Journal article
Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs
The Journal of clinical investigation, Vol.123(6), pp.2685-2693
06/03/2013
DOI: 10.1172/JCI68867
PMCID: PMC3668832
PMID: 23676501
Abstract
Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (
pCFTR
) cDNA under control of the intestinal fatty acid–binding protein (
iFABP
) promoter would alleviate the meconium ileus. We produced 5
CFTR
–/–
;TgFABP>pCFTR
lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type
CFTR
mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.
Details
- Title: Subtitle
- Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs
- Creators
- David A Stoltz - Department of Internal MedicineTatiana Rokhlina - Department of Internal MedicineSarah E Ernst - Department of Internal MedicineAlejandro A Pezzulo - Department of Internal MedicineLynda S Ostedgaard - Department of Internal MedicinePhilip H Karp - Department of Internal MedicineMelissa S Samuel - Department of Internal MedicineLeah R Reznikov - Department of Internal MedicineMichael V Rector - Department of Internal MedicineNicholas D Gansemer - Department of Internal MedicineDrake C Bouzek - Department of Internal MedicineMahmoud H. Abou Alaiwa - Department of Internal MedicineMark J Hoegger - Department of Internal MedicinePaula S Ludwig - Department of Internal MedicinePeter J Taft - Department of Internal MedicineTanner J Wallen - Department of Internal MedicineChristine Wohlford-Lenane - Department of Internal MedicineJames D McMenimen - Department of Internal MedicineJeng-Haur Chen - Department of Internal MedicineKatrina L Bogan - Department of Internal MedicineRyan J Adam - Department of Internal MedicineEmma E Hornick - Department of Internal MedicineGeorge A Nelson - Department of Internal MedicineEric A Hoffman - Department of Internal MedicineEugene H Chang - Department of Internal MedicineJoseph Zabner - Department of Internal MedicinePaul B McCray - Department of Internal MedicineRandall S Prather - Department of Internal MedicineDavid K Meyerholz - Department of Internal MedicineMichael J Welsh - Department of Internal Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.123(6), pp.2685-2693
- DOI
- 10.1172/JCI68867
- PMID
- 23676501
- PMCID
- PMC3668832
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 06/03/2013
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
- Record Identifier
- 9984020799202771
Metrics
31 Record Views