title: The organotelluride catalyst (PHTE)₂NQ prevents HOCl-induced systemic sclerosis in mouse.
abstract: Systemic sclerosis (SSc) is a connective tissue disorder characterized by skin and visceral fibrosis, microvascular damage, and autoimmunity. HOCl-induced mouse SSc is a murine model that mimics the main features of the human disease, especially the activation and hyperproliferation rate of skin fibroblasts. We demonstrate here the efficiency of a tellurium-based catalyst 2,3-bis(phenyltellanyl)naphthoquinone ((PHTE)(2)NQ) in the treatment of murine SSc, through its selective cytotoxic effects on activated SSc skin fibroblasts. SSc mice treated with (PHTE)(2)NQ displayed a significant decrease in lung and skin fibrosis and in alpha-smooth muscle actin (α-SMA) expression in the skin compared with untreated mouse SSc animals. Serum concentrations of advanced oxidation protein products, nitrate, and anti-DNA topoisomerase I autoantibodies were increased in SSc mice, but were significantly reduced in SSc mice treated with (PHTE)(2)NQ. To assess the mechanism of action of (PHTE)(2)NQ, the cytotoxic effect of (PHTE)(2)NQ was compared in normal fibroblasts and in mouse SSc skin fibroblasts. ROS production is higher in mouse SSc fibroblasts than in normal fibroblasts, and was still increased by (PHTE)(2)NQ to reach a lethal threshold and kill mouse SSc fibroblasts. Therefore, the effectiveness of (PHTE)(2)NQ in the treatment of mouse SSc seems to be linked to the selective pro-oxidative and cytotoxic effects of (PHTE)(2)NQ on hyperproliferative fibroblasts.
authors.affiliation: Université Paris Descartes, Sorbonne-Paris-Cité, Faculté de Médecine, EA 1833 et Laboratoire d'Immunologie Biologique, Hôpital Cochin AP-HP, Paris, France.
authors.forename: Wioleta K
authors.initials: WK
authors.lastname: Marut
authors.forename: Niloufar
authors.initials: N
authors.lastname: Kavian
authors.forename: Amélie
authors.initials: A
authors.lastname: Servettaz
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.forename: Lalla A
authors.initials: LA
authors.lastname: Ba
authors.forename: Mandy
authors.initials: M
authors.lastname: Doering
authors.forename: Christiane
authors.initials: C
authors.lastname: Chéreau
authors.forename: Claus
authors.initials: C
authors.lastname: Jacob
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; D001323:Autoantibodies / Q000097:blood; D002478:Cells, Cultured; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000009:adverse effects*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000097:blood; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013691:Tellurium / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C572249:2,3-bis(phenyltellanyl)naphthoquinone; D000199:Actins; D001323:Autoantibodies; D009285:Naphthoquinones; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C544013:alpha-smooth muscle actin, mouse; D009569:Nitric Oxide; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; D004264:DNA Topoisomerases, Type I; D005978:Glutathione; D013691:Tellurium