Antifibrotic role of αB-crystallin inhibition in pleural and subpleural fibrosis.

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.

• Authors: Pierre-Simon Bellaye, Olivier Burgy, Julien Colas, Aurélie Fabre, Joëlle Marchal-Somme, Bruno Crestani, Martin Kolb, Philippe Camus, Carmen Garrido, Philippe Bonniaud
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 52 Issue 2 Pg. 244-52 (Feb 2015) ISSN: 1535-4989 [Electronic] United States
• PMID: 25032514 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Crystallins
• Transforming Growth Factor beta1
• Bleomycin

Topics

• Animals
• Bleomycin (pharmacology)
• Crystallins (metabolism)
• Cytoskeleton (drug effects)
• Disease Models, Animal
• Epithelial Cells (drug effects)
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, pathology)
• Mice
• Mice, Knockout
• Myofibroblasts (drug effects)
• Pleura (drug effects, metabolism)
• Signal Transduction (drug effects)
• Transforming Growth Factor beta1 (metabolism)