Bioelectric Properties of Chloride Channels in Human, Pig, Ferret, and Mouse Airway Epithelia

Liu, Xiaoming; Luo, Meihui; Zhang, Liang; Ding, Wei; Yan, Ziying; Engelhardt, John F.

doi:10.1165/rcmb.2006-0286oc

Cited by 80 publications

(73 citation statements)

References 53 publications

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“…Table E1 in the online supplement). The WT I SC responses to each of these compounds were remarkably similar to previously published data using polarized cultured adult ferret tracheal epithelia (40). Amiloride was used to inhibit ENaCs and resulted in I SC changes of 23.65 (61.93) and 20.64 (61.8) mA/cm 2 for WT and CF, respectively ( Figure 1C).…”

Section: Discussionsupporting

confidence: 86%

“…Interestingly, the inhibition of these currents with GlyH-101 was organ specific. Previous findings have shown that species-specific differences exist in the sensitivities of human, pig, ferret, and mouse CFTR to different CFTR inhibitors using cultured primary polarized airway epithelia (40). In the ferret, GlyH-101 was most effective at inhibiting cAMP-mediated electrogenic chloride secretion in the airway epithelium (40).…”

Section: Discussionmentioning

confidence: 96%

“…Previous findings have shown that species-specific differences exist in the sensitivities of human, pig, ferret, and mouse CFTR to different CFTR inhibitors using cultured primary polarized airway epithelia (40). In the ferret, GlyH-101 was most effective at inhibiting cAMP-mediated electrogenic chloride secretion in the airway epithelium (40). In WT trachea, GlyH-101 inhibited all of the cAMP-mediated chloride current assigned to CFTR based on the lack of current in CF animals.…”

Section: Discussionmentioning

confidence: 98%

See 2 more Smart Citations

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Fisher¹,

Tyler

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

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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 (I SC ) 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 4,49-diisothiocyano-2,29-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 I SC 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 I SC 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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Fisher¹,

Tyler

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

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“…Second, the expression pattern of the CFTR gene is extremely similar in ferret and human airways (9,10), with the highest levels in submucosal glands. Bioelectric and pharmacologic properties of the CFTR chloride channel in ferret airway epithelia are also similar to those seen in human airway epithelia (11). In contrast to those of mice, ferret and human tracheobronchial airways contain abundant submucosal glands that express high levels of CFTR (9,10,12); these glands have been shown to be critical for airway innate immunity in the ferret (13), as predicted for humans (14,15).…”

Section: Introductionmentioning

confidence: 58%

Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

Sun

Yan²,

Yi³

et al. 2008

J. Clin. Invest.

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139

122

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Somatic cell gene targeting combined with nuclear transfer cloning presents tremendous potential for the creation of new, large-animal models of human diseases. Mouse disease models often fail to reproduce human phenotypes, underscoring the need for the generation and study of alternative disease models. Mice deficient for CFTR have been poor models for cystic fibrosis (CF), lacking many aspects of human CF lung disease. In this study, we describe the production of a CFTR gene-deficient model in the domestic ferret using recombinant adeno-associated virus-mediated gene targeting in fibroblasts, followed by nuclear transfer cloning. As part of this approach, we developed a somatic cell rejuvenation protocol using serial nuclear transfer to produce live CFTR-deficient clones from senescent gene-targeted fibroblasts. We transferred 472 reconstructed embryos into 11 recipient jills and obtained 8 healthy male ferret clones heterozygous for a disruption in exon 10 of the CFTR gene. To our knowledge, this study represents the first description of genetically engineered ferrets and describes an approach that may be of substantial utility in modeling not only CF, but also other genetic diseases.

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“…This pretreatment is confirmed to inhibit acid-induced HCO 3 Ϫ secretion due to CFTR inhibition in rat duodenum (4). Furthermore, CFTRinh-172 has been recognized as a potent and selective CFTR inhibitor in the gastrointestinal tract of rodents (26,36), although its efficacy is dependent on tissue type (less potent in airway epithelia) and species (less potent in pig and ferret than in human and mouse) (25). CFTR inh-172 inhibition can mimic CFTR dysfunction in human tracheal epithelia (29).…”

Section: Measurement Of Luminal Ph and [Co2]mentioning

confidence: 78%

CFTR inhibition augments NHE3 activity during luminal high CO₂exposure in rat duodenal mucosa

Mizumori

Choi²,

Guth³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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We hypothesized that the function of duodenocyte apical membrane acid-base transporters are essential for H ϩ absorption from the lumen. We thus examined the effect of inhibition of Na ϩ /H ϩ exchanger-3 (NHE3), cystic fibrosis transmembrane regulator (CFTR), or apical anion exchangers on transmucosal CO 2 diffusion and HCO 3 Ϫ secretion in rat duodenum. Duodena were perfused with a pH 6.4 high CO 2 solution or pH 2.2 low CO2 solution with the NHE3 inhibitor, S3226, the anion transport inhibitor, DIDS, or pretreatment with the potent CFTR inhibitor, CFTRinh-172, with simultaneous measurements of luminal and portal venous (PV) pH and carbon dioxide concentration ([CO2] Ϫ loss by NHE3 inhibition and reduced intracellular acidification during CFTR inhibition is consistent with activation or unmasking of NHE3 activity by CFTR inhibition, increasing cell surface H ϩ available to neutralize luminal HCO 3 Ϫ with consequent CO2 absorption. NHE3, by secreting H ϩ into the luminal microclimate, facilitates net transmucosal HCO 3 Ϫ absorption with a mechanism similar to proximal tubular HCO 3 Ϫ absorption.CO 2 absorption; bicarbonate secretion; portal venous PCO2 EPITHELIAL HCO 3 Ϫ SECRETION is considered to be the primary defense against duodenal injury from gastric acid. One of the unexplained mysteries of duodenal HCO 3 Ϫ secretion is why it is needed, given that secretion into the lumen from pancreas and liver is more than adequate to fully neutralize the bulk luminal content (13). Epithelial HCO 3 Ϫ secretion has thus been hypothesized to neutralize a distinct "preepithelial layer" adjacent to the apical plasma membrane of the mucosa (10, 24). Moreover, the upper intestine absorbs HCO 3 Ϫ by an electroneutral Na ϩ -dependent mechanism, hypothesized to be Na ϩ /H ϩ exchange (37). Since the epithelial Na ϩ /H ϩ exchanger (NHE) 3, which helps facilitate intestinal neutral NaCl absorption, is highly expressed in duodenum (31), we wondered whether duodenal NHE3 additionally functions as an H ϩ secretor, as it does in the proximal tubule (33, 38), facilitating HCO 3 Ϫ absorption. The duodenum must also absorb ϳ450 mmol of gastric H ϩ /24 h to decrease luminal hydrogen concentration ([H ϩ ]) by 6 log orders over its 15-cm length (12). HCl in the duodenal lumen is neutralized by HCO 3 Ϫ secreted by the pancreas and duodenal epithelium. This generates extremely high luminal CO 2 pressures (PCO 2 Ͼ 400 Torr), which are dissipated by the proximal jejunum (32). Gastric mucosal CO 2 and H ϩ permeability is low, since pyloric obstruction leads to severe metabolic alkalosis due to the inability of the normal stomach to absorb substantial quantities of H ϩ or CO 2 (16). Thus the duodenum is the major site for intestinal H ϩ and CO 2 absorption.We have demonstrated sequential transmucosal CO 2 and H ϩ movement from duodenal lumen into the portal vein (PV), facilitated by epithelial cytosolic and membrane-bound carbonic anhydrases (CAs) in the rat (27). Cellular acidification by luminal CO 2 /H ϩ rapidly induces protective responses su...

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Bioelectric Properties of Chloride Channels in Human, Pig, Ferret, and Mouse Airway Epithelia

Cited by 80 publications

References 53 publications

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

CFTR inhibition augments NHE3 activity during luminal high CO₂exposure in rat duodenal mucosa

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Bioelectric Properties of Chloride Channels in Human, Pig, Ferret, and Mouse Airway Epithelia

Cited by 80 publications

References 53 publications

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

CFTR inhibition augments NHE3 activity during luminal high CO2exposure in rat duodenal mucosa

Contact Info

Product

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CFTR inhibition augments NHE3 activity during luminal high CO₂exposure in rat duodenal mucosa