PF-1355, a Mechanism-Based Myeloperoxidase Inhibitor, Prevents Immune Complex Vasculitis and Anti–Glomerular Basement Membrane Glomerulonephritis
| Autor: | Samuel Bell, Tristan S. Maurer, Athanasia Skoura, Dexue Sun, Thomas T. Kawabe, Wei Zheng, Jessica Ward, Chunyan Su, Kent J. Johnson, Amit Kalgutkar, Carlin Okerberg, Bhupesh Kapoor, Kay Ahn, Leonard Buckbinder, Christian Cortes, Roscoe L. Warner, Paul Bonin, Yanwei Zhang, Walter Bobrowski, Timothy M. Coskran, Roger B. Ruggeri |
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| Rok vydání: | 2015 |
| Předmět: |
Vasculitis
Pathology medicine.medical_specialty Pyrimidinones Nitric oxide Mice chemistry.chemical_compound Glomerulonephritis Acetamides Glomerular Basement Membrane Animals Humans Immune Complex Diseases Medicine Enzyme Inhibitors Lung Peroxidase Pharmacology Basement membrane biology business.industry Glomerular basement membrane Neutrophil extracellular traps medicine.disease Immune complex Pyrimidines medicine.anatomical_structure Neutrophil Infiltration chemistry Myeloperoxidase Immunology biology.protein Molecular Medicine business Signal Transduction |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 353:288-298 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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