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 Ϸ90% 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 2O2) 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 H 2O2; 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 ␤ cell line) SCN ؊ at concentrations of >100 M 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 M. 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.hydrogen peroxide ͉ hypochlorite ͉ hypothiocyanite ͉ lactoperoxidase ͉ myeloperoxidase

Selective Metabolism of Hypothiocyanous Acid by Mammalian Thioredoxin Reductase Promotes Lung Innate Immunity and Antioxidant Defense

“…The identities of the hypohalites formed during the experiment was confirmed as described previously (11).…”

“…lactoperoxidase (LPO) (2); myeloperoxidase (MPO) (3); and eosinophil peroxidase (4)). HOSCN is a potent and selective oxidizer of nucleophilic thiols (5) that inhibits and kills multiple species of bacteria (6 -8), viruses (9), and fungi (10) but paradoxically is well tolerated by healthy mammalian tissue (11). For example, the human oral cavity is exposed to steady-state concentrations of HOSCN up to 70 M (12).…”

CFTR: Break a pump, make a channel

“…The molecular culprit underlying the disease has been known for 20 years: cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial, ATP-gated Cl − channel that normally functions to secrete fluid onto the air-exposed alveolar surface, thus maintaining mucus at a viscosity just right for capture and clearance of inhaled microorganisms and other junk and, according to an appealingly idiosyncratic proposal (2), to deliver to this surface a natural antimicrobial agent, the pseudohalide anion SCN − . The prominence of CF in the human population has provoked much research on the workings of CFTR and, in this issue, Csanády and coworkers (3) nail down a key featureappealing in its own mechanistic idiosyncrasy-of how this Cl − channel opens and closes.…”

Антиоксидантная Система Респираторного Тракта Антиоксидантные Эффекторы В Надэпителиальном И Экстрацеллюлярном Пространстве (Часть 2)

“…Кроме того, высокая активность MPO ассоциирована с разви-тием атеросклероза. У людей, которые отличаются высокой активностью MPO в сыворотке крови, в 15-20 раз выше риск развития стеноза коронарных артерий [51].…”