title: Sequential expression of IGF-IB followed by active TGF-β1 induces synergistic pulmonary fibroproliferation in vivo.
abstract: Pulmonary fibrosis, the end stage of a variety of fibroproliferative lung diseases, is usually induced after repetitive or chronic lung injury or inflammation. The mechanisms of fibroproliferation are poorly understood. Insulin-like growth factor-I (IGF-I) is significantly elevated in patients with pulmonary fibrosis and fibroproliferative acute respiratory distress syndrome. However, we showed that IGF-I overexpression alone in wild-type mouse lungs does not cause fibroproliferation. We therefore questioned whether IGF-I, acting together with active TGF-β1, a known profibrotic cytokine, enhances pulmonary fibroproliferation caused by active TGF-β1. A unique sequential adenoviral transgene mouse model was used expressing AdEmpty/AdTGF-β1 or AdhIGF-IB/AdTGF-β1 transgenes. IGF-IB plus active TGF-β1 transgene expression synergistically increased collagen deposition in the lung parenchyma compared with active TGF-β1 expression alone. The enhanced fibrosis was accompanied by an increased recruitment of macrophages and lymphocytes into the bronchoalveolar lavage fluid (BALF) and inflammatory cells in the lungs. α-Smooth muscle actin expression, a marker of myofibroblast proliferation and differentiation, was also increased. Finally, fibroblasts exposed ex vivo to BALF isolated from AdhIGF-IB/AdTGF-β1-transduced mice showed synergistic collagen induction compared with BALF from AdEmpty/AdTGF-β1-transduced mice. This study provides the first direct evidence that IGF-I is able to synergistically enhance pulmonary fibroproliferation in cooperation with TGF-β1.
authors.affiliation: Department of Critical Care Medicine, Faculty of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andonegui
authors.forename: Ai
authors.initials: A
authors.lastname: Ni
authors.forename: Caroline
authors.initials: C
authors.lastname: Léger
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Kelly
authors.forename: Josée F
authors.initials: JF
authors.lastname: Wong
authors.forename: Ali
authors.initials: A
authors.lastname: Jalloul
authors.forename: Brent W
authors.initials: BW
authors.lastname: Winston
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002460:Cell Line; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D034421:Sus scrofa; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D016207:Cytokines; D018836:Inflammation Mediators; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I