Journal article
Keratinocyte growth factor induced epithelial proliferation facilitates retroviral-mediated gene transfer to distal lung epithelia in vivo
The journal of gene medicine, Vol.1(1), pp.22-30
01/1999
DOI: 10.1002/(SICI)1521-2254(199901/02)1:1<22::AID-JGM1>3.0.CO;2-X
PMID: 10738582
Abstract
Background
Cell proliferation, vector titer and accessibility of target cells represent hurdles for efficient gene transfer to lung epithelia in vivo using recombinant murine leukemia (MuLV)-based retroviruses. We tested the hypothesis that the pulmonary epithelium is susceptible to retroviral-mediated gene transfer when stimulated to proliferate by a mitogen, keratinocyte growth factor (KGF).
Methods
Rats received keratinocyte growth factor (KGF, 2.5 µg/g×4 doses, two consecutive days) intratracheally followed by high titer amphotropic retrovirus expressing β-galactosidase. Gene transfer was assessed five days later.
Results
KGF stimulated transient proliferation in the bronchiolar and alveolar epithelia (30–40% PCNA positive cells at peak) which decreased to background levels seven days after administration. Gene transfer to epithelia (X-Gal positive cells) occurred more frequently in KGF treated rats, but proliferation exceeded the level of gene transfer. X-gal positive cells were noted in the alveolar epithelium and occasionally in the bronchiolar epithelium. In order to understand the discrepancy between the number of proliferating and transduced cells, primary rat tracheal epithelium cultured at the air-liquid interface was infected from either the apical or basolateral side. Gene transfer was achieved only through basolateral application of vector, suggesting that epithelial polarity represents a barrier to MuLV-based lung gene transfer in vivo.
Conclusions
KGF transiently stimulates epithelial proliferation in vivo, facilitating MuLV-based gene transfer. Retroviral vectors may encounter multiple barriers which have evolved to defend the lung from infections.
Details
- Title: Subtitle
- Keratinocyte growth factor induced epithelial proliferation facilitates retroviral-mediated gene transfer to distal lung epithelia in vivo
- Creators
- Joseph Zabner - Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USAGuoshun Wang - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA, USAPaul B McCray Jr - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA, USAVladimir A Slepushkin - Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USAMordechai Bodner - Chiron Technologies-Center for Gene Therapy, San Diego, CA, USAHelmuth H. G van Es - IntroGene, Leiden, NetherlandsPatricia Thomas - Department of Pathology, University of Iowa College of Medicine, Iowa City, IA, USADoug J Jolly - Chiron Technologies-Center for Gene Therapy, San Diego, CA, USABeverly L Davidson - Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- The journal of gene medicine, Vol.1(1), pp.22-30
- DOI
- 10.1002/(SICI)1521-2254(199901/02)1:1<22::AID-JGM1>3.0.CO;2-X
- PMID
- 10738582
- NLM abbreviation
- J Gene Med
- ISSN
- 1099-498X
- eISSN
- 1521-2254
- Publisher
- John Wiley & Sons, Ltd
- Number of pages
- 9
- Language
- English
- Date published
- 01/1999
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984093358702771
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