title: Overexpression of transforming growth factor-beta1 in fetal monkey lung results in prenatal pulmonary fibrosis.
abstract: Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident. Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.
authors.affiliation: Center for Fetal Monkey Gene Transfer for Heart, Lung, and Blood Diseases, California National Primate Research Center and Dept of Pediatrics, School of Medicine, University of California, Davis, CA, USA.
authors.forename: A F
authors.initials: AF
authors.lastname: Tarantal
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: T T
authors.initials: TT
authors.lastname: Shi
authors.forename: C-H
authors.initials: CH
authors.lastname: Lu
authors.forename: A B
authors.initials: AB
authors.lastname: Fang
authors.forename: S
authors.initials: S
authors.lastname: Buckley
authors.forename: M
authors.initials: M
authors.lastname: Kolb
authors.forename: J
authors.initials: J
authors.lastname: Gauldie
authors.forename: D
authors.initials: D
authors.lastname: Warburton
authors.forename: W
authors.initials: W
authors.lastname: Shi
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D049109:Cell Proliferation; D004549:Elastin / Q000737:chemistry; D005260:Female; D005355:Fibrosis / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D000882:Haplorhini; D006801:Humans; D008168:Lung / Q000196:embryology*; D008253:Macaca mulatta; D011247:Pregnancy; D011270:Pregnancy, Animal; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
chemical_list: D001391:Azo Compounds; D053773:Transforming Growth Factor beta1; C009798:C.I. direct red 80; D004549:Elastin