2016
DOI: 10.1172/jci.insight.85717
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Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π

Abstract: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione-S-transferase π (GSTP). To date, no published infor… Show more

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Cited by 38 publications
(39 citation statements)
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“…The increased expression of this enzyme is observed, in particular, in pulmonary fibrosis, which may be related to its involvement into the Sglutathionylation of FAS-a tumor necrosis factor (TNF) superfamily member, whose activation by binding the FAS ligand triggers apoptosis of the airway epitheliocytes. The latter leads to an imbalance between populations of epitheliocytes and myofibroblasts and stimulates fibrous tissue remodeling [55]. That is, an increase in GST activity may be a sign of myofibroblast activation and fibrous liver tissue degeneration.…”
Section: Discussionmentioning
confidence: 99%
“…The increased expression of this enzyme is observed, in particular, in pulmonary fibrosis, which may be related to its involvement into the Sglutathionylation of FAS-a tumor necrosis factor (TNF) superfamily member, whose activation by binding the FAS ligand triggers apoptosis of the airway epitheliocytes. The latter leads to an imbalance between populations of epitheliocytes and myofibroblasts and stimulates fibrous tissue remodeling [55]. That is, an increase in GST activity may be a sign of myofibroblast activation and fibrous liver tissue degeneration.…”
Section: Discussionmentioning
confidence: 99%
“…Moreover, contrary to suggestions that GSTP1 and GRX can both similarly promote S -glutathionylation of target proteins in the presence of GSSG, experimental studies typically demonstrate opposing actions of these enzymes on protein S -glutathionylation in biological systems (e.g. [76, 77]). Although the importance of GSSG-driven mechanisms in promoting protein S -glutathionylation may be unlikely, they are difficult to rule out completely, since localized oxidative events (as highlighted in the previous section) might conceivably generate localized conditions that could allow GSSG-driven S -glutathionylation reactions.…”
Section: Chemical Detection Of Sulfenic Acid: Is It In Fact Sulfenmentioning
confidence: 95%
“…Experiments in a clinically relevant disease model of lung fibrosis recently demonstrated the importance of GSTs for protein S-glutathionylation. GSTp ablation in mice attenuates protein S-glutathionylation and lung fibrosis due to the mitigation of Fas ligand (CD95L) mediated cell death of lung epithelial cells (125). S-glutathionylation of the Fas receptor amplifies epithelial cell apoptosis (9,12), and thus, using therapeutic strategies to diminish protein glutathionylation including airway delivery of Glrx (10,11) or the GSTp inhibitor TLK117 (125) attenuates lung fibrosis.…”
Section: Reversible Protein S-glutathionylationmentioning
confidence: 99%
“…Intra-tracheal administration of recombinant Glrx also suppresses fibrosis in mouse lungs, suggesting the potential therapeutic use of Glrx to treat pulmonary fibrosis (11). Decreasing S-glutathionylation by inhibiting GSTp, such as using GSTp inhibitor TLK117, is another strategy to treat lung fibrosis (125).…”
Section: Airway and Lungmentioning
confidence: 99%