title: Inhibitory effects of pitavastatin on fibrogenic mediator production by human lung fibroblasts.
abstract: OBJECTIVE
  Idiopathic pulmonary fibrosis continues to be a devastating clinical disorder for which there are few therapeutic options, and the pathogenesis of this disease remains largely unknown. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in cholesterol biosynthesis, and they have been reported to exert pleiotropic effects on the cellular signaling involved in tissue inflammation and in organ fibrosis/remodeling. We examined the preventive effects of statins on fibrogenic mediator expression and production in normal human lung fibroblasts (NHLF).
  
  
  METHODS
  NHLF were pretreated with 100nM pitavastatin or medium alone (control), and were then stimulated with transforming growth factor-β1 (TGF-β1). mRNA expression and protein secretion of several mediators from cells were analyzed by real-time polymerase chain reaction, enzyme-linked immunosorbent assay or multiplex assay.
  
  
  RESULTS
  TGF-β1-induced expression or production of mediators, such as collagen-1, vascular endothelial growth factor and chemokine C-X-C motif ligand 8, in NHLF pretreated with pitavastatin was significantly suppressed with inhibition of Smad-3 phosphorylation, as compared to untreated controls. In addition, the inhibitory effects of pitavastatin were negated by addition of mevalonate.
  
  
  CONCLUSIONS
  Pitavastatin appeared to inhibit TGF-β1-induced fibrogenic mediator production from lung fibroblasts via the mevalonic cascade. Although further evaluation of the signaling pathways for these phenomena is necessary, our results suggest the potential benefits of pitavastatin.
authors.affiliation: Department of Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine, 1-1 Idaigaoka, Yufu, Oita 879-5593, Japan. Electronic address: m10d9007@oita-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Oka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Atsuko
authors.initials: A
authors.lastname: Iwata
authors.forename: Hisako
authors.initials: H
authors.lastname: Kushima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Toba
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hashinaga
authors.forename: Kenji
authors.initials: K
authors.lastname: Umeki
authors.forename: Issei
authors.initials: I
authors.lastname: Tokimatsu
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Hiramatsu
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kadota
mesh_terms: D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016209:Interleukin-8; D011804:Quinolines; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; C108475:pitavastatin; D008798:Mevalonic Acid
keywords: Mevalonate; Pulmonary fibrosis; Statin; Transforming growth factor-β