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Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20515-9. doi: 10.1073/pnas.0911412106. Epub 2009 Nov 16.

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

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  • 1Department of Physiology, Howard Hughes Medical Institute, University of Pennsylvania, 3700 Hamilton Walk, Philadelphia, PA 19104, USA.

Abstract

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.

PMID:
19918082
[PubMed - indexed for MEDLINE]
PMCID:
PMC2777967
Free PMC Article
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