title: p70 ribosomal S6 kinase regulates subpleural fibrosis following transforming growth factor-α expression in the lung.
abstract: The p70 ribosomal S6 kinase (S6K) is a downstream substrate that is phosphorylated and activated by the mammalian target of rapamycin complex and regulates multiple cellular processes associated with fibrogenesis. Recent studies demonstrate that aberrant mTORC1-S6K signaling contributes to various pathological conditions, but a direct role in pulmonary fibroproliferation has not been established. Increased phosphorylation of the S6K pathway is detected immediately following transforming growth factor-α (TGF-α) expression in a transgenic model of progressive lung fibrosis. To test the hypothesis that the S6K directly regulates pulmonary fibroproliferative disease we determined the cellular sites of S6K phosphorylation during the induction of fibrosis in the TGF-α model and tested the efficacy of specific pharmacological inhibition of the S6K pathway to prevent and reverse fibrotic disease. Following TGF-α expression increased phosphorylation of the S6K was detected in the airway and alveolar epithelium and the mesenchyme of advanced subpleural fibrotic regions. Specific inhibition of the S6K with the small molecule inhibitor LY-2584702 decreased TGF-α and platelet-derived growth factor-β-induced proliferation of lung fibroblasts in vitro. Administration of S6K inhibitors to TGF-α mice prevented the development of extensive subpleural fibrosis and alterations in lung mechanics, and attenuated the increase in total lung hydroxyproline. S6K inhibition after fibrosis was established attenuated the progression of subpleural fibrosis. Together these studies demonstrate targeting the S6K pathway selectively modifies the progression of pulmonary fibrosis in the subpleural compartment of the lung.
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Satish K
authors.initials: SK
authors.lastname: Madala
authors.affiliation: Metabolic Disease Institute, University of Cincinnati School of Medicine, Cincinnati, Ohio; and.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Edukulla
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Cynthia
authors.initials: C
authors.lastname: Davidson
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Angelica
authors.initials: A
authors.lastname: Schehr
authors.affiliation: Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; william.hardie@cchmc.org.
authors.forename: William D
authors.initials: WD
authors.lastname: Hardie
mesh_terms: D000818:Animals; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008822:Mice, Transgenic; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
chemical_list: D010982:Platelet-Derived Growth Factor; D016211:Transforming Growth Factor alpha; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus
keywords: epidermal growth factor receptor; mammalian target of rapamycin; pleural fibrosis