title: Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis.
abstract: A hallmark of cystic fibrosis (CF) lung disease is neutrophilic airway inflammation. Elevated neutrophil counts have been associated with decreased forced expiratory volume in 1 second and poor clinical measures in patients with CF. Interleukin 8 (IL-8), epithelial neutrophil activating protein 78 (ENA-78), tumor necrosis factor alpha (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF) contribute to neutrophil activation and disease pathogenesis in the airways of patients with CF. Drugs that modify the production of these chemokines in the airways could potentially benefit CF patients. Thus, we determined the effects of fenofibrate on their production in cell populations obtained from the airways. Human small airway epithelial cells and CF bronchial epithelial cells were treated with IL-1β to induce inflammation. We cotreated the cells with fenofibrate at concentrations ranging from 10 to 50 μM to determine if this drug could attenuate the inflammation. IL-8, ENA-78, TNF-α, GM-CSF, and G-CSF production were measured from the cell culture supernates by ELISA. ANOVA statistical testing was conducted using SPSS 17.0. IL-1β increased the production of each of the chemokines by several fold. Fenofibrate reduced IL-1β induced production of each of these neutrophilic chemokines at the concentrations used. IL-1β increases the production of neutrophilic chemokines in airway epithelial cells. Cotreatment with fenofibrate blunts these processes. Fenofibrate should be explored as a therapeutic option to modulate the abundant neutrophilic inflammation observed in CF.
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Stolarz
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Farris
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA.
authors.forename: Charla A
authors.initials: CA
authors.lastname: Wiley
authors.affiliation: Department of Pharmacy Practice, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: O'Brien
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical, Sciences College of Pharmacy, Little Rock, Arkansas, USA.
authors.forename: Elvin T
authors.initials: ET
authors.lastname: Price
mesh_terms: D001980:Bronchi / Q000166:cytology; D002478:Cells, Cultured; D054365:Chemokine CXCL5 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D003550:Cystic Fibrosis / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D011345:Fenofibrate / Q000627:therapeutic use*; D005541:Forced Expiratory Volume; D020869:Gene Expression Profiling; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016209:Interleukin-8 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C486263:CXCL5 protein, human; C508606:CXCL8 protein, human; D054365:Chemokine CXCL5; D018925:Chemokines; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011345:Fenofibrate
keywords: chemokines; cystic fibrosis; drug repurposing; fenofibrate; neutrophils