Back to Search
Start Over
Antifibrotic role of αB-crystallin inhibition in pleural and subpleural fibrosis.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2015 Feb; Vol. 52 (2), pp. 244-52. - Publication Year :
- 2015
-
Abstract
- Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and extracellular-matrix accumulation. IPF typically starts in subpleural lung regions, and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts (mesothelio-mesenchymal transition) is induced by the profibrotic cytokine, transforming growth factor (TGF)-β1, and is thought to play a role in the development and progression of IPF. The Mothers Against Decapentaplegic homolog (Smad)-dependent pathway is the main TGF-β1 pathway involved in fibrosis. αB-crystallin is constitutively expressed in the lungs, and is inducible by stress, acts as a chaperon, and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of αB-crystallin hampered TGF-β1 signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here, for the first time, that αB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from patients with IPF and in rodent models of pleural/subpleural fibrosis. αB-crystallin-deficient mice are protected from pleural/subpleural fibrosis induced by the transient adenoviral-mediated overexpression of TGF-β1 or the intrapleural injection of bleomycin combined with carbon particles. We show that αB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of mesothelio-mesenchymal transition. αB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts, thus limiting their migration in vivo and the progression of fibrosis in the lung parenchyma. In conclusion, our work demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF.
- Subjects :
- Animals
Cytoskeleton drug effects
Disease Models, Animal
Epithelial Cells drug effects
Humans
Idiopathic Pulmonary Fibrosis pathology
Mice
Mice, Knockout
Pleura metabolism
Signal Transduction drug effects
Transforming Growth Factor beta1 metabolism
Bleomycin pharmacology
Crystallins metabolism
Idiopathic Pulmonary Fibrosis drug therapy
Myofibroblasts drug effects
Pleura drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 52
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 25032514
- Full Text :
- https://doi.org/10.1165/rcmb.2014-0011OC