Small vessel
vasculitis is a life-threatening condition and patients typically present with renal and
pulmonary injury. Disease pathogenesis is associated with neutrophil accumulation, activation, and oxidative damage, the latter being driven in large part by
myeloperoxidase (MPO), which generates
hypochlorous acid among other
oxidants. MPO has been associated with
vasculitis, disseminated vascular
inflammation typically involving pulmonary and renal microvasculature and often resulting in critical consequences. MPO contributes to
vascular injury by 1) catabolizing
nitric oxide, impairing vasomotor function; 2) causing oxidative damage to
lipoproteins and endothelial cells, leading to
atherosclerosis; and 3) stimulating formation of neutrophil extracellular traps, resulting in vessel occlusion and
thrombosis. Here we report a selective 2-
thiouracil mechanism-based MPO inhibitor (PF-1355 [2-(6-(2,5-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)
acetamide) and demonstrate that MPO is a critical mediator of
vasculitis in mouse disease models. A pharmacokinetic/pharmacodynamic response model of PF-1355 exposure in relation with MPO activity was derived from mouse
peritonitis. The contribution of MPO activity to
vasculitis was then examined in an
immune complex model of
pulmonary disease.
Oral administration of PF-1355 reduced plasma MPO activity, vascular
edema, neutrophil recruitment, and elevated circulating
cytokines. In a model of
anti-glomerular basement membrane disease, formerly known as Goodpasture disease,
albuminuria and chronic renal dysfunction were completely suppressed by PF-1355 treatment. This study shows that MPO activity is critical in driving
immune complex vasculitis and provides confidence in testing the hypothesis that MPO inhibition will provide benefit in treating human vasculitic diseases.