Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts.
Skin fibrosis is characterized by the proliferation and accumulation of activated fibroblasts called myofibroblasts. They exhibit specific cytoskeletal differentiation, overexpress the fibrogenic cytokine TGF-beta1, synthesize 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 irreversibility. We postulated that myofibroblasts could be a direct target for this therapeutic effect. To test this hypothesis, we used three-dimensional co-culture models of skin, in which specific phenotypes of normal fibroblasts versus myofibroblasts are retained. These 3-D models were treated with liposomal 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 actin, of beta-actin, and of the extracellular matrix components alpha1(I) collagen and tenascin-C. In conclusion, our results suggest that SOD antifibrotic action occurred in vitro through the reversion of myofibroblasts into normal fibroblasts.
Vozenin-Brotons
M C
MC
Laboratoire de Radiobiologie et Etude du Génome, DRR, DSV, CEA, Saclay, France.
Sivan
V
V
Gault
N
N
Renard
C
C
Geffrotin
C
C
Delanian
S
S
Lefaix
J L
JL
Martin
M
M
D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002452:Cell Count; D003094:Collagen / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D008954:Models, Biological; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D013482:Superoxide Dismutase / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D019063:Tenascin / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
D000199:Actins; D019063:Tenascin; D016212:Transforming Growth Factor beta; D003094:Collagen; D013482:Superoxide Dismutase