The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases
2009
Xu, Yanping | Szép, Szilvia | Lu, Zhe
Cystic fibrosis (CF) is a pleiotropic disease, originating from mutations in the CF transmembrane conductance regulator (CFTR). Lung injuries inflicted by recurring infection and excessive inflammation cause [almost equal to]90% of the morbidity and mortality of CF patients. It remains unclear how CFTR mutations lead to lung illness. Although commonly known as a Cl⁻ channel, CFTR also conducts thiocyanate (SCN⁻) ions, important because, in several ways, they can limit potentially harmful accumulations of hydrogen peroxide (H₂O₂) and hypochlorite (OCl⁻). First, lactoperoxidase (LPO) in the airways catalyzes oxidation of SCN⁻ to tissue-innocuous hypothiocyanite (OSCN⁻), while consuming H₂O₂. Second, SCN⁻ even at low concentrations competes effectively with Cl⁻ for myeloperoxidase (MPO) (which is released by white blood cells), thus limiting OCl⁻ production by the enzyme. Third, SCN⁻ can rapidly reduce OCl⁻ without catalysis. Here, we show that SCN⁻ and LPO protect a lung cell line from injuries caused by H₂O₂; and that SCN⁻ protects from OCl⁻ made by MPO. Of relevance to inflammation in other diseases, we find that in three other tested cell types (arterial endothelial cells, a neuronal cell line, and a pancreatic β cell line) SCN⁻ at concentrations of greater-than-or-equal100 μM greatly attenuates the cytotoxicity of MPO. Humans naturally derive SCN⁻ from edible plants, and plasma SCN⁻ levels of the general population vary from 10 to 140 μM. Our findings raise the possibility that insufficient levels of antioxidant SCN⁻ provide inadequate protection from OCl⁻, thus worsening inflammatory diseases, and predisposing humans to diseases linked to MPO activity, including atherosclerosis, neurodegeneration, and certain cancers.
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