title: Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients.
abstract: Obliterative bronchiolitis (OB), the major cause of chronic lung allograft dysfunction, is characterized by airway neutrophilia, inflammation, and remodeling, with progressive fibroproliferation and obliteration of small airways that ultimately leads to patient death. Statins have potential anti-inflammatory effects and have been demonstrated to confer a survival advantage in lung transplant patients. We postulated that the beneficial effects of simvastatin in lung transplantation are in part due to inhibition of the epithelial production of key mediators of neutrophil chemotaxis, inflammation, and airway remodeling. Our objective was to assess the effect of simvastatin on a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts, with specific reference to airway neutrophilia and remodeling. PBEC cultures were stimulated with IL-17 or transforming growth factor (TGF)-beta, with and without simvastatin. Supernatant levels of factors critical to driving airway neutrophilia and remodeling were measured. IL-17 upregulated IL-8, IL-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor (GM-CSF), and VEGF, whereas TGF-beta increased IL-6, GM-CSF, matrix metalloproteinase (MMP)-2, and MMP-9. Simvastatin attenuated effects of both IL-17 and TGF-beta. We have demonstrated the ability of simvastatin to attenuate release of airway neutrophilic and remodeling mediators and to inhibit their upregulation by TGF-beta and IL-17. These data illustrate the potential of simvastatin to alleviate neutrophilic airway inflammation and remodeling in the transplanted lung and may have additional relevance to other neutrophilic airway conditions, such as chronic obstructive pulmonary disease.
authors.affiliation: Applied Immunobiology and Transplantation Group, Institute of Molecular Medicine, Faculty of Medical Sciences, University of Newcastle upon Tyne, The William Leech Centre for Lung Research, The Freeman Hospital, High Heaton, Newcastle-upon-Tyne, UK.
authors.forename: Desmond M
authors.initials: DM
authors.lastname: Murphy
authors.forename: Ian A
authors.initials: IA
authors.lastname: Forrest
authors.forename: Paul A
authors.initials: PA
authors.lastname: Corris
authors.forename: Gail E
authors.initials: GE
authors.lastname: Johnson
authors.forename: Therese
authors.initials: T
authors.lastname: Small
authors.forename: Debbie
authors.initials: D
authors.lastname: Jones
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fisher
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Egan
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Cawston
authors.forename: Chris
authors.initials: C
authors.lastname: Ward
authors.forename: James L
authors.initials: JL
authors.lastname: Lordan
mesh_terms: D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D016040:Lung Transplantation / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D016209:Interleukin-8; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019821:Simvastatin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9