TY - JOUR
T1 - Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis
AU - Hashimoto, Naozumi
AU - Phan, Sem H.
AU - Imaizumi, Kazuyoshi
AU - Matsuo, Masaki
AU - Nakashima, Harunori
AU - Kawabe, Tsutomu
AU - Shimokata, Kaoru
AU - Hasegawa, Yoshinori
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/8/1
Y1 - 2010/8/1
N2 - 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 fibrosismaybe 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 α-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-β on the microvascular endothelial cell line MS1 were analyzed. Combined treatment with activated Ras and TGF-β 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-β 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.
AB - 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 fibrosismaybe 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 α-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-β on the microvascular endothelial cell line MS1 were analyzed. Combined treatment with activated Ras and TGF-β 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-β 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.
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U2 - 10.1165/rcmb.2009-0031OC
DO - 10.1165/rcmb.2009-0031OC
M3 - Article
C2 - 19767450
AN - SCOPUS:77955481200
VL - 43
SP - 161
EP - 172
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 2
ER -