| Abstract
| - Small particles of crystalline silicon dioxide (crystallites) are exceptionally toxic. Inhalation of quartzcrystallites causes silicosis, a devastating lung disease afflicting miners, particularly coal and stone workers.Poly(vinylpyridine-N-oxide)s (PVPNOs) have been applied in the prevention and treatment of silicosis,but their mode of action has been obscure. Recently, the sites of inducible •NO synthase activation andof nitrotyrosine formation were associated anatomically with the pathological quartz particle-caused lesionsin the lungs. It has been suggested that the •NO formed combines rapidly with O2•- to yield ONOO-, apotential mediator of lung injury following silica exposure. Here, we show that PVPNOs do not reactwith peroxynitrite but scavenge exceptionally rapidly CO3•- radicals, which are produced in thedecomposition of ONOO- in bicarbonate solutions. The rate constant for the reaction of CO3•- withPVPNO was found to be independent of the type and size of PVPNO, i.e., k = (1.9 ± 0.2) × 105 M-1s-1 per monomer. In contrast, the rate constant for the reaction of CO3•- with the small molecule4-methylpyridine N-oxide did not exceed 1 × 104 M-1 s-1. The underlying reason for the difference isthat, in the dissolved polymeric PVPNOs, the electrostatic repulsion between the N-oxide zwitterionsdestabilizes them, increasing dramatically their pKa. The protonated N-oxides at physiological pH haveabstractable hydrogen atoms and are expected to react rapidly with CO3•-, just as cyclic hydroxylaminesdo. It is also shown that PVPNO inhibits tyrosine nitration by peroxynitrite at pH 7.6 in the presence ofexcess of CO2 in a concentration-dependent manner. Hence, binding of PVPNO to the quartz particlesand eliminating CO3•- could prevent the killing of macrophages, the associated release of macrophage-recruiting cytokines, and the amplification of the local concentration of •NO by the recruited macrophages.The latter causes necrosis of the macrophage-infiltrated lung tissue and, upon repair of the necrotic lesion,results in the growth of the dysfunctional fibrotic tissue, which is the hallmark of silicosis.
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