Abstract 11586: A Novel MPO Inhibitor, PF-1355, Significantly Attenuates Disease Activity in Immune Complex Vasculitis and Glomerulonephritis Mouse Models
A mounting body of evidence implicates myeloperoxidase (MPO) as a central participant in the link between inflammation and cardiovascular and renal diseases. MPO is abundant in neutrophils and some macrophages, and utilizes H2O2 to produce HOCl (bleach), the strongest oxidant produced in humans. MPO activity is linked to: 1) oxidation of HDL and LDL resulting in more atherogenic forms within the vessel wall, 2) impaired endothelial function by reducing NO bioavailability, 3) oxidative tissue damage, which can lead to fibrosis and adverse remodeling, and 4) the formation of NETs (neutrophil extracellular traps) implicated in microvascular endothelial damage and thrombosis. To test the hypothesis that MPO inhibition would have broad ranging cardiovascular and renal health benefits, we developed a highly-selective, mechanism-based MPO inactivator. This compound, PF-1355, when tested in isolated human neutrophils was found to inhibit the formation of taurine chloramines and to reduce NET formation in isolated human neutrophils (IC50 = 1.65 uM and 0.97 uM, respectively). When tested in an immune complex model of pulmonary vasculitis in C57/Bl6 mice, prophylactic administration of PF-1355 was found to reduce vascular edema, neutrophil recruitment, and significantly attenuated the expression of cytokines and chemokines in both plasma and in the broncheolar lavage. Plasma levels of active MPO were significantly reduced by PF-1355 treatment, whereas total MPO mass was unaffected. We then examined the effect of PF-1355 on anti-GBM (glomerular basement membrane) induced glomerulonephritis in C57/Bl6 mice. A single injection of anti-GBM serum increased albuminuria acutely and renal dysfunction was maintained throughout the 21 days of study. Transmission electron microscope analysis revealed evidence of subendothelial electron dense deposits in mice receiving anti-GBM serum. Animals treated with PF-1355 were protected from anti-GBM induced albuminuria, accompanied by reduced MPO activity in plasma. Our findings demonstrate that MPO plays a central role in the pathogenesis of immune complex vasculitis and glomerulonephritis in mice and indicates that MPO inhibition may provide a therapeutic benefit in related human diseases.
- © 2013 by American Heart Association, Inc.