title: Targeted gene transfer of hepatocyte growth factor to alveolar type II epithelial cells reduces lung fibrosis in rats.
abstract: Inefficient alveolar wound repair contributes to the development of pulmonary fibrosis. Hepatocyte growth factor (HGF) is a potent growth factor for alveolar type II epithelial cells (AECII) and may improve repair and reduce fibrosis. We studied whether targeted gene transfer of HGF specifically to AECII improves lung fibrosis in bleomycin-induced lung fibrosis. A plasmid encoding human HGF expressed from the human surfactant protein C promoter (pSpC-hHGF) was designed, and extracorporeal electroporation-mediated gene transfer of HGF specifically to AECII was performed 7 days after bleomycin-induced lung injury in the rat. Animals were killed 7 days after hHGF gene transfer. Electroporation-mediated HGF gene transfer resulted in HGF expression specifically in AECII at biologically relevant levels. HGF gene transfer reduced pulmonary fibrosis as assessed by histology, hydroxyproline determination, and design-based stereology compared with controls. Our results indicate that the antifibrotic effect of HGF is due in part to a reduction of transforming growth factor-β(1), modulation of the epithelial-mesenchymal transition, and reduction of extravascular fibrin deposition. We conclude that targeted HGF gene transfer specifically to AECII decreases bleomycin-induced lung fibrosis and may therefore represent a novel cell-specific gene transfer technology to treat pulmonary fibrosis.
authors.affiliation: Department of Pulmonary Medicine, University Hospital Bern, 3010 Bern, Switzerland.
authors.forename: Amiq
authors.initials: A
authors.lastname: Gazdhar
authors.forename: Almas
authors.initials: A
authors.lastname: Temuri
authors.forename: Lars
authors.initials: L
authors.lastname: Knudsen
authors.forename: Mathias
authors.initials: M
authors.lastname: Gugger
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Schmid
authors.forename: Matthias
authors.initials: M
authors.lastname: Ochs
authors.forename: Thomas
authors.initials: T
authors.lastname: Geiser
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D018274:Electroporation; D004847:Epithelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018390:Gene Targeting / Q000379:methods*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008854:Microscopy, Electron; D011650:Pulmonary Alveoli / Q000166:cytology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D001761:Bleomycin; D017228:Hepatocyte Growth Factor