We examined glomerular synthesis of the 5-lipoxygenase metabolite, LTB4, in normal and immune-injured rat glomeruli.Glomeruli isolated from normal rats and from rats with nephrotoxic serum nephritis (NSN), passive Heymann nephritis (PHN) and cationic bovine gamma globulin (CBGG)-induced glomerulonephritis were incubated with the calcium ionophore A23187 (3 ,M). Lipids in the glomeruli and media were extracted with ethyl acetate, and were purified and fractionated by HPLC. Immunoreactive-LTB4 (i-LTB4) was determined by radioimmunoassay on HPLC fractions with a detection limit of 50 pg of i-LTB4. A large peak of i-LTB4 that comigrated with authentic LTB4 was found exclusively in glomeruli isolated from the CBGG-injected rats. Addition of the lipoxygenase inhibitor BW755C (50 ;&g/ml) to glomerular incubation resulted in > 90% inhibition of i-LTB4. Synthesis of i-LTB4 by glomeruli from normal, NSN and PHN rats was undetectable. Glomerular LTB4 synthesis by CBGG-injected rats was confirmed by radiometric HPLC and by gas chromatography mass-spectroscopy (GC-MS) analysis.In order to rule out synthesis of LTB4 by neutrophils entrapped in the glomeruli, a group of rats received 1,000 rad total body x irradiation, with shielding of the kidneys before induction of CBGG glomerulonephritis. Despite > 95% reduction in total leukocyte count, glomerular synthesis of LTB4 remained enhanced. Augmented glomerular synthesis of the proinflammatory lipid, LTB4, in the CBGG model of glomerular disease could have an important role in the development of glomerular injury and proteinuria. Introduction Several lipoxygenase products of arachidonic acid are synthesized in the kidney, especially in glomeruli. Murine and human glomeruli have lipoxygenase activity and metabolize arachidonic acid to 12-hydroxyeicosa tetraenoic acid (12-HETE) and 12-and 15-HETE, respectively (1, 2). Enhanced

We investigated the effect of proteolytic enzyme treatment on the course of passive Heymann nephritis (PHN). PHN was induced by intravenous injection of Heymann antibody into Sprague Dawley rats. Protease-treated rats received intraperitoneal chymopapain and subtilisin. In rats given subnephritogenic doses of Heymann antibody (5 or 10 mg, insufficient to cause proteinuria), glomerular immune deposits were assessed by immunofluorescence and electron microscopy. In rats given 5 mg Heymann antibody and treated with protease in the heterologous phase of the disease (days 1-7), fewer animals were positive for rabbit IgG and rat IgG, as determined by immunofluorescence on day 12, compared with controls (p less than 0.01). Rats given 10 mg Heymann antibody and treated on days 1-5 were less frequently positive for rabbit IgG on day 5 than controls (p less than 0.05). When treatment was given on days 6-12 (autologous phase), fewer rats had glomerular rabbit and rat IgG compared with controls (p less than 0.025). Protease treatment of rats given nephritogenic doses of Heymann antibody (greater than or equal to 40 mg, causing proteinuria) did not result in significant differences in immunofluorescence deposits. However, protease treatment significantly reduced the number of electron dense deposits at all doses of antibody (p less than 0.01). Furthermore, rats given 60 mg Heymann antibody followed by enzyme treatment in the heterologous phase (days 1-7) or throughout the autologous phase (days 6-18) had significantly reduced protein excretion during the autologous phase compared with control rats (p less than 0.05). After onset of significant proteinuria on day 15 in rats given 40 mg Heymann antibody and treated from day 15 until day 25, there was significantly less (p less than 0.05) proteinuria on days 21-22 and 24-25 than in control rats; thus, enzymes could reverse proteinuria. In normal rats, administration of proteases did not have significant effects on urinary protein excretion, serum creatinine, or renal morphology, nor did protease affect anti-rabbit IgG antibody production in rats injected with Heymann antibody. The overall results indicate that proteolytic enzyme treatment can prevent or remove glomerular immune deposits and can prevent or reverse proteinuria.

A 57-year-old female patient with Sjogren's syndrome was complicated with pulmonary hypertension (PH) and antiphospholipid antibody (aPL). She had a history offetal losses, deep vein thrombosis and chronic thyroiditis. On admission, severe pulmonary hypertension, thrombocytopenia, lupus anticoagulant and a decreased level of protein C were found. Pulmonary artery per fusion scintigram revealed multiple defects. She died suddenly despite an intensive therapy. Intimal proliferation with angiomatoid lesions in small pulmonary arteries was observed by autopsy. Since a close relationship between PH and aPL in connective tissue disease is found, it is important to carefully analyze the antiphospholipid antibodies in patients with PH. (Internal Medicine 33: 768-772, 1994)

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