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Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts
TGF‐β has an important role in fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Detailed analysis of TGF‐β signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine‐rich alpha‐2 glycoprotein (LRG) was reported to functi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742708/ https://www.ncbi.nlm.nih.gov/pubmed/29279415 http://dx.doi.org/10.14814/phy2.13556 |
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author | Honda, Hiromi Fujimoto, Minoru Serada, Satoshi Urushima, Hayato Mishima, Takashi Lee, Hyun Ohkawara, Tomoharu Kohno, Nobuoki Hattori, Noboru Yokoyama, Akihito Naka, Tetsuji |
author_facet | Honda, Hiromi Fujimoto, Minoru Serada, Satoshi Urushima, Hayato Mishima, Takashi Lee, Hyun Ohkawara, Tomoharu Kohno, Nobuoki Hattori, Noboru Yokoyama, Akihito Naka, Tetsuji |
author_sort | Honda, Hiromi |
collection | PubMed |
description | TGF‐β has an important role in fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Detailed analysis of TGF‐β signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine‐rich alpha‐2 glycoprotein (LRG) was reported to function as a modulator of TGF‐β signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including IPF, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout (KO) mice with bleomycin‐induced lung fibrosis, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild‐type (WT) mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, lung fibrosis was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of α‐SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the TGF‐β‐induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory TGF‐β receptor, is essential for LRG to promote TGF‐β signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes lung fibrosis by modulating TGF‐β‐induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts. |
format | Online Article Text |
id | pubmed-5742708 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57427082018-01-03 Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts Honda, Hiromi Fujimoto, Minoru Serada, Satoshi Urushima, Hayato Mishima, Takashi Lee, Hyun Ohkawara, Tomoharu Kohno, Nobuoki Hattori, Noboru Yokoyama, Akihito Naka, Tetsuji Physiol Rep Original Research TGF‐β has an important role in fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Detailed analysis of TGF‐β signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine‐rich alpha‐2 glycoprotein (LRG) was reported to function as a modulator of TGF‐β signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including IPF, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout (KO) mice with bleomycin‐induced lung fibrosis, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild‐type (WT) mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, lung fibrosis was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of α‐SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the TGF‐β‐induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory TGF‐β receptor, is essential for LRG to promote TGF‐β signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes lung fibrosis by modulating TGF‐β‐induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts. John Wiley and Sons Inc. 2017-12-26 /pmc/articles/PMC5742708/ /pubmed/29279415 http://dx.doi.org/10.14814/phy2.13556 Text en © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Honda, Hiromi Fujimoto, Minoru Serada, Satoshi Urushima, Hayato Mishima, Takashi Lee, Hyun Ohkawara, Tomoharu Kohno, Nobuoki Hattori, Noboru Yokoyama, Akihito Naka, Tetsuji Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts |
title | Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts |
title_full | Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts |
title_fullStr | Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts |
title_full_unstemmed | Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts |
title_short | Leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating TGF‐β signaling in fibroblasts |
title_sort | leucine‐rich α‐2 glycoprotein promotes lung fibrosis by modulating tgf‐β signaling in fibroblasts |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742708/ https://www.ncbi.nlm.nih.gov/pubmed/29279415 http://dx.doi.org/10.14814/phy2.13556 |
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