mediated by at least 12 different G protein-associated primary receptors, which differ in tissue distribution, signaling mechanisms, and cellular behavior, as well as binding specificity. Transient localized increases in tissue concentrations of eicosanoids and the concurrent upregulation of complementary receptors influence differentiation, migration, and specific activities of cells in immunity and other integrated physiological responses.