Long-term thromboxane-synthase inhibition prolongs survival in murine lupus nephritis.
Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by nephritis, in which mortality is largely influenced by the severity of renal involvement. As there are evidences that thromboxane (TX)A2 plays an important role in the pathogenesis of lupus nephritis, we decided to assess the effects of long-term suppression of TXA2 synthesis on the progression of the disease, by designing a study of TXA2-synthase inhibition having adequate size to detect an effect on mortality as the primary end-point. Thus, we randomized 362 NZBxNZW mice (11-week-old at entry) to one of the following treatments: a TXA2 synthase inhibitor, FCE 22178 (300 mg/kg daily), saline or cyclophosphamide (5 mg/mouse weekly x 4 weeks) used as reference treatment. The TXA2 synthase inhibitor suppressed TXA2 biosynthesis, as reflected by urinary TXB2 and 2,3-dinor-TXB2 excretion (by 78% and 90%, respectively) and significantly reduced mortality (death rate: 34% vs. 61% in controls, at 37 weeks, P < 0.01). A significant reduction in proteinuria (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 NZBxNZW mice. These parameters were further depressed by cyclophosphamide (by 48% and 45% vs. age-matched controls, respectively, P < 0.01) but were not altered significantly by FCE 22178.(ABSTRACT TRUNCATED AT 250 WORDS)
Salvati
P
P
Pharmacia-Farmitalia Carlo Erba Research Laboratories, Nerviano, Italy.
Lamberti
E
E
Ferrario
R
R
Ferrario
R G
RG
Scampini
G
G
Pugliese
F
F
Barsotti
P
P
Patrono
C
C
D000818:Animals; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008181:Lupus Nephritis / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality / Q000503:physiopathology; D051379:Mice; D008814:Mice, Inbred NZB; D009281:Naphthalenes / Q000494:pharmacology*; D011507:Proteinuria / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control* / Q000652:urine; D015996:Survival Rate; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D007093:Imidazoles; D009281:Naphthalenes; D013929:Thromboxane B2; D003520:Cyclophosphamide; D013930:Thromboxane-A Synthase; C066217:rolafagrel