title: Reactive oxygen species-mediated killing of activated fibroblasts by arsenic trioxide ameliorates fibrosis in a murine model of systemic sclerosis.
abstract: OBJECTIVE
  In patients with systemic sclerosis (SSc), activated fibroblasts produce reactive oxygen species (ROS) that stimulate their proliferation and collagen synthesis. By analogy with tumor cells that undergo apoptosis upon cytotoxic treatment that increases ROS levels beyond a lethal threshold, we tested whether activated fibroblasts could be selectively killed by the cytotoxic molecule arsenic trioxide (As(2) O(3) ) in a murine model of SSc.
  
  
  METHODS
  SSc was induced in BALB/c mice by daily intradermal injections of HOCl. Mice were simultaneously treated with daily intraperitoneal injections of As(2) O(3) .
  
  
  RESULTS
  As(2) O(3)  limited dermal thickness and inhibited collagen deposition, as assessed by histologic examination and measurement of mouse skin and lung collagen contents. As(2) O(3)  abrogated vascular damage, as shown by serum vascular cell adhesion molecule 1 level, and inhibited the production of autoantibodies, interleukin-4 (IL-4), and IL-13 by activated T cells. These beneficial effects were mediated through ROS generation that selectively killed activated fibroblasts containing low levels of glutathione.
  
  
  CONCLUSIONS
  Our findings indicate that treatment with As(2) O(3)  dramatically improves skin and lung fibrosis in a mouse model of SSc, providing a rationale for the evaluation of As(2) O(3)  treatment in patients with SSc.
authors.affiliation: Université Paris Descartes, EA 1833, and Hôpital Cochin, AP-HP, Paris, France.
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.forename: Wioleta
authors.initials: W
authors.lastname: Marut
authors.forename: Amélie
authors.initials: A
authors.lastname: Servettaz
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Hervé
authors.initials: H
authors.lastname: Lemaréchal
authors.forename: Didier
authors.initials: D
authors.lastname: Borderie
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupin
authors.forename: Bernard
authors.initials: B
authors.lastname: Weill
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001323:Autoantibodies / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005978:Glutathione / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D001152:Arsenicals; D001323:Autoantibodies; D018793:Interleukin-13; D010087:Oxides; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4; D003094:Collagen; D005978:Glutathione; D000077237:Arsenic Trioxide