antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-12, Vol.106 (48), p.20515-20519
• Main Authors: Xu, Yanping, Szép, Szilvia, Lu, Zhe
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Antioxidants; Antioxidants - metabolism; Biological Sciences; Cell Line; Cell lines; Cell Survival; Cells; Cystic fibrosis; Cystic Fibrosis - metabolism; Cystic Fibrosis - physiopathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Enzymes; Epithelial cells; Humans; Hydrogen Peroxide - toxicity; Hypochlorous Acid - toxicity; Infections; Inflammation; Inflammation - metabolism; Inflammation - physiopathology; Lactoperoxidase - metabolism; Lung - drug effects; Lung - metabolism; Lungs; Mortality; Mutation; Nervous system diseases; Oxidation; Peroxidase - metabolism; Physical trauma; Thiocyanates; Thiocyanates - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0911412106

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.