title: Radical oxygen species production induced by advanced oxidation protein products predicts clinical evolution and response to treatment in systemic sclerosis.
abstract: OBJECTIVE
  To investigate the role of reactive oxygen species (ROS) in the development of the various patterns of systemic sclerosis (SSc) and the mechanisms of ROS production by endothelial cells and fibroblasts.
  
  
  METHODS
  Production of hydrogen peroxide (H(2)O(2)), nitric oxide (NO) and cellular proliferation were determined following incubation of endothelial cells and fibroblasts with 56 SSc and 30 healthy sera. Correlations were established between those markers, the type and the severity of the clinical involvements, and the response to treatment. The factors leading to ROS production were determined.
  
  
  RESULTS
  H(2)O(2) production by endothelial cells and fibroblasts was higher after incubation with SSc sera than with normal sera (p<0.001) and with sera from SSc patients with severe complications than sera from other patients (p<0.05). Sera from patients with lung fibrosis triggered the proliferation of fibroblasts more than other SSc sera (p<0.001), whereas sera from patients with vascular complications exerted no proliferative effect on fibroblasts, but inhibited endothelial cell growth (p<0.05) and induced NO overproduction (p<0.05). Bosentan reduced NO release by 32%, whereas N-acetylcystein potentiated 5-fluorouracil (5FU) to inhibit fibroblast proliferation by 78%. Those serum-mediated effects did not involve antibodies but advanced oxidation protein products that selectively triggered cells to produce H(2)O(2) or NO.
  
  
  CONCLUSIONS
  SSc sera induce the production of different types of ROS that selectively activate endothelial cells or fibroblasts, leading to vascular or fibrotic complications. Assaying serum-induced ROS production allows clinical activity of the disease to be followed and appropriate treatments to be selected.
authors.affiliation: Université Paris-Descartes, Faculté de Médecine, IFR Alfred Jost, Paris, France, and Service de Médecine Interne, Centre National de Référence Sclérodermie-Vascularites, AP-HP, Hôpital Cochin, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Servettaz
authors.forename: P
authors.initials: P
authors.lastname: Guilpain
authors.forename: C
authors.initials: C
authors.lastname: Goulvestre
authors.forename: C
authors.initials: C
authors.lastname: Chéreau
authors.forename: C
authors.initials: C
authors.lastname: Hercend
authors.forename: C
authors.initials: C
authors.lastname: Nicco
authors.forename: L
authors.initials: L
authors.lastname: Guillevin
authors.forename: B
authors.initials: B
authors.lastname: Weill
authors.forename: L
authors.initials: L
authors.lastname: Mouthon
authors.forename: F
authors.initials: F
authors.lastname: Batteux
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000097:blood; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000378:metabolism* / Q000473:pathology
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D006861:Hydrogen Peroxide