title: Cystic fibrosis transmembrane conductance regulator dysfunction in VIP knockout mice.
abstract: Vasoactive intestinal peptide (VIP), a neuropeptide, controls multiple functions in exocrine tissues, including inflammation, and relaxation of airway and vascular smooth muscles, and regulates CFTR-dependent secretion, which contributes to mucus hydration and local innate defense of the lung. We had previously reported that VIP stimulates the VPAC1 receptor, PKCϵ signaling cascade, and increases CFTR stability and function at the apical membrane of airway epithelial cells by reducing its internalization rate. Moreover, prolonged VIP stimulation corrects the molecular defects associated with F508del, the most common CFTR mutation responsible for the genetic disease cystic fibrosis. In the present study, we have examined the impact of the absence of VIP on CFTR maturation, cellular localization, and function in vivo using VIP knockout mice. We have conducted pathological assessments and detected signs of lung and intestinal disease. Immunodetection methods have shown that the absence of VIP results in CFTR intracellular retention despite normal expression and maturation levels. A subsequent loss of CFTR-dependent chloride current was measured in functional assays with Ussing chamber analysis of the small intestine ex vivo, creating a cystic fibrosis-like condition. Interestingly, intraperitoneal administration of VIP corrected tissue abnormalities, close to the wild-type phenotype, as well as associated defects in the vital CFTR protein. The results show in vivo a primary role for VIP chronic exposure in CFTR membrane stability and function and confirm in vitro data.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada;
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Alcolado
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada;
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Conrad
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada;
authors.forename: Diogo
authors.initials: D
authors.lastname: Poroca
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada;
authors.forename: Mansong
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada;
authors.forename: Walaa
authors.initials: W
authors.lastname: Alshafie
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada;
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Chappe
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada;
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Pelis
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Obstetrics and Gynecology, Dalhousie University, Halifax, Nova Scotia, Canada; and.
authors.forename: Younes
authors.initials: Y
authors.lastname: Anini
authors.affiliation: Department of Pathology, Dalhousie University and QE II Health Sciences Centre, Halifax, Nova Scotia, Canada;
authors.forename: Zhaolin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Medicine and Pulmonary Critical Care, Stony Brook University, Stony Brook, New York.
authors.forename: Sayyed
authors.initials: S
authors.lastname: Hamidi
authors.affiliation: Department of Medicine and Pulmonary Critical Care, Stony Brook University, Stony Brook, New York.
authors.forename: Sami I
authors.initials: SI
authors.lastname: Said
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada; valerie.chappe@dal.ca.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Chappe
mesh_terms: D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D007421:Intestine, Small / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020545:Respiratory Mucosa / Q000166:cytology; D014132:Trachea / Q000166:cytology; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism*
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014660:Vasoactive Intestinal Peptide
keywords: CFTR; VIP; VIP-knockout mice; cystic fibrosis; epithelium