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.
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-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) on a BLM-induced lung fibrosis model in mice. SB216763 prevented lung inflammation and the subsequent fibrosis when coadministered 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.
Gurrieri
Carmela
C
Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy.
Piazza
Francesco
F
Gnoato
Marianna
M
Montini
Barbara
B
Biasutto
Lucia
L
Gattazzo
Cristina
C
Brunetta
Enrico
E
Cabrelle
Anna
A
Cinetto
Francesco
F
Niero
Raffaele
R
Facco
Monica
M
Garbisa
Spiridione
S
Calabrese
Fiorella
F
Semenzato
Gianpietro
G
Agostini
Carlo
C
D000818:Animals; D001761:Bleomycin; D018932:Chemokine CCL2 / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007211:Indoles / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008301:Maleimides / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018932:Chemokine CCL2; D007211:Indoles; D008301:Maleimides; C417521:SB 216763; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D038362:Glycogen Synthase Kinase 3