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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-?), 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-1? to induce inflammation. We cotreated the cells with fenofibrate at concentrations ranging from 10 to 50 ?M to determine if this drug could attenuate the inflammation. IL-8, ENA-78, TNF-?, 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-1? increased the production of each of the chemokines by several fold. Fenofibrate reduced IL-1? induced production of each of these neutrophilic chemokines at the concentrations used. IL-1? 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.

SUBMITTER: Stolarz AJ

PROVIDER: S-EPMC5351137 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis.

Stolarz Amanda J AJ Farris Ryan A RA Wiley Charla A CA O'Brien Catherine E CE Price Elvin T ET

Clinical and translational science 20150810 6

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 disea ...[more]

PMID: 26258991

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Project description:Key pointsCl- and HCO3- had similar paracellular permeabilities in human airway epithelia. PCl /PNa of airway epithelia was unaltered by pH 7.4 vs. pH 6.0 solutions. Under basal conditions, calculated paracellular HCO3- flux was secretory. Cytokines that increased airway surface liquid pH decreased or reversed paracellular HCO3- flux. HCO3- flux through the paracellular pathway may counterbalance effects of cellular H+ and HCO3- secretion.AbstractAirway epithelia control the pH of airway surface liquid (ASL), thereby optimizing respiratory defences. Active H+ and HCO3- secretion by airway epithelial cells produce an ASL that is acidic compared with the interstitial space. The paracellular pathway could provide a route for passive HCO3- flux that also modifies ASL pH. However, there is limited information about paracellular HCO3- flux, and it remains uncertain whether an acidic pH produced by loss of cystic fibrosis transmembrane conductance regulator anion channels or proinflammatory cytokines might alter the paracellular pathway function. To investigate paracellular HCO3- transport, we studied differentiated primary cultures of human cystic fibrosis (CF) and non-CF airway epithelia. The paracellular pathway was pH-insensitive at pH 6.0 vs. pH 7.4 and was equally permeable to Cl- and HCO3- . Under basal conditions at pH ∼6.6, calculated paracellular HCO3- flux was weakly secretory. Treating epithelia with IL-17 plus TNFα alkalinized ASL pH to ∼7.0, increased paracellular HCO3- permeability, and paracellular HCO3- flux was negligible. Applying IL-13 increased ASL pH to ∼7.4 without altering paracellular HCO3- permeability, and calculated paracellular HCO3- flux was absorptive. These results suggest that HCO3- flux through the paracellular pathway counterbalances, in part, changes in the ASL pH produced via cellular mechanisms. As the pH of ASL increases towards that of basolateral liquid, paracellular HCO3- flux becomes absorptive, tempering the alkaline pH generated by transcellular HCO3- secretion.

Dataset Information

Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis.

Publications

Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis.

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