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

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.

• Authors: Yanping Xu, Szilvia Szép, Zhe Lu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 48 Pg. 20515-9 (Dec 01 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19918082 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• CFTR protein, human
• Thiocyanates
• Cystic Fibrosis Transmembrane Conductance Regulator
• Hypochlorous Acid
• Hydrogen Peroxide
• Lactoperoxidase
• Peroxidase
• thiocyanate

Topics

• Analysis of Variance
• Antioxidants (metabolism)
• Cell Line
• Cell Survival
• Cystic Fibrosis (metabolism, physiopathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, metabolism)
• Humans
• Hydrogen Peroxide (toxicity)
• Hypochlorous Acid (toxicity)
• Inflammation (metabolism, physiopathology)
• Lactoperoxidase (metabolism)
• Lung (drug effects, metabolism)
• Peroxidase (metabolism)
• Thiocyanates (metabolism)