| First Author | Boren J | Year | 2017 |
| Journal | Am J Pathol | Volume | 187 |
| Issue | 11 | Pages | 2461-2472 |
| PubMed ID | 29073967 | Mgi Jnum | J:249036 |
| Mgi Id | MGI:6094502 | Doi | 10.1016/j.ajpath.2017.07.007 |
| Citation | Boren J, et al. (2017) Inhibition of Glycogen Synthase Kinase 3beta Blocks Mesomesenchymal Transition and Attenuates Streptococcus pneumonia-Mediated Pleural Injury in Mice. Am J Pathol 187(11):2461-2472 |
| abstractText | Pleural loculation affects about 30,000 patients annually in the United States and in severe cases can resolve with restrictive lung disease and pleural fibrosis. Pleural mesothelial cells contribute to pleural rind formation by undergoing mesothelial mesenchymal transition (MesoMT), whereby they acquire a profibrotic phenotype characterized by increased expression of alpha-smooth muscle actin and collagen 1. Components of the fibrinolytic pathway (urokinase plasminogen activator and plasmin) are elaborated in pleural injury and strongly induce MesoMT in vitro. These same stimuli enhance glycogen synthase kinase (GSK)-3beta activity through increased phosphorylation of Tyr-216 in pleural mesothelial cells and GSK-3beta mobilization from the cytoplasm to the nucleus. GSK-3beta down-regulation blocked induction of MesoMT. Likewise, GSK-3beta inhibitor 9ING41 blocked induction of MesoMT and reversed established MesoMT. Similar results were demonstrated in a mouse model of Streptococcus pneumoniae-induced empyema. Intraperitoneal administration of 9ING41, after the induction of pleural injury, attenuated injury progression and improved lung function (lung volume and compliance; P < 0.05 compared with untreated and vehicle controls). MesoMT marker alpha-smooth muscle actin was reduced in 9ING41-treated mice. Pleural thickening was also notably reduced in 9ING41-treated mice (P < 0.05). Collectively, these studies identify GSK-3beta as a newly identified target for amelioration of empyema-related pleural fibrosis and provide a strong rationale for further investigation of GSK-3beta signaling in the control of MesoMT and pleural injury. |
