Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats

S Dooley, J Hamzavi, K Breitkopf, E Wiercinska… - Gastroenterology, 2003 - Elsevier
S Dooley, J Hamzavi, K Breitkopf, E Wiercinska, HM Said, J Lorenzen, P Ten Dijke
Gastroenterology, 2003Elsevier
BACKGROUND & AIMS:: Numerous studies implicate transforming growth factor (TGF)-β
signaling in liver fibrogenesis. To perturb the TGF-β pathway during this process, we
overexpressed Smad7, an intracellular antagonist of TGF-β signaling, in vivo and in primary-
cultured hepatic stellate cells (HSCs). METHODS:: Ligation of the common bile duct (BDL)
was used to induce liver fibrosis in rats. Animals received injections of an adenovirus
carrying Smad7 cDNA into the portal vein during surgery and via the tail vein at later stages …
BACKGROUND & AIMS
Numerous studies implicate transforming growth factor (TGF)-β signaling in liver fibrogenesis. To perturb the TGF-β pathway during this process, we overexpressed Smad7, an intracellular antagonist of TGF-β signaling, in vivo and in primary-cultured hepatic stellate cells (HSCs).
METHODS
Ligation of the common bile duct (BDL) was used to induce liver fibrosis in rats. Animals received injections of an adenovirus carrying Smad7 cDNA into the portal vein during surgery and via the tail vein at later stages. The effect of Smad7 on TGF-β signaling and activation of HSC was further analyzed in primary-cultured cells.
RESULTS
Smad7-overexpressing BDL rats displayed reduced collagen and α-SMA expression and reduced hydroxyproline content in the liver, when compared with animals administered AdLacZ. Such a beneficial effect was also observed when Smad7 was expressed in animals with established fibrosis. Accordingly, Smad7 arrested transdifferentiation of primary-cultured HSCs. AdSmad7 infected cells remained in a quiescent stage and retained storage of vitamin A droplets. Smad7 expression totally blocked TGF-β signal transduction, shown by inhibiting Smad2/3 phosphorylation, nuclear translocation of activated Smad complexes, and activation of (CAGA)9-MLP-Luc, resulting in decreased collagen I expression. Smad7 also abrogated TGF-β-dependent proliferation inhibition of HSC. Smad7 did not decrease expression of α-SMA, but immunofluorescent staining with anti α-SMA antibodies displayed destruction of the fibrillar organization of the actin cytoskeleton.
CONCLUSIONS
In summary, gene transfer of Smad7 inhibits experimental fibrogenesis in vivo. Studies with isolated HSC suggest that the underlying mechanisms involve inhibition of TGF-β signaling and HSC transdifferentiation.
Elsevier