Bortezomib Inhibits Lung Fibrosis and Fibroblast Activation without Proteasome Inhibition
| Autor: | Christina Draijer, Loka R. Penke, Scott H. Wettlaufer, Jennifer M. Speth, Marc Peters-Golden |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Adult
Pulmonary and Respiratory Medicine Transcription Genetic Pulmonary Fibrosis Clinical Biochemistry Apoptosis Cell Line Bortezomib Bleomycin Transforming Growth Factor beta Fibrosis In vivo Pulmonary fibrosis medicine Humans fas Receptor Myofibroblasts Fibroblast Molecular Biology Cell Proliferation Original Research Gene knockdown Kinase Chemistry NF-kappa B Dual Specificity Phosphatase 1 Cell Biology Cell Dedifferentiation Fibroblasts medicine.disease medicine.anatomical_structure Proteasome Prostaglandins Cancer research Fibroblast Growth Factor 2 Proteasome Inhibitors Myofibroblast Signal Transduction medicine.drug |
| Zdroj: | Am J Respir Cell Mol Biol |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2021-0112oc |
| Popis: | The U.S. Food and Drug Administration–approved proteasomal inhibitor bortezomib (BTZ) has attracted interest for its potential antifibrotic actions. However, neither its in vivo efficacy in lung fibrosis nor its dependence on proteasome inhibition has been conclusively defined. In this study, we assessed the therapeutic efficacy of BTZ in a mouse model of pulmonary fibrosis, developed an in vitro protocol to define its actions on diverse fibroblast activation parameters, determined its reliance on proteasome inhibition for these actions in vivo and in vitro, and explored alternative mechanisms of action. The therapeutic administration of BTZ diminished the severity of pulmonary fibrosis without reducing proteasome activity in the lung. In experiments designed to mimic this lack of proteasome inhibition in vitro, BTZ reduced fibroblast proliferation, differentiation into myofibroblasts, and collagen synthesis. It promoted dedifferentiation of myofibroblasts and overcame their characteristic resistance to apoptosis. Mechanistically, BTZ inhibited kinases important for fibroblast activation while inducing the expression of DUSP1 (dual-specificity protein phosphatase 1), and knockdown of DUSP1 abolished its antifibrotic actions in fibroblasts. Collectively, these findings suggest that BTZ exhibits a multidimensional profile of robust inhibitory actions on lung fibroblasts as well as antifibrotic actions in vivo. Unexpectedly, these actions appear to be independent of proteasome inhibition, instead attributable to the induction of DUSP1. |
| Databáze: | OpenAIRE |
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