Amplification of the arachidonic acid cascade: implications for pharmacologic intervention

The signal transduction pathway that results in prostaglandin production is thought to occur in a stepwise manner that involves agonist-stimulated action of a phospholipase that releases the second messenger arachidonic acid from membrane phospholipids. Prostaglandin endoperoxide synthase (PGH synthase) then converts arachidonic acid to the prostaglandin precursors. Further delineation of this cascade has recently occurred with the identification of two distinct prostaglandin endoperoxide synthases, PGH synthase-1 and PGH synthase-2. There is evidence that PGH synthase-1 may have broad cellular expression and may be constitutively expressed in most cells. In contrast, PGH synthase-2 expression may be more limited and has been shown to be stimulated by a variety of cytokines and growth factors. Dexamethasone inhibits the expression of an early response gene, TIS10, which is homologous to PGH synthase-2. The exact mechanism of PGH synthase-2 gene regulation in mesangial cells is unknown; however, it may be a potential site for pharmacologic intervention. Regulation of PGH synthase-2 could in turn modulate prostaglandin production and temper the production of extracellular matrix and thus scar formation that occurs in a wide variety of inflammatory renal diseases.