Methylprednisolone normalizes superoxide anion production by polymorphs from patients with ANCA-positive vasculitides.
It has been convincingly documented that reactive oxygen species released from activated neutrophils mediate glomerular damage in experimental glomerulonephritis. Recent findings that antineutrophil cytoplasmic autoantibodies (ANCA) induce neutrophils to degranulate and produce oxygen radicals in vitro led us to explore whether neutrophils from patients with ANCA-positive vasculitides and necrotizing glomerulonephritis generated an increased amount of superoxide anion (O2-). Since glucocorticoids inhibit oxygen radicals generation in vitro we also evaluated the effect of intravenous pulses of methylprednisolone. Polymorphs were isolated from peripheral blood collected before (basal), 6 and 24 hours after the first infusion of methylprednisolone and 24 hours after the third one. O2- release by cells was assessed after 30 minute incubation without specific stimuli. Basal O2- release was significantly higher in patients than in controls (P < 0.01). Intravenous infusion of high doses of methylprednisolone markedly reduced O2- production with respect to the basal value, and the difference was statistically significant at various time interval considered after the steroid infusion. Besides reducing the excessive O2- formation, methylprednisolone induced an increase in polymorph expression of the gene encoding for manganese superoxide dismutase (Mn-SOD) enzyme. We conclude that polymorphs taken from patients with ANCA-positive vasculitides and necrotizing glomerulonephritis generate higher amounts of O2- than those from normal subjects. Methylprednisolone normalizes the abnormal generation of O2-, likely through its ability to up-regulate the gene for Mn-SOD, a potent antioxidant enzyme.
Mario Negri Institute for Pharmacological Research, Ospedali Riuniti di Bergamo, Italy.
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Macconi
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Zanoli
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S
Orisio
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Longaretti
L
L
Magrini
S
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Rota
A
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Radice
C
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Pozzi
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Remuzzi
D000328:Adult; D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies / Q000097:blood; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005921:Glomerulonephritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000378:metabolism*; D014657:Vasculitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D013481:Superoxides; D004247:DNA; D013482:Superoxide Dismutase; D008775:Methylprednisolone