Regulation of Transforming Growth Factor-beta 1-driven Lung Fibrosis by Galectin-3
(2012) In American Journal of Respiratory and Critical Care Medicine 185(5). p.537-546- Abstract
- Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: To examine the role of galectin-3 in pulmonary fibrosis. Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF. Measurements and Main Results:... (More)
- Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: To examine the role of galectin-3 in pulmonary fibrosis. Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF. Measurements and Main Results: Transforming growth factor (TGF)-beta and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-beta 1 induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of beta-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin -3, TD139, blocked TGF-beta-induced beta-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that. galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF. Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF. (Less)
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https://lup.lub.lu.se/record/2379325
- author
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- fibrosis, epithelial cells, fibroblasts
- in
- American Journal of Respiratory and Critical Care Medicine
- volume
- 185
- issue
- 5
- pages
- 537 - 546
- publisher
- American Thoracic Society
- external identifiers
-
- wos:000300858400014
- scopus:84857881755
- pmid:22095546
- ISSN
- 1535-4970
- DOI
- 10.1164/rccm.201106-0965OC
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Division of Microbiology, Immunology and Glycobiology - MIG (013025200), Organic chemistry (S/LTH) (011001240)
- id
- 0ae9c1cc-1e82-466b-b259-1da220437290 (old id 2379325)
- date added to LUP
- 2016-04-01 09:48:07
- date last changed
- 2022-04-19 19:23:32
@article{0ae9c1cc-1e82-466b-b259-1da220437290,
abstract = {{Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic dysregulated response to alveolar epithelial injury with differentiation of epithelial cells and fibroblasts into matrix-secreting myofibroblasts resulting in lung scaring. The prognosis is poor and there are no effective therapies or reliable biomarkers. Galectin-3 is a beta-galactoside binding lectin that is highly expressed in fibrotic tissue of diverse etiologies. Objectives: To examine the role of galectin-3 in pulmonary fibrosis. Methods: We used genetic deletion and pharmacologic inhibition in well-characterized murine models of lung fibrosis. Further mechanistic studies were performed in vitro and on samples from patients with IPF. Measurements and Main Results: Transforming growth factor (TGF)-beta and bleomycin-induced lung fibrosis was dramatically reduced in mice deficient in galectin-3, manifest by reduced TGF-beta 1 induced EMT and myofibroblast activation and collagen production. Galectin-3 reduced phosphorylation and nuclear translocation of beta-catenin but had no effect on Smad2/3 phosphorylation. A novel inhibitor of galectin -3, TD139, blocked TGF-beta-induced beta-catenin activation in vitro and in vivo and attenuated the late-stage progression of lung fibrosis after bleomycin. There was increased expression of galectin-3 in the bronchoalveolar lavage fluid and serum from patients with stable IPF compared with nonspecific interstitial pneumonitis and controls, which rose sharply during an acute exacerbation suggesting that. galectin-3 may be a marker of active fibrosis in IPF and that strategies that block galectin-3 may be effective in treating acute fibrotic exacerbations of IPF. Conclusions: This study identifies galectin-3 as an important regulator of lung fibrosis and provides a proof of principle for galectin-3 inhibition as a potential novel therapeutic strategy for IPF.}},
author = {{MacKinnon, Alison C. and Gibbons, Michael A. and Farnworth, Sarah L. and Leffler, Hakon and Nilsson, Ulf and Delaine, Tamara and Simpson, A. John and Forbes, Stuart J. and Hirani, Nik and Gauldie, Jack and Sethi, Tariq}},
issn = {{1535-4970}},
keywords = {{fibrosis; epithelial cells; fibroblasts}},
language = {{eng}},
number = {{5}},
pages = {{537--546}},
publisher = {{American Thoracic Society}},
series = {{American Journal of Respiratory and Critical Care Medicine}},
title = {{Regulation of Transforming Growth Factor-beta 1-driven Lung Fibrosis by Galectin-3}},
url = {{http://dx.doi.org/10.1164/rccm.201106-0965OC}},
doi = {{10.1164/rccm.201106-0965OC}},
volume = {{185}},
year = {{2012}},
}