ABSTRACT
To test the hypothesis that simvastatin is capable of blocking human neutrophil degranulation induced by proteinase 3 [PR3]-anti-neutrophil cytoplasm auto-antibodies [ANCA] and myeloperoxidase [MPO]-ANCA, and by the chemotactic and inflammatory peptide N-formyl-methionine-leucine-phenylalanine [fMLP]. This study was conducted between March 2010 and September 2011 at the Renal Institute of Birmingham, University of Birmingham, Birmingham, United Kingdom. Immunoglobulin G [IgG] was purified from the plasma of 20 randomly selected patients with ANCA-associated vasculitis [10 PR3- and 10 MPO-ANCA], and their ability to induce neutrophil degranulation in the presence or absence of simvastatin [10 micro M] was tested. The ability of the same dose of simvastatin to block fMLP-induced neutrophil degranulation was also tested. In addition, the ability of serum obtained from rats that received simvastatin at a dose of 25 mg/kg/day to block neutrophil degranulation in vitro was tested. The addition of simvastatin significantly inhibited ANCA IgG-induced neutrophil degranulation by 48% [p=0.02]. There was no significant difference in response to simvastatin inhibition [p=0.73] between PR3- and MPO-ANCA. Simvastatin also inhibited neutrophil degranulation induced by 1 micro M fMLP [30%, p=0.04]. We further demonstrated that serum from rats that received simvastatin significantly inhibited neutrophil degranulation induced by ANCA [31.7%, p=0.01] and fMLP [23.5%, p=0.03] compared to serum from control animals. Simvastatin blocked both ANCA and fMLP-induced neutrophil degranulation. It is worth pursuing further therapeutic investigation of statins in vascular inflammatory diseases that involve neutrophil degranulation in their pathogenesis