Cystic Fibrosis Transmembrane Conductance Regulator dysfunction in VIP knockout mice
Authors
Nicole G Alcolado, Dustin J Conrad, Diogo Poroca, Mansong Li, Walaa Alshafie, Frederic G Chappe, Ryan M Pelis, Younes Anini, Zhaolin Xu, Sayyed Hamidi, Sami I Said & Valerie M Chappe
Institution
Dalhousie Univ
Country
Canada
Year
2014
Journal
Am J Physiol Cell Physiol
Abstract
VIP, a neuropeptide, controls multiple functions in exocrine tissues, including inflammation,
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, PKCĪµ 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.
Key words: CFTR, cystic fibrosis, VIP, epithelium, VIP-KO mice