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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-\u03b2, Factor Xa, thrombin, plasmin and uPA all induced fibroblast\/myofibroblast differentiation. These same mediators enhanced GSK-3\u03b2 activation via phosphorylation of tyrosine-216 (p-Y216). Inhibition of GSK-3\u03b2 signaling with the novel inhibitor 9-ING-41 blocked the induction of myofibroblast markers; \u03b1-SMA and Col-1 and reduced morphological changes of myofibroblast differentiation. In <jats:italic>in vivo<\/jats:italic> studies, the progression of TGF-\u03b2 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\u2009&lt;\u20090.05) of TGF-\u03b2 adenovirus treated mice compared to controls. Similar results were found in mice with bleomycin-induced PF. These studies clearly show that activation of the GSK-3\u03b2 signaling pathway is critical for the induction of myofibroblast differentiation in lung fibroblasts <jats:italic>ex vivo<\/jats:italic> and pulmonary fibrosis <jats:italic>in vivo<\/jats:italic>. The results offer a strong premise supporting the continued investigation of the GSK-3\u03b2 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.<\/jats:p>","DOI":"10.1038\/s41598-019-55176-w","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T15:10:09Z","timestamp":1576163409000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Glycogen Synthase Kinase-3\u03b2 Inhibition with 9-ING-41 Attenuates the Progression of Pulmonary Fibrosis"],"prefix":"10.1038","volume":"9","author":[{"given":"Ann","family":"Jeffers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuzi","family":"Owens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen B.","family":"Koenig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Komatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis J.","family":"Giles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M.","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Idell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torry A.","family":"Tucker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"55176_CR1","doi-asserted-by":"publisher","first-page":"10490","DOI":"10.1074\/jbc.M116.752469","volume":"292","author":"S Ghatak","year":"2017","unstructured":"Ghatak, S. et al. 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