Intratracheal cell transfer demonstrates the profibrotic potential of resident fibroblasts in pulmonary fibrosis

Pulmonary fibrosis is a devastating disease for which there are few effective therapies. Activated fibroblasts form subepithelial clusters known as fibroblastic foci, which are characterized by excessive collagen deposition. The origin of activated fibroblasts is controversial and needs to be clarif...

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Veröffentlicht in:The American journal of pathology Jg. 185; H. 11; S. 2939
Hauptverfasser: Tsukui, Tatsuya, Ueha, Satoshi, Shichino, Shigeyuki, Inagaki, Yutaka, Matsushima, Kouji
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.11.2015
Schlagworte:
Animals
Bleomycin - adverse effects
Collagen - metabolism
Disease Models, Animal
Epithelial Cells - metabolism
Epithelial Cells - pathology
Epithelium - metabolism
Epithelium - pathology
Female
Fibroblasts - metabolism
Fibroblasts - pathology
Gene Expression Regulation
Genes, Reporter
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pulmonary Alveoli - metabolism
Pulmonary Alveoli - pathology
Pulmonary Fibrosis - metabolism
Pulmonary Fibrosis - pathology
Up-Regulation
ISSN:1525-2191, 1525-2191
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Zusammenfassung:Pulmonary fibrosis is a devastating disease for which there are few effective therapies. Activated fibroblasts form subepithelial clusters known as fibroblastic foci, which are characterized by excessive collagen deposition. The origin of activated fibroblasts is controversial and needs to be clarified to understand their pathogenicity. Here, using an intratracheal adoptive cell transfer method, we show that resident fibroblasts in alveolar walls have the highest profibrotic potential. By using collagen I(α)2-green fluorescent protein and neural/glial antigen 2-DsRed fluorescent reporter mice, we identified resident fibroblasts and pericytes in the alveolar walls based on surface marker expression and ultrastructural characteristics. In the early phase of bleomycin-induced pulmonary fibrosis, activated fibroblasts migrated into epithelium-denuded alveolar airspaces. Purified resident fibroblasts delivered into injured alveoli by an intratracheal route showed similar activated signatures as activated fibroblasts and formed fibroblastic foci. Neither pericytes nor epithelial cells had the same profibrotic potential. Transferred resident fibroblasts highly up-regulated profibrotic genes including α-smooth muscle actin and were a significant source of collagen deposition. These data provide insights into the cellular mechanisms of fibrogenesis and show intratracheal cell transfer to be a useful tool for exploring novel therapeutic targets against pulmonary fibrosis.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1525-2191
1525-2191
DOI:10.1016/j.ajpath.2015.07.022