Effect of thromboxane A2 inhibition and antagonism on prostaglandin and leukotriene synthesis in glomerular immune injury

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In glomerulonephritis there is co-activation of the arachidonic acid cyclooxygenase pathway toward synthesis of prostaglandins (PG) and thromboxane (Tx) and of lipoxypenase pathways toward synthesis of hydroxyeicosatetraenoic acids (HETEs) and leukotrienes (LTs). Cyclooxygenase inhibition with non-steroidal anti-inflammatory drugs results in enhanced glomerular LT synthesis with potentially adverse effects on the severity of the inflammation. The effect of Tx inhibition or antagonism on LT synthesis is unknown. Because TxA2 is the most abundant elcosanoid synthesized in nephritic glomeruli, and because TxA2 synthase inhibitors and receptor antagonists are now available for the treatment of glomerulonephritis, it becomes important to address this question. In this study we assessed the effect of a TxA2 synthase inhibitor, Dazmegrel, and a TxA2 receptor antagonist, SQ-29 548, on glomerular PGE2, LTB4, and 12-HETE synthesis in a model of mesangial nephritis induced in the rat by the administration of a monoclonal antibody against the Thy 1.1 antigen of rat mesangial cells. Dazmegrel, in doses sufficient to effectively block glomerular TxA2 synthesis, significantly increased 12-HETE and PGE2 synthesis without an effect on the synthesis of LTB4. SQ-29 548 had no effect on glomerular PGE2, LTB4, or 12-HETE production. Because PGE2 preserves kidney function in glomerulonephritis, and because 12-HETE inhibits 5-lipoxygenase, the enhanced PGE2 and 12-HETE production within nephritic glomerull after TxA2 synthase inhibition may be a superior anti-inflammatory strategy when compared with TxA2 receptor antagonism.