GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis
| Autor: | Carlo Agostini, Fiorella Calabrese, Fabrizio Vianello, Ilaria Caputo, Carla Felice, Carmela Gurrieri, Francesco Cinetto, Jessica Ceccato, Gianpietro Semenzato, Marcello Rattazzi, Maria Piazza, Barbara Montini, Riccardo Scarpa, Francesca Lunardi, Daniela Cangiano |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
QH301-705.5 bleomycin-induced lung injury Inflammation macromolecular substances Lung injury Biochemistry Genetics and Molecular Biology (miscellaneous) Biochemistry Alveolar cells 03 medical and health sciences Idiopathic pulmonary fibrosis 0302 clinical medicine Fibrosis GSK-3 medicine Molecular Biosciences Biology (General) metalloproteases Molecular Biology Original Research medicine.diagnostic_test Chemistry respiratory system medicine.disease extracellular matrix (ECM) glycogen synthase kinase 3 idiopathic lung fibrosis 030104 developmental biology Bronchoalveolar lavage medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research medicine.symptom Myofibroblast |
| Zdroj: | Frontiers in Molecular Biosciences Frontiers in Molecular Biosciences, Vol 8 (2021) |
| Popis: | Idiopathic pulmonary fibrosis (IPF) is mainly characterized by aberrant extracellular matrix deposition, consequent to epithelial lung injury and myofibroblast activation, and inflammatory response. Glycogen synthase kinase 3 (GSK-3) is a serine–threonine kinase involved in several pathways, and its inhibition has been already suggested as a therapeutic strategy for IPF patients. There is evidence that GSK-3 is able to induce matrix metalloproteinase (MMP) expression and that its inhibition modulates MMP expression in the tissues. The aim of our study was to investigate the role of GSK-3 and its inhibition in the modulation of MMP-9 and -2 in anin vivomouse model of lung fibrosis andin vitrousing different cell lines exposed to pro-inflammatory or pro-fibrotic stimuli. We found that GSK-3 inhibition down-modulates gene expression and protein levels of MMP-9, MMP-2, and their inhibitors TIMP-1 and TIMP-2 in inflammatory cells harvested from bronchoalveolar lavage fluid (BALF) of mice treated with bleomycin as well as in interstitial alveolar macrophages and cuboidalized epithelial alveolar cells. To the same extent, GSK-3 inhibition blunted the increased MMP-9 and MMP-2 activity induced by pro-fibrotic stimuli in a human lung fibroblast cell line. Moreover, the αSMA protein level, a marker of fibroblast-to-myofibroblast transition involved in fibrosis, was decreased in primary fibroblasts treated with TGFβ following GSK-3 inhibition. Our results confirm the implication of GSK-3 in lung inflammation and fibrosis, suggesting that it might play its role by modulating MMP expression and activity but also pushing fibroblasts toward a myofibroblast phenotype and therefore enhancing extracellular matrix deposition. Thus, its inhibition could represent a possible therapeutic strategy. |
| Databáze: | OpenAIRE |
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