Mc. Vozenin-brotons et al., Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta 1 repression and phenotypic reversion of myofibroblasts, FREE RAD B, 30(1), 2001, pp. 30-42
Skin fibrosis is characterized by the proliferation and accumulation of act
ivated fibroblasts called myofibroblasts. They exhibit specific cytoskeleta
l differentiation, overexpress the fibrogenic cytokine TGF-beta1, synthesiz
e excess extracellular matrix compounds and exhibit a depleted antioxidant
metabolism. Recently, SOD was successfully used as an antifibrotic agent in
vivo, thus challenging the postulate of established fibrosis irreversibili
ty. We postulated that myofibroblasts could be a direct target for this the
rapeutic effect. To test this hypothesis, we used three-dimensional co-cult
ure models of skin, in which specific phenotypes of normal fibroblasts vers
us myofibroblasts are retained. These 3-D models were treated with liposoma
l and carrier-free Cu/Zn SOD, and examined for their effects on cell number
, cell death, and phenotypic differentiation. The results show that SOD did
not induce myofibroblast cell death, whereas it significantly reduced TGF-
beta1 expression, thus demonstrating that SOD might be proposed as a potent
antagonist of this major fibrogenic growth factor. We also found that SOD
significantly lowered the levels of the myofibroblast marker alpha -sm acti
n, of beta -actin, and of the extracellular matrix components alpha1(1) col
lagen and tenascin-C. In conclusion, our results suggest that SOD antifibro
tic action occurred in vitro through the reversion of myofibroblasts into n
ormal fibroblasts. (C) 2000 Elsevier Science Inc.