title: The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis.
abstract: BACKGROUND
  Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc.
  
  
  OBJECTIVE
  To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis.
  
  
  METHODS
  Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO(-/-) mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO(-/-) mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms
  
  
  RESULTS
  In both models, 12/15-LO(-/-) mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO(-/-) fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects.
  
  
  CONCLUSIONS
  These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.forename: Nicole
authors.initials: N
authors.lastname: Reich
authors.forename: Carina
authors.initials: C
authors.lastname: Scholtysek
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Stefan
authors.initials: S
authors.lastname: Uderhardt
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Veronika
authors.initials: V
authors.lastname: Lang
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured; D020405:Dermis / Q000201:enzymology / Q000473:pathology; D015777:Eicosanoids / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D005355:Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D044045:Lipoxins / Q000378:metabolism; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C475064:12-15-lipoxygenase; D000903:Antibiotics, Antineoplastic; D015777:Eicosanoids; D044045:Lipoxins; D016212:Transforming Growth Factor beta; C475219:Tsk1 protein, mouse; C040527:lipoxin A4; D001761:Bleomycin; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D017346:Protein Serine-Threonine Kinases