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Glycogen Synthase Kinase-3β Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis
- Source :
- Scientific Reports, Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
- Publication Year :
- 2019
-
Abstract
- Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a median survival of 3 years after diagnosis. Although the etiology of IPF is unknown, it is characterized by extensive alveolar epithelial cell apoptosis and proliferation of myofibroblasts in the lungs. While the origins of these myofibroblast appear to be diverse, fibroblast differentiation contributes to expansion of myofibroblasts and to disease progression. We found that agents that contribute to neomatrix formation and remodeling in pulmonary fibrosis (PF); TGF-β, Factor Xa, thrombin, plasmin and uPA all induced fibroblast/myofibroblast differentiation. These same mediators enhanced GSK-3β activation via phosphorylation of tyrosine-216 (p-Y216). Inhibition of GSK-3β signaling with the novel inhibitor 9-ING-41 blocked the induction of myofibroblast markers; α-SMA and Col-1 and reduced morphological changes of myofibroblast differentiation. In in vivo studies, the progression of TGF-β and bleomycin mediated PF was significantly attenuated by 9-ING-41 administered at 7 and 14 days respectively after the establishment of injury. Specifically, 9-ING-41 treatment significantly improved lung function (compliance and lung volumes; p ex vivo and pulmonary fibrosis in vivo. The results offer a strong premise supporting the continued investigation of the GSK-3β signaling pathway in the control of fibroblast-myofibroblast differentiation and fibrosing lung injury. These data provide a strong rationale for extension of clinical trials of 9-ING-41 to patients with IPF.
- Subjects :
- 0301 basic medicine
Indoles
Pulmonary Fibrosis
lcsh:Medicine
macromolecular substances
Lung injury
Bleomycin
Article
Target validation
Maleimides
03 medical and health sciences
chemistry.chemical_compound
Idiopathic pulmonary fibrosis
Mice
0302 clinical medicine
GSK-3
Pulmonary fibrosis
medicine
Animals
lcsh:Science
Lung
Multidisciplinary
Glycogen Synthase Kinase 3 beta
business.industry
lcsh:R
Interstitial lung disease
Growth factor signalling
respiratory system
medicine.disease
3. Good health
030104 developmental biology
medicine.anatomical_structure
chemistry
030220 oncology & carcinogenesis
Cancer research
lcsh:Q
business
Myofibroblast
Signal Transduction
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 9
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific reports
- Accession number :
- edsair.doi.dedup.....8845d982a43ee30212fe0d5362d2476d