title: The natural organosulfur compound dipropyltetrasulfide prevents HOCl-induced systemic sclerosis in the mouse.
abstract: BACKGROUND
  The aim of this study was to test the naturally occurring organosulfur compound dipropyltetrasulfide (DPTTS), found in plants, which has antibiotic and anticancer properties, as a treatment for HOCl-induced systemic sclerosis in the mouse.
  
  
  METHODS
  The prooxidative, antiproliferative, and cytotoxic effects of DPTTS were evaluated ex vivo on fibroblasts from normal and HOCl mice. In vivo, the antifibrotic and immunomodulating properties of DPTTS were evaluated in the skin and lungs of HOCl mice.
  
  
  RESULTS
  H2O2 production was higher in fibroblasts derived from HOCl mice than in normal fibroblasts (P < 0.05). DPTTS did not increase H2O2 production in normal fibroblasts, but DPTTS dose-dependently increased H2O2 production in HOCl fibroblasts (P < 0.001 with 40 μM DPTTS). Because H2O2 reached a lethal threshold in cells from HOCl mice, the antiproliferative, cytotoxic, and proapoptotic effects of DPTTS were significantly higher in HOCl fibroblasts than for normal fibroblasts. In vivo, DPTTS decreased dermal thickness (P < 0.001), collagen content in skin (P < 0.01) and lungs (P < 0.05), αSMA (P < 0.01) and pSMAD2/3 (P < 0.01) expression in skin, formation of advanced oxidation protein products and anti-DNA topoisomerase-1 antibodies in serum (P < 0.05) versus untreated HOCl mice. Moreover, in HOCl mice, DPTTS reduced splenic B-cell counts (P < 0.01), the proliferative rates of B-splenocytes stimulated by lipopolysaccharide (P < 0.05), and T-splenocytes stimulated by anti-CD3/CD28 mAb (P < 0.001). Ex vivo, it also reduced the production of IL-4 and IL-13 by activated T cells (P < 0.05 in both cases).
  
  
  CONCLUSIONS
  The natural organosulfur compound DPTTS prevents skin and lung fibrosis in the mouse through the selective killing of diseased fibroblasts and its immunomodulating properties. DPTTS may be a potential treatment for systemic sclerosis.
authors.forename: Wioleta
authors.initials: W
authors.lastname: Marut
authors.forename: Vincent
authors.initials: V
authors.lastname: Jamier
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.forename: Amélie
authors.initials: A
authors.lastname: Servettaz
authors.forename: Paul G
authors.initials: PG
authors.lastname: Winyard
authors.forename: Paul
authors.initials: P
authors.lastname: Eggleton
authors.forename: Awais
authors.initials: A
authors.lastname: Anwar
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Claus
authors.initials: C
authors.lastname: Jacob
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000517:prevention & control; D005434:Flow Cytometry; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006997:Hypochlorous Acid; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*
chemical_list: D000199:Actins; D001323:Autoantibodies; D018793:Interleukin-13; D051785:Smad Proteins; D013440:Sulfides; C560444:dipropyl tetrasulfide; D015847:Interleukin-4; D006997:Hypochlorous Acid; D003094:Collagen; D006861:Hydrogen Peroxide; D004264:DNA Topoisomerases, Type I