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

Thiocyanate (SCN) is utilized 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 (HOSCN), 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 anti-inflammatory effects of SCN, we administered nebulized SCN or saline to 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, pro-inflammatory cytokines and bacterial load. SCN also decreased airway neutrophil chemokine KC 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 HOSCN 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.