Mode of action of poly(vinylpyridine-N-oxide) in preventing silicosis: effective scavenging of carbonate anion radical.
Small particles of crystalline silicon dioxide (crystallites) are exceptionally toxic. Inhalation of quartz crystallites 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 and of nitrotyrosine formation were associated anatomically with the pathological quartz particle-caused lesions in the lungs. It has been suggested that the *NO formed combines rapidly with O2*- to yield ONOO-, a potential mediator of lung injury following silica exposure. Here, we show that PVPNOs do not react with peroxynitrite but scavenge exceptionally rapidly CO3*- radicals, which are produced in the decomposition of ONOO- in bicarbonate solutions. The rate constant for the reaction of CO3*- with PVPNO was found to be independent of the type and size of PVPNO, i.e., k = (1.9 +/- 0.2) x 10(5) M(-1) s(-1) per monomer. In contrast, the rate constant for the reaction of CO3*- with the small molecule 4-methylpyridine N-oxide did not exceed 1 x 10(4) M(-1) s(-1). The underlying reason for the difference is that, in the dissolved polymeric PVPNOs, the electrostatic repulsion between the N-oxide zwitterions destabilizes them, increasing dramatically their pKa. The protonated N-oxides at physiological pH have abstractable hydrogen atoms and are expected to react rapidly with CO3*-, just as cyclic hydroxylamines do. It is also shown that PVPNO inhibits tyrosine nitration by peroxynitrite at pH 7.6 in the presence of excess of CO2 in a concentration-dependent manner. Hence, binding of PVPNO to the quartz particles and 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.
Goldstein
Sara
S
Department of Physical Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. sarag@vms.huji.ac.il
Czapski
Gideon
G
Heller
Adam
A
D001639:Bicarbonates / Q000737:chemistry*; D016166:Free Radical Scavengers / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017665:Hydroxyl Radical / Q000737:chemistry*; D007700:Kinetics; D030421:Peroxynitrous Acid / Q000737:chemistry; D011144:Polyvinylpyridine N-Oxide / Q000737:chemistry* / Q000627:therapeutic use; D011791:Quartz / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry*; D012829:Silicosis / Q000517:prevention & control; D014443:Tyrosine / Q000737:chemistry
D001639:Bicarbonates; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D011791:Quartz; D017665:Hydroxyl Radical; D014443:Tyrosine; D011144:Polyvinylpyridine N-Oxide