LONG-TERM THROMBOXANE-SYNTHASE INHIBITION PROLONGS SURVIVAL IN MURINELUPUS NEPHRITIS

Systemic lupus erythematosus (SLE) is an autoimmune disease, character ized by nephritis, in which mortality is largely influenced by the sev erity of renal involvement. As there are evidences that thromboxane (T X)A(2) plays an important role in the pathogenesis of lupus nephritis, we decided to assess the effects of long-term suppression of TXA(2) s ynthesis on the progression of the disease, by designing a study of TX A(2)-synthase inhibition having adequate size to detect an effect on m ortality as the primary end-point. Thus, we randomized 362 NZBxNZW mic e (11-week-old at entry) to one of the following treatments: a TXA(2) synthase inhibitor, FCE 22178 (300 mg/kg daily), saline or cyclophosph amide (5 mg/mouse weekly X 4 weeks) used as reference treatment. The T XA(2) synthase inhibitor suppressed TXA(2) biosynthesis, as reflected by urinary TXB(2) and 2,3-dinor-TXB(2) excretion (by 78% and 90%, resp ectively) and significantly reduced mortality (death rate: 34% vs. 61% in controls, at 37 weeks, P < 0.01). A significant reduction in prote inuria (9 +/- 1.6 vs. 17.3 +/- 2.4 mg/24 hr in FCE 22178 vs. saline, P < 0.01) and glomerular lesions was observed up to 30 weeks but not at 37 weeks. In contrast, cyclophosphamide prevented the development of proteinuria and histologic lesions, and reduced mortality to 8% at 37 weeks. Renal plasma flow and glomerular filtration rate were lower (by 29% and 52%, respectively) in 37-week-old as compared to young NZBxNZ W mice. These parameters were further depressed by cyclophosphamide (b y 48% and 45% vs. age-matched controls, respectively, P < 0.01) but we re not altered significantly by FCE 22178. We conclude that TXA(2) bio synthesis contributes importantly to renal disease progression and mor tality of NZBxNZW mice, though other mechanisms are likely to be respo nsible for proteinuria at later stages.