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Inhibition of Glycogen Synthase Kinase 3β Blocks Mesomesenchymal Transition and Attenuates Streptococcus pneumonia-Mediated Pleural Injury in Mice. | LitMetric

AI Article Synopsis

  • - Pleural loculation affects around 30,000 patients in the U.S. each year and can lead to serious lung conditions like restrictive lung disease due to a process where pleural mesothelial cells transition to a profibrotic state (MesoMT).
  • - The fibrinolytic pathway components can induce MesoMT, and the involvement of the enzyme GSK-3β is crucial, as its down-regulation prevents this transition and restores normal cell behavior.
  • - Treatment with GSK-3β inhibitor 9ING41 showed promising results in mouse models, improving lung function and reducing pleural fibrosis, suggesting it could be a new target for treating complications related to empyema.

Article Abstract

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 α-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)-3β activity through increased phosphorylation of Tyr-216 in pleural mesothelial cells and GSK-3β mobilization from the cytoplasm to the nucleus. GSK-3β down-regulation blocked induction of MesoMT. Likewise, GSK-3β 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 α-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-3β as a newly identified target for amelioration of empyema-related pleural fibrosis and provide a strong rationale for further investigation of GSK-3β signaling in the control of MesoMT and pleural injury.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809597PMC
http://dx.doi.org/10.1016/j.ajpath.2017.07.007DOI Listing

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