3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a glycogen synthase kinase-3 inhibitor, displays therapeutic properties in a mouse model of pulmonary inflammation and fibrosis

Carmela Gurrieri, Francesco Piazza, Marianna Gnoato, Barbara Montini, Lucia Biasutto, Cristina Gattazzo, Enrico Brunetta, Anna Cabrelle, Francesco Cinetto, Raffaele Niero, Monica Facco, Spiridione Garbisa, Fiorella Calabrese, Gianpietro Semenzato, Carlo Agostini

Research output: Contribution to journalArticle

Abstract

Glycogen synthase kinase (GSK)-3 modulates the production of inflammatory cytokines. Because bleomycin (BLM) causes lung injury, which is characterized by an inflammatory response followed by a fibrotic degeneration, we postulated that blocking GSK-3 activity with a specific inhibitor could affect the inflammatory and profibrotic cytokine network generated in the BLM-induced process of pulmonary inflammation and fibrosis. Thus, here we investigated the effects of the GSK-3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1Hindol-3-yl)- 1H-pyrrole-2,5-dione (SB216763) on a BLMinduced lung fibrosis model in mice. SB216763 prevented lung inflammation and the subsequent fibrosis when coad-ministered with BLM. Bronchoalveolar lavage fluid analysis of mice treated with BLM plus SB216763 revealed a significant reduction in BLM-induced alveolitis. Furthermore, SB216763 treatment was associated with a significantly lower production of inflammatory cytokines by macrophages. BLM-treated mice that received SB216763 developed alveolar epithelial cell damage and pulmonary fibrosis to a significantly lower extent compared with BLM-treated controls. These findings suggest that GSK-3 inhibition has a protective effect on lung fibrosis induced by BLM and candidate GSK-3 as a potential therapeutic target for preventing pulmonary fibrosis.

Original languageEnglish
Pages (from-to)785-794
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number3
DOIs
Publication statusPublished - Mar 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Gurrieri, C., Piazza, F., Gnoato, M., Montini, B., Biasutto, L., Gattazzo, C., Brunetta, E., Cabrelle, A., Cinetto, F., Niero, R., Facco, M., Garbisa, S., Calabrese, F., Semenzato, G., & Agostini, C. (2010). 3-(2,4-Dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a glycogen synthase kinase-3 inhibitor, displays therapeutic properties in a mouse model of pulmonary inflammation and fibrosis. Journal of Pharmacology and Experimental Therapeutics, 332(3), 785-794. https://doi.org/10.1124/jpet.109.153049