AUTHOR=Cinetto Francesco , Ceccato Jessica , Caputo Ilaria , Cangiano Daniela , Montini Barbara , Lunardi Francesca , Piazza Maria , Agostini Carlo , Calabrese Fiorella , Semenzato Gianpietro , Rattazzi Marcello , Gurrieri Carmela , Scarpa Riccardo , Felice Carla , Vianello Fabrizio TITLE=GSK-3 Inhibition Modulates Metalloproteases in a Model of Lung Inflammation and Fibrosis JOURNAL=Frontiers in Molecular Biosciences VOLUME=8 YEAR=2021 URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2021.633054 DOI=10.3389/fmolb.2021.633054 ISSN=2296-889X ABSTRACT=

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 an in vivo mouse model of lung fibrosis and in vitro using 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.