title: Dabigatran aggravates topoisomerase I peptide-loaded dendritic cells-induced lung and skin fibrosis.
abstract: OBJECTIVE
  Dysregulated coagulation cascade has been implicated in development of fibrosis in systemic sclerosis (SSc). Thrombin, a key mediator of the coagulation pathway, has both proinflammatory and procoagulant properties. Here, we evaluated the efficacy of oral dabigatran, a direct thrombin inhibitor, on topoisomerase I dendritic cells (TOPOIA DCs)-induced lung and skin fibrosis, an experimental model of SSc.
  
  
  METHODS
  Mice were repeatedly immunized with TOPOIA DCs. Dabigatran was administered in food either during the onset of fibrotic (late treatment) or inflammatory (early treatment) phase.
  
  
  RESULTS
  Early administration of dabigatran caused an aggravation of pulmonary fibrosis associated with signs of severe perivascular inflammation while late treatment was not protective when compared to the untreated TOPOIA DCs group. Thrombin was increased in lungs of TOPOIA DCs immunized group and, paradoxically, further augmented by administration of dabigatran to immunized mice. As in lungs, early and not late drug administration exacerbated skin fibrosis. Moreover, early dabigatran treatment induced a profibrotic and inflammatory skin gene expression signature with upregulated expression of Col5a1, Timp1, Tweakr, Vwf, Il6, Il33, Il4 and Ifng.
  
  
  CONCLUSIONS
  Dabigatran aggravated lung and skin fibrosis in a TOPOIA DCs-induced model of SSc-like disease. Therefore, our results argue against the use of dabigatran to treat patients with SSc.
authors.affiliation: Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Heena
authors.initials: H
authors.lastname: Mehta
authors.affiliation: Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Shunya
authors.initials: S
authors.lastname: Mashiko
authors.affiliation: Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Philippe-Olivier
authors.initials: PO
authors.lastname: Goulet
authors.affiliation: Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Jade
authors.initials: J
authors.lastname: Desjardins
authors.affiliation: Laboratory for Research in Autoimmunity, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Gemma
authors.initials: G
authors.lastname: Pérez
authors.affiliation: Laboratory for Research in Autoimmunity, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Martial
authors.initials: M
authors.lastname: Koenig
authors.affiliation: Laboratory for Research in Autoimmunity, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Senécal
authors.affiliation: Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada. m.sarfati@umontreal.ca.
authors.forename: Marika
authors.initials: M
authors.lastname: Sarfati
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000633:toxicity*; D004264:DNA Topoisomerases, Type I / Q000276:immunology*; D000069604:Dabigatran / Q000633:toxicity*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005355:Fibrosis; D008297:Male; D051379:Mice; D011658:Pulmonary Fibrosis / Q000209:etiology*; D012595:Scleroderma, Systemic / Q000188:drug therapy*; D012867:Skin / Q000473:pathology*
chemical_list: D000991:Antithrombins; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D000069604:Dabigatran