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Bioelectric characterization of epithelia from neonatal CFTR knockout ferrets
Journal article   Open access   Peer reviewed

Bioelectric characterization of epithelia from neonatal CFTR knockout ferrets

John T Fisher, Scott R Tyler, Yulong Zhang, Ben J Lee, Xiaoming Liu, Xingshen Sun, Hongshu Sui, Bo Liang, Meihui Luo, Weiliang Xie, …
American journal of respiratory cell and molecular biology, Vol.49(5), pp.837-844
11/2013
DOI: 10.1165/rcmb.2012-0433OC
PMCID: PMC3931095
PMID: 23782101
url
https://doi.org/10.1165/rcmb.2012-0433OCView
Published (Version of record) Open Access

Abstract

Cystic fibrosis (CF) is a life-shortening, recessive, multiorgan genetic disorder caused by the loss of CF transmembrane conductance regulator (CFTR) chloride channel function found in many types of epithelia. Animal models that recapitulate the human disease phenotype are critical to understanding pathophysiology in CF and developing therapies. CFTR knockout ferrets manifest many of the phenotypes observed in the human disease, including lung infections, pancreatic disease and diabetes, liver disease, malnutrition, and meconium ileus. In the present study, we have characterized abnormalities in the bioelectric properties of the trachea, stomach, intestine, and gallbladder of newborn CF ferrets. Short-circuit current (ISC) analysis of CF and wild-type (WT) tracheas revealed the following similarities and differences: (1) amiloride-sensitive sodium currents were similar between genotypes; (2) responses to 4,4'-diisothiocyano-2,2'-stilbene disulphonic acid were 3.3-fold greater in CF animals, suggesting elevated baseline chloride transport through non-CFTR channels in a subset of CF animals; and (3) a lack of 3-isobutyl-1-methylxanthine (IBMX)/forskolin-stimulated and N-(2-Naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide (GlyH-101)-inhibited currents in CF animals due to the lack of CFTR. CFTR mRNA was present throughout all levels of the WT ferret and IBMX/forskolin-inducible ISC was only observed in WT animals. However, despite the lack of CFTR function in the knockout ferret, the luminal pH of the CF ferret gallbladder, stomach, and intestines was not significantly changed relative to WT. The WT stomach and gallbladder exhibited significantly enhanced IBMX/forskolin ISC responses and inhibition by GlyH-101 relative to CF samples. These findings demonstrate that multiple organs affected by disease in the CF ferret have bioelectric abnormalities consistent with the lack of cAMP-mediated chloride transport.
 Enzyme Activators - pharmacology Intestinal Mucosa - metabolism Epithelial Cells - metabolism Respiratory Mucosa - drug effects Epithelial Cells - drug effects Gallbladder - drug effects Sodium - metabolism Gastric Mucosa - metabolism Intestinal Mucosa - drug effects Cystic Fibrosis Transmembrane Conductance Regulator - drug effects Chlorides - metabolism Membrane Transport Modulators - pharmacology Gastric Mucosa - drug effects Ion Transport Cystic Fibrosis Transmembrane Conductance Regulator - deficiency Cyclic AMP - metabolism Ferrets - genetics Disease Models, Animal Animals, Newborn Gallbladder - metabolism Animals, Genetically Modified Cystic Fibrosis - metabolism Phosphodiesterase Inhibitors - pharmacology Genotype Adenylyl Cyclases - metabolism Electric Impedance Gene Knockout Techniques Phenotype Animals Membrane Potentials Cystic Fibrosis - genetics Cystic Fibrosis Transmembrane Conductance Regulator - genetics Enzyme Activation Respiratory Mucosa - metabolism Hydrogen-Ion Concentration

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