Liver international : official journal of the International Association for the Study of the Liver · 2009
Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice.
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Latella Giovanni, Vetuschi Antonella, Sferra Roberta, Catitti Valentina, D'Angelo Angela, Zanninelli Giuliana, Flanders Kathleen C, Gaudio Eugenio
Аннотация
BACKGROUND: Hepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins including collagen, which occurs in most types of chronic liver diseases. Transforming growth factor-beta (TGF-beta)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of ECM accumulation.
AIM: To evaluate the potential protective role of Smad3 deficiency in the pathogenesis of liver fibrosis induced by dimethylnitrosamine (DMN) in Smad3 null mice.
METHODS: Chronic hepatitis-associated fibrosis was induced in 13 Smad3 null and 13 wild-type (WT) mice by intraperitoneal DMN administration (10 microg/g body weight/day) for three consecutive days per week for 6 weeks. The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta1, connective tissue growth factor (CTGF), Smad3, Smad7 and CD3 antibodies were used.
RESULTS: At macroscopic examination, the liver of DMN-treated Smad3 WT appeared harder with a dark brown colouring and necrotic areas compared with that from null mice. Histological and morphometric evaluation revealed a significantly higher degree of hepatic fibrosis and accumulation of connective tissue in the Smad3 WT compared with null mice. IHC evaluation showed a marked increase in alpha-SMA, CTGF, collagen I-III, TGF-beta and Smad3 staining in the liver of Smad3 WT compared with that in null mice, whereas Smad7 was increased only in null mice.
CONCLUSIONS: The results indicate that Smad3 loss confers resistance to the development of DMN-induced hepatic fibrosis. The reduced fibrotic response appears to be due to a reduction of fibrogenic myofibroblast activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of fibrosis complicating chronic hepatitis.
AIM: To evaluate the potential protective role of Smad3 deficiency in the pathogenesis of liver fibrosis induced by dimethylnitrosamine (DMN) in Smad3 null mice.
METHODS: Chronic hepatitis-associated fibrosis was induced in 13 Smad3 null and 13 wild-type (WT) mice by intraperitoneal DMN administration (10 microg/g body weight/day) for three consecutive days per week for 6 weeks. The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, alpha-smooth muscle actin (alpha-SMA), collagen types I-III, TGF-beta1, connective tissue growth factor (CTGF), Smad3, Smad7 and CD3 antibodies were used.
RESULTS: At macroscopic examination, the liver of DMN-treated Smad3 WT appeared harder with a dark brown colouring and necrotic areas compared with that from null mice. Histological and morphometric evaluation revealed a significantly higher degree of hepatic fibrosis and accumulation of connective tissue in the Smad3 WT compared with null mice. IHC evaluation showed a marked increase in alpha-SMA, CTGF, collagen I-III, TGF-beta and Smad3 staining in the liver of Smad3 WT compared with that in null mice, whereas Smad7 was increased only in null mice.
CONCLUSIONS: The results indicate that Smad3 loss confers resistance to the development of DMN-induced hepatic fibrosis. The reduced fibrotic response appears to be due to a reduction of fibrogenic myofibroblast activation and ECM production and accumulation. Smad3 could be a novel target for potential treatment of fibrosis complicating chronic hepatitis.