| First Author | Latella G | Year | 2009 |
| Journal | Liver Int | Volume | 29 |
| Issue | 7 | Pages | 997-1009 |
| PubMed ID | 19422482 | Mgi Jnum | J:166109 |
| Mgi Id | MGI:4839714 | Doi | 10.1111/j.1478-3231.2009.02011.x |
| Citation | Latella G, et al. (2009) Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice. Liver Int 29(7):997-1009 |
| abstractText | 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. |
