TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo.
FASEB J
; 33(8): 9466-9475, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31100032
ABSTRACT
Hepatic fibrosis, characterized by an excessive extracellular matrix (ECM) accumulation, leading to scar-tissue formation is a growing health problem worldwide. Hepatocellular damage due to liver injury triggers inflammation and transdifferentiation of quiescent hepatic stellate cells (HSCs) into proliferative, contractile, and ECM-producing myofibroblasts. Involvement of the Janus kinase (JAK)-2 pathway in the pathogenesis of fibrosis has been reported earlier. However, in this study, we have investigated the effect of selective JAK2 antagonist TG101348 in fibroblasts and inflammatory macrophages and in vivo in an acute carbon tetrachloride-induced liver injury mouse model. In vitro, TG101348 significantly inhibited TGF-ß-induced collagen I expression in murine 3T3 fibroblasts. In human HSCs (LX2 cells), TG101348 potently attenuated TGF-ß-induced contractility and the protein and gene expression of major fibrotic parameters (collagen I, vimentin, and α-smooth muscle actin). In LPS- and IFN-γ-stimulated inflammatory macrophages, TG101348 significantly reduced the NO release and strongly inhibited the expression of inflammatory markers (inducible nitric oxide synthase, C-C motif chemokine ligand 2, IL-1ß, IL-6, and C-C chemokine receptor type 2). In vivo in an acute liver injury mouse model, TG101348 significantly attenuated collagen accumulation and HSC activation. Interestingly, TG101348 drastically inhibited macrophage infiltration and intrahepatic inflammation. Pharmacological inhibition of the JAK2 signaling pathway in activated HSCs and inflammatory macrophages using TG101348 suggests a potential therapeutic approach for the treatment of liver fibrosis.-Akcora, B. O., Dathathri, E., Ortiz-Perez, A., Gabriël, A. V., Storm, G., Prakash, J., Bansal, R. TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Pirrolidinas
/
Sulfonamidas
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Fígado
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Cirrose Hepática
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Holanda