Enzymatic formation and regulatory function of lipoxins and leukotriene B4 in rat kidney mesangial cells.

Abstract

Many metabolites of arachidonic acid (AA) have been demonstrated to act as second messengers for cellular functions and signal transduction. Following liberation from membrane phospholipids by the actions of phospholipases, arachidonic acid (AA) can be further metabolized by cyclooxygenase (CO), lipoxygenase (LO), and epoxygenase enzyme systems to generate oxygenated metabolites of AA that participate in the regulation of cell function. There are at least three lipoxygenases responsible for the generation of biologically active metabolites from AA. These are the 5-, 12-and 15-lipoxygenases, which give rise to the predominately pro-inflammatory leukotrienes (LTs) and the mono and di-hydroxy eicosatetraenoic acids (HETEs). Recently lipoxins, a class of structurally related trihydroxytetraenes derived from AA and eicosapentaenoic acid (EPA) have been described (1, 2). These compounds are formed by the sequential oxidation of these polyunsaturated fatty acids by 5-lipoxygenase and 15-Lipoxygenase or 12-Lipoxygenase (3,4). Lipoxins possess potent biological activities which are distinct from those of other lipoxygenase and cyclooxygenase products (5) and in many respects lipoxin have an apparent anti-inflammatory function. For example, prior exposure of neutrophils to LXA4, inhibits LTB4 induced phosphoinositol hydrolysis and impairs the chemotic response of polymorphonuclear cells to both LTB4 and formyl-methionyl-leucyl-phenylalanine (fMLP) (6).