Comparative Processing and Function of Human and Ferret Cystic Fibrosis Transmembrane Conductance Regulator

Fisher, John T.; Liu, Xiaoming; Yan, Ziying; Luo, Meihui; Zhou, Weihong; Lee, Benjamin; Song, Yi; Guo, Chenhong; Wang, Yujiong; Lukacs, Gergely L.; Engelhardt, John F.

doi:10.1074/jbc.m111.336537

Cited by 34 publications

(32 citation statements)

References 35 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Short-circuit current (I SC ) was measured using a VCC MC8 Multichannel voltage/ current clamp (Physiologic Instruments, San Diego, CA) as previously reported (19,20). For more details, see the MATERIALS AND METHODS in the online supplement.…”

Section: Electrophysiologic Studiesmentioning

confidence: 99%

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

Sun¹,

Olivier²,

Liang³

et al. 2014

Am J Respir Cell Mol Biol

Self Cite

114

122

View full text Add to dashboard Cite

Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets.

show abstract

Section: Electrophysiologic Studiesmentioning

confidence: 99%

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

Sun¹,

Olivier²,

Liang³

et al. 2014

Am J Respir Cell Mol Biol

Self Cite

114

122

View full text Add to dashboard Cite

show abstract

“…All tissues were harvested into Ringer's solution containing 1 mM indomethacin, and this level of indomethacin was maintained throughout the experiment to eliminate stimulation of cAMP production by endogenous prostaglandins (22,38). I SC and resistances (R) were measured using a VCC MC8 Multichannel voltage/current clamp (Physiologic Instruments) as previously reported (10,39). For more details on electrophysiologic measurements see the online supplement.…”

Section: Ussing Chamber Analysismentioning

confidence: 99%

“…To date, there are three reported species of CF animal models, including the mouse, pig, and ferret (5)(6)(7)(8). Characterization of each of these models has clearly demonstrated that species-specific differences in organ physiology and CFTR biology influence the extent of pathologic and electrophysiologic changes observed when CFTR is deleted or mutated (8)(9)(10)(11). CF ferrets have been shown to develop intestinal complications, diabetes, pancreatic disease, absence of the vas deferens, growth retardation, liver disease, and an elevated risk of developing lung infections (9,(11)(12)(13).…”

mentioning

confidence: 99%

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

Fisher¹,

Tyler

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Studies in animal models for CF with modification of CFTR develop multi-system disease, including pancreas and lung disease that have very similar pathology to that in patients (47,48,49). Endocrine pancreas function in the CFTR-null ferret is abnormal from birth, which suggests that it is an intrinsic defect in b-cell function in CF (47). In the same way as in humans, the glucose abnormalities progress with age in the Cftrnull animals as pancreatic fibrosis worsens.…”

Section: B-cell-specific Dysfunctionmentioning

confidence: 93%

“…For these patients, impaired insulin secretion is mostly apparent during the first phase, strongly indicating a defect at the level of the pancreatic b-cell. Studies in animal models for CF with modification of CFTR develop multi-system disease, including pancreas and lung disease that have very similar pathology to that in patients (47,48,49). Endocrine pancreas function in the CFTR-null ferret is abnormal from birth, which suggests that it is an intrinsic defect in b-cell function in CF (47).…”

Section: B-cell-specific Dysfunctionmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues

Barrio¹

2015

European Journal of Endocrinology

View full text Add to dashboard Cite

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). CFTR is primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver, and also the pancreas. CF-related diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence has confirmed that CFTR is an important regulator of insulin secretion by islet b-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either b-cell mass reduction or b-cell malfunction. Understanding such mechanisms is crucial for the development of the so-called 'transformational' therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators have recently shown in vitro capacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.

show abstract

Comparative Processing and Function of Human and Ferret Cystic Fibrosis Transmembrane Conductance Regulator

Cited by 34 publications

References 35 publications

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues

Contact Info

Product

Resources

About