6-ketoprostaglandin-f1-alpha and Lupus-Erythematosus--Systemic

Abnormalities of prostanoid metabolism, which may affect renal function, were studied in lupus nephritis. The subjects were 31 patients with lupus nephritis, ten with non-renal SLE, and four with renal, non-SLE collagen disease. Urinary levels of various prostanoids, thromboxane B2(TXB2), 11-dehydro-TXB2, 6-keto-PGF1 alpha,2,3-dinor-6-keto-PGF1 alpha and PGE2, and plasma level of 11-dehydro-TXB2, were determined. The effects of four days' dosing of a selective thromboxane A2 (TXA2) synthetase inhibitor, DP-1904 (DP), on prostanoid metabolism, were also studied. Urinary excretion of TXB2, which reflects the renal production of TXA2, was significantly increased in patients with lupus nephritis as compared with non-renal SLE (p < 0.05). The urinary TXB2/6-keto-PGF1 alpha ratio was also increased in lupus nephritis as compared with non-renal SLE or healthy controls (p < 0.01), indicating a prostanoid imbalance, which may lead to impaired renal function and subsequent pathology. The urinary TXB2/6-keto-PGF1 alpha ratio in these lupus nephritis patients showed negative correlations with Ccr and positive correlations with anti-DNA antibody titer (p < 0.001). DP was administered orally (400 mg/day, given in two divided doses) for four days to eight lupus nephritis patients. The urinary excretion of TXB2 and urinary TXB2/6-keto-PGF1 alpha ratio were decreased after one to two days of treatment in all patients. An increase in creatinine clearance used as a measure of renal function was observed in four of eight patients. Furthermore, no side effects were elicited during the four days of treatment. The conclusion reached were that the abnormal prostanoid metabolism observed in lupus nephritis could aggravate renal function through hemodynamic mediation, and that the deviated metabolism was reversible and, at least partially, corrected by a TXA2 synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Enzyme Inhibitors; Female; Humans; Imidazoles; Kidney Diseases; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Prostaglandins; Reference Values; Regression Analysis; Tetrahydronaphthalenes; Thromboxane B2; Thromboxane-A Synthase

Polyclonal antibodies to double stranded DNA (dsDNA) purified from pooled serum samples of patients with systemic lupus erythematosus (SLE) exerted cytotoxic effects on cultured rat mesangial cells. At concentrations from 5 to 150 IU/ml, antibodies to dsDNA inhibited the incorporation of thymidine labelled with 3H into rat mesangial cells in a dose response manner after three days of culture. In contrast, normal human IgG (1 mg/ml), heat aggregated human IgG (1 mg/ml), N-formyl-methionyl-leucyl-phenylalanine (1 x 10(-7) mol/l), tumour necrosis factor alpha (16 U/ml), lipopolysaccharides (1 microgram/ml), 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA) (20 ng/ml), interleukin 1 beta (10 U/ml), and 20% v/v phytohaemagglutinin stimulated mononuclear cell supernatant showed no significant effect on these cells. Anticardiolipin antibody, another autoantibody purified from the serum of patients with SLE, also inhibited the proliferation of rat mesangial cells but to a lesser extent. In the presence of antibodies to dsDNA (100 IU/ml), the mesangial cells became spherical and clustered together, which was very different from the original stellate appearance. These autoantibodies also depolarised the membrane potential of mesangial cells. Antibodies to dsDNA decreased the syntheses of prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 by mesangial cells. In an in vivo study, the antibodies to dsDNA showed a strong affinity for the glomeruli when intravenously injected into rats. These results suggest that the nephrotropic antibodies to dsDNA can directly damage the glomerular mesangial cells in addition to the formation of immune complexes with DNA which may cause kidney inflammation and tissue destruction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies, Antinuclear; Cell Division; Cells, Cultured; Dinoprostone; Glomerular Mesangium; Humans; Lupus Erythematosus, Systemic; Male; Membrane Potentials; Rats; Rats, Inbred Strains; Thromboxane B2

To elucidate the mechanism of vascular thrombosis in patients with systemic lupus erythematosus and the lupus anticoagulant changes in factors associated with haemostasis were investigated. The lupus anticoagulant was associated with an increased incidence of thrombosis, particularly cerebral thrombosis. Concentrations of fibrinopeptide A and fibrinopeptide B beta 15-42 were significantly raised in the plasma of patients with systemic lupus erythematosus and the anticoagulant compared with concentrations in patients without the lupus anticoagulant. The tendency towards formation of thrombosis was not found in all lupus patients with the anticoagulant, however. Concentrations of thromboxane B2 were remarkably raised in the plasma of the two patients with the lupus anticoagulant who had recently had thrombosis. Concentrations of 6-keto-prostaglandin F1 alpha, protein C, antithrombin III, and plasminogen were similar in both groups. No significant decrease in serum stimulatory activity on prostacyclin production by cultured aortic endothelial cells was noted in lupus patients with the anticoagulant, but inhibition was present in the two patients with recent thrombosis. These results indicate that although patients with the lupus anticoagulant are not always in a hypercoagulable state, haemostatic abnormalities found in some patients with the anticoagulant may be predictive of thrombotic events.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Animals; Antibodies; Blood Coagulation Factors; Cardiolipins; Cattle; Female; Hemostasis; Humans; Lupus Coagulation Inhibitor; Lupus Erythematosus, Systemic; Male; Middle Aged; Thromboembolism; Thrombosis

A disturbance in endothelial cell (EC) function may be pathogenetic in the thrombotic tendency of patients with the lupus anticoagulant (LA). The ability of serum from normal subjects and patients with systemic lupus erythematosus (SLE), with and without the LA, to modulate the release of prostacyclin (PGI2) and the expression of procoagulant activity by cultured human EC was investigated. Only the 10% and 20% serum concentrations from patients with SLE-LA produced a significantly greater inhibition of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) release (the stable metabolite of PGI2) than control serum. However, when patients with SLE-LA having Raynaud's phenomenon were excluded from this group, there was then no significant difference between the effect of the patient and control serum. Serum from patients with SLE +/- LA caused a significant increase in EC procoagulant activity compared to healthy controls. The two-stage partial thromboplastin time expressed in seconds decreased from 66 (normal) to 34 (SLE - LA) and 31 (SLE + LA), but there was no significant difference between the patients with and without the LA. The significantly increased EC procoagulant activity induced by serum from patients with SLE +/- LA may account for the observed increased incidence of thrombotic events in patients with SLE. Our data suggest that factors other than decreased prostacyclin release are responsible for the altered hemostasis observed in patients with SLE + LA.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Blood Coagulation Factors; Endothelium; Epoprostenol; Female; Humans; Lupus Coagulation Inhibitor; Lupus Erythematosus, Systemic; Male; Middle Aged; Thromboplastin

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Cardiolipins; Epoprostenol; Humans; Lupus Erythematosus, Systemic; Thrombosis

Sera obtained from normal subjects and juvenile-onset diabetes (JD) and systemic lupus erythromatus (SLE) patients were examined for free fatty acid composition and 6-keto-PGF1 alpha content. In addition, prostaglandins in urine samples from normal and diabetic individuals were separated by HPLC, and 6-keto-PGF1 alpha levels were monitored by RIA. Arachidonate (20:4) content in diabetic and SLE individuals were significantly lower than that of controls. Urine from diabetic individuals showed decreased levels of 6-keto-PG F1 alpha. The study also indicated that RIA measurements on crude biological samples may yield erroneous data due to immune cross reactivity with other compounds.

Topics: 6-Ketoprostaglandin F1 alpha; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 1; Fatty Acids, Essential; Fatty Acids, Nonesterified; Humans; Lupus Erythematosus, Systemic; Radioimmunoassay