title: Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π.
abstract: Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione-S-transferase π (GSTP). To date, no published information exists linking GSTP and IPF to our knowledge. We hypothesized that GSTP mediates lung fibrogenesis in part through FAS S-glutathionylation, a critical event in epithelial cell apoptosis. Our results demonstrate that GSTP immunoreactivity is increased in the lungs of IPF patients, notably within type II epithelial cells. The FAS-GSTP interaction was also increased in IPF lungs. Bleomycin- and AdTGFβ-induced increases in collagen content, α-SMA, FAS S-glutathionylation, and total protein S-glutathionylation were strongly attenuated inGstp-/-mice. Oropharyngeal administration of the GSTP inhibitor, TLK117, at a time when fibrosis was already apparent, attenuated bleomycin- and AdTGFβ-induced remodeling, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. GSTP is an important driver of protein S-glutathionylation and lung fibrosis, and GSTP inhibition via the airways may be a novel therapeutic strategy for the treatment of IPF.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: McMillan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Jos Lj
authors.initials: JL
authors.lastname: van der Velden
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Karolyn G
authors.initials: KG
authors.lastname: Lahue
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schneider
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Martina S
authors.initials: MS
authors.lastname: Iberg
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Nolin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Abdalla
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Dylan T
authors.initials: DT
authors.lastname: Casey
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Tew
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.affiliation: Division of Cancer Research, University of Dundee, Dundee, United Kingdom.
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Butnor
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Taatjes
authors.affiliation: Department of Medicine and.
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
authors.affiliation: Department of Medicine and.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: van der Vliet
authors.affiliation: Department of Chemistry, University of Vermont, Burlington, Vermont, USA.
authors.forename: Stevenson
authors.initials: S
authors.lastname: Flemer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
authors.forename: Yvonne Mw
authors.initials: YM
authors.lastname: Janssen-Heininger