Antiinflammatory and Antimicrobial Effects of Thiocyanate in a Cystic Fibrosis Mouse Model.

Abstract

Thiocyanate (SCN) is used by the innate immune system, but less is known about its impact on inflammation and oxidative stress. Granulocytes oxidize SCN to evolve the bactericidal hypothiocyanous acid, which we previously demonstrated is metabolized by mammalian, but not bacterial, thioredoxin reductase (TrxR). There is also evidence that SCN is dysregulated in cystic fibrosis (CF), a disease marked by chronic infection and airway inflammation. To investigate antiinflammatory effects of SCN, we administered nebulized SCN or saline to β epithelial sodium channel (βENaC) mice, a phenotypic CF model. SCN significantly decreased airway neutrophil infiltrate and restored the redox ratio of glutathione in lung tissue and airway epithelial lining fluid to levels comparable to wild type. Furthermore, in Pseudomonas aeruginosa-infected βENaC and wild-type mice, SCN decreased inflammation, proinflammatory cytokines, and bacterial load. SCN also decreased airway neutrophil chemokine keratinocyte chemoattractant (also known as C-X-C motif chemokine ligand 1) and glutathione sulfonamide, a biomarker of granulocyte oxidative activity, in uninfected βENaC mice. Lung tissue TrxR activity and expression increased in inflamed lung tissue, providing in vivo evidence for the link between hypothiocyanous acid metabolism by TrxR and the promotion of selective biocide of pathogens. SCN treatment both suppressed inflammation and improved host defense, suggesting that nebulized SCN may have important therapeutic utility in diseases of both chronic airway inflammation and persistent bacterial infection, such as CF.

• Authors: Joshua D Chandler, Elysia Min, Jie Huang, Cameron S McElroy, Nina Dickerhof, Tessa Mocatta, Ashley A Fletcher, Christopher M Evans, Liping Liang, Manisha Patel, Anthony J Kettle, David P Nichols, Brian J Day
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 53 Issue 2 Pg. 193-205 (Aug 2015) ISSN: 1535-4989 [Electronic] United States
• PMID: 25490247 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Anti-Inflammatory Agents
• Thiocyanates
• Thioredoxin-Disulfide Reductase
• thiocyanate

Topics

• Administration, Inhalation
• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacology)
• Anti-Inflammatory Agents (administration & dosage, pharmacology)
• Cell Line
• Cystic Fibrosis (drug therapy, immunology, metabolism)
• Drug Evaluation, Preclinical
• Female
• Lung (enzymology, microbiology)
• Male
• Mice, Inbred C57BL
• Oxidative Stress
• Pneumonia, Bacterial (drug therapy, enzymology, immunology)
• Pseudomonas Infections (drug therapy, enzymology, immunology)
• Pseudomonas aeruginosa (immunology)
• Thiocyanates (administration & dosage, pharmacology)
• Thioredoxin-Disulfide Reductase (metabolism)