The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases.
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 approximately 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 (H(2)O(2)) and hypochlorite (OCl(-)). First, lactoperoxidase (LPO) in the airways catalyzes oxidation of SCN(-) to tissue-innocuous hypothiocyanite (OSCN(-)), while consuming H(2)O(2). 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 H(2)O(2); 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 beta cell line) SCN(-) at concentrations of > or =100 microM 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 microM. 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.
Xu
Yanping
Y
Department of Physiology, Howard Hughes Medical Institute, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA.
Szép
Szilvia
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Lu
Zhe
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D000704:Analysis of Variance; D000975:Antioxidants / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D003550:Cystic Fibrosis / Q000378:metabolism / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D006997:Hypochlorous Acid / Q000633:toxicity; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D007784:Lactoperoxidase / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D013861:Thiocyanates / Q000378:metabolism*
D000975:Antioxidants; C505032:CFTR protein, human; D013861:Thiocyanates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D007784:Lactoperoxidase; D009195:Peroxidase; C031760:thiocyanate