Abstract
ABSTRACTCystic fibrosis (CF) is a fatal genetic disease associated with widespread exocrine gland dysfunction. Studies have suggested activating effects of resveratrol, a naturally-occurring polyphenol compound with antioxidant and anti-inflammatory properties, on CF transmembrane conductance regulator (CFTR) protein function. We assayed, in F508del-CFTR homozygous (CF) and in wild-type mice, the effect of resveratrol on salivary secretion in basal conditions, in response to inhibition by atropine (basal β-adrenergic-dependent component) and to stimulation by isoprenaline (CFTR-dependent component). Both components of the salivary secretion were smaller in CF mice than in controls. Two hours after intraperitoneal administration of resveratrol (50 mg/kg) dissolved in DMSO, the compound was detected in salivary glands. As in both CF and in wild-type mice, DMSO alone increased the response to isoprenaline in males but not in females, the effect of resveratrol was only measured in females. In wild-type mice, isoprenaline increased secretion by more than half. In CF mice, resveratrol rescued the response to isoprenaline, eliciting a 2.5-fold increase of β-adrenergic-stimulated secretion. We conclude that the salivary secretion assay is suitable to test DMSO-soluble CFTR modulators in female mice. We show that resveratrol applied in vivo to mice reaches salivary glands and increases β-adrenergic secretion. Immunolabelling of CFTR in human bronchial epithelial cells suggests that the effect is associated with increased CFTR protein expression. Our data support the view that resveratrol is beneficial for treating CF. The salivary secretion assay has a potential application to test efficacy of novel CF therapies.
Highlights
Cystic Fibrosis (CF), a complex disease associated with widespread exocrine gland dysfunction, is caused by loss of function of the CFTR homozygous (CF) transmembrane conductance regulator (CFTR) chloride channel
Influence of Resveratrol on CFTR mRNA and protein expression in human bronchial epithelial cells To assess the potential mechanism involved in the activating effect of resveratrol on CFTR-dependent salivary secretion, we examined the cellular expression of CFTR mRNA and protein in human immortalized CF and wild-type bronchial cells after incubation with the compound
In CF cells, resveratrol increased both the intensity of the whole fluorescence signal and the modified the localization of the perinuclear versus peripheral CFTR labelling. These findings suggest that the increased rate of isoprenaline-induced salivary secretion in CF salivary glands after resveratrol treatment could be associated with an increased CFTR protein expression
Summary
Cystic Fibrosis (CF), a complex disease associated with widespread exocrine gland dysfunction, is caused by loss of function of the CF transmembrane conductance regulator (CFTR) chloride channel. Almost 2000 mutations have been described, but ∼70% of patients carry at least one F508del-CFTR mutation. Received 17 November 2014; Accepted 20 May 2015 phenylalanine at position 508 of CFTR impairs the folding of the protein which is retained in the endoplasmic reticulum and undergoes early degradation by the proteasome. The loss of CFTR contribution to ion homeostasis drives an impaired mucociliary clearance and promotes cycles of chronic inflammation and bacterial infection. CF patients would strongly benefit from pharmacological compounds combining the ability to correct both the deficient ion transport and the deregulated inflammatory responses
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