title: Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts.
abstract: 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.
authors.affiliation: Laboratoire de Radiobiologie et Etude du Génome, DRR, DSV, CEA, Saclay, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Vozenin-Brotons
authors.forename: V
authors.initials: V
authors.lastname: Sivan
authors.forename: N
authors.initials: N
authors.lastname: Gault
authors.forename: C
authors.initials: C
authors.lastname: Renard
authors.forename: C
authors.initials: C
authors.lastname: Geffrotin
authors.forename: S
authors.initials: S
authors.lastname: Delanian
authors.forename: J L
authors.initials: JL
authors.lastname: Lefaix
authors.forename: M
authors.initials: M
authors.lastname: Martin
mesh_terms: 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*
chemical_list: D000199:Actins; D019063:Tenascin; D016212:Transforming Growth Factor beta; D003094:Collagen; D013482:Superoxide Dismutase