title: Adenovirus-mediated gene transfer of hIGF-IB in mouse lungs induced prolonged inflammation but no fibroproliferation.
abstract: Pulmonary fibrosis (PF), the end stage of a variety of fibroproliferative lung diseases, is characterized by excessive lung mesenchymal cell activation and extracellular matrix deposition. Most PF is induced after repetitive or chronic lung inflammation; however, a significant portion of PF occurs without apparent inflammation. The mechanisms of fibroproliferation are poorly understood. Studies have shown that cytokines regulating inflammation and tissue repair processes play essential roles in the development of PF. Insulin-like growth factor I (IGF-I) has been shown to stimulate lung mesenchymal cell proliferation and extracellular matrix synthesis in vitro and is significantly elevated in patients with PF. In this study, we investigated whether human IGF-IB (hIGF-IB) expression in the lungs induces PF in a C57BL/6 mouse model. Mice were subjected to adenoviral gene transfer, and the effects of hIGF-IB expression on the lungs were examined 3, 7, 14, 21, and 42 days after gene delivery. hIGF-IB expression induced significant and prolonged inflammatory cell infiltration into the lungs, with an early neutrophil infiltration followed by a late macrophage infiltration. No significant fibroblast or matrix accumulation could be detected in the lungs of these mice. No significant collagen accumulation could be detected in vivo, despite in vitro evidence that hIGF-IB induces collagen mRNA expression in fibroblasts. Therefore, IGF-IB alone is not sufficient to induce fibrosis, and it is possible that a coactivator is required to induce significant fibroproliferation in vivo.
authors.affiliation: Department of Physiology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Léger
authors.forename: Ai
authors.initials: A
authors.lastname: Ni
authors.forename: Graciela
authors.initials: G
authors.lastname: Andonegui
authors.forename: Josée
authors.initials: J
authors.lastname: Wong
authors.forename: Connie
authors.initials: C
authors.lastname: Mowat
authors.forename: Brent W
authors.initials: BW
authors.lastname: Winston
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002465:Cell Movement; D049109:Cell Proliferation; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000150:complications / Q000473:pathology*; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I