title: Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis.
abstract: The pathological hallmark lesions in idiopathic pulmonary fibrosis are the fibroblastic foci, in which fibroblasts are thought to be involved in the tissue remodeling, matrix deposition, and cross-talk with alveolar epithelium. Recent evidence indicates that some fibroblasts in fibrosis may be derived from bone marrow progenitors as well as from epithelial cells through epithelial-mesenchymal transition. To evaluate whether endothelial cells could represent an additional source for fibroblasts, bleomycin-induced lung fibrosis was established in Tie2-Cre/CAG-CAT-LacZ double-transgenic mice, in which LacZ was stably expressed in pan-endothelial cells. Combined X-gal staining and immunocytochemical staining for type I collagen and alpha-smooth muscle actin revealed the presence of X-gal-positive cells in lung fibroblast cultures from bleomycin-treated mice. To explore the underlying mechanisms, by which loss of endothelial-specific markers and gain of mesenchymal phenotypes could be involved in microvascular endothelial cells, the effects of activated Ras and TGF-beta on the microvascular endothelial cell line MS1 were analyzed. Combined treatment with activated Ras and TGF-beta caused a significant loss of endothelial-specific markers, while inducing de novo mesenchymal phenotypes. The altered expression of these markers in MS1 cells with activated Ras persisted after withdrawal of TGF-beta in vitro and in vivo. These findings are the first to show that lung capillary endothelial cells could give rise to significant numbers of fibroblasts through an endothelial-mesenchymal transition in bleomycin-induced lung fibrosis model.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Japan.
authors.forename: Naozumi
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Sem H
authors.initials: SH
authors.lastname: Phan
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsuo
authors.forename: Harunori
authors.initials: H
authors.lastname: Nakashima
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawabe
authors.forename: Kaoru
authors.initials: K
authors.lastname: Shimokata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D001761:Bleomycin / Q000009:adverse effects*; D001854:Bone Marrow Cells / Q000166:cytology; D004727:Endothelium / Q000473:pathology*; D004848:Epithelium / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005434:Flow Cytometry / Q000379:methods; D008168:Lung / Q000473:pathology; D008648:Mesoderm / Q000473:pathology*; D051379:Mice; D011650:Pulmonary Alveoli / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin