RT Journal Article
SR Electronic
T1 PF-1355, a Mechanism-Based Myeloperoxidase Inhibitor, Prevents Immune Complex Vasculitis and Anti–Glomerular Basement Membrane Glomerulonephritis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 288
OP 298
DO 10.1124/jpet.114.221788
VO 353
IS 2
A1 Zheng, Wei
A1 Warner, Roscoe
A1 Ruggeri, Roger
A1 Su, Chunyan
A1 Cortes, Christian
A1 Skoura, Athanasia
A1 Ward, Jessica
A1 Ahn, Kay
A1 Kalgutkar, Amit
A1 Sun, Dexue
A1 Maurer, Tristan S.
A1 Bonin, Paul D.
A1 Okerberg, Carlin
A1 Bobrowski, Walter
A1 Kawabe, Thomas
A1 Zhang, Yanwei
A1 Coskran, Timothy
A1 Bell, Sammy
A1 Kapoor, Bhupesh
A1 Johnson, Kent
A1 Buckbinder, Leonard
YR 2015
UL http://jpet.aspetjournals.org/content/353/2/288.abstract
AB 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.