title: 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.affiliation: 1 Department of Pharmaceutical Sciences and.|Departments of 2 Medicine and.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Chandler
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Elysia
authors.initials: E
authors.lastname: Min
authors.affiliation: Departments of 2 Medicine and.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: 1 Department of Pharmaceutical Sciences and.|Departments of 2 Medicine and.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: McElroy
authors.affiliation: 3 Centre for Free Radical Research, Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Nina
authors.initials: N
authors.lastname: Dickerhof
authors.affiliation: 3 Centre for Free Radical Research, Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Tessa
authors.initials: T
authors.lastname: Mocatta
authors.affiliation: 4 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Fletcher
authors.affiliation: 4 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.affiliation: 1 Department of Pharmaceutical Sciences and.
authors.forename: Liping
authors.initials: L
authors.lastname: Liang
authors.affiliation: 1 Department of Pharmaceutical Sciences and.
authors.forename: Manisha
authors.initials: M
authors.lastname: Patel
authors.affiliation: 3 Centre for Free Radical Research, Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kettle
authors.affiliation: Departments of 2 Medicine and.|5 Pediatrics, National Jewish Health, Denver, Colorado; and.
authors.forename: David P
authors.initials: DP
authors.lastname: Nichols
authors.affiliation: 1 Department of Pharmaceutical Sciences and.|Departments of 2 Medicine and.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D008168:Lung / Q000201:enzymology / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D018410:Pneumonia, Bacterial / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000276:immunology; D013861:Thiocyanates / Q000008:administration & dosage* / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D013861:Thiocyanates; D013880:Thioredoxin-Disulfide Reductase; C031760:thiocyanate
keywords: antioxidant; glutathione sulfonamide; hypothiocyanous acid; innate immunity; nebulization