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Updated: Mar 30, 2026
Refined Murine Model of Idiopathic Pulmonary Fibrosis
Published on: June 17, 2025
p70 ribosomal S6 kinase regulates subpleural fibrosis following transforming growth factor-α expression in the lung
Satish K Madala1, George Thomas2, Ramakrishna Edukulla1
1Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;
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.
Insights
Targeting the p70 ribosomal S6 kinase (S6K) pathway can prevent and reverse lung fibrosis. Inhibiting S6K reduces fibroblast proliferation and fibrotic disease progression in preclinical models.
Area of Science:
- Cellular Biology
- Molecular Medicine
- Pulmonary Research
Background:
- Aberrant mammalian target of rapamycin complex 1 (mTORC1)-p70 ribosomal S6 kinase (S6K) signaling is implicated in various diseases.
- The specific role of S6K in pulmonary fibroproliferation remains unclear.
- Increased S6K pathway phosphorylation is observed following transforming growth factor-α (TGF-α) expression in a lung fibrosis model.
Purpose of the Study:
- To investigate the direct role of S6K in regulating pulmonary fibroproliferative disease.
- To determine the cellular localization of S6K phosphorylation during fibrosis induction.
- To evaluate the efficacy of pharmacological S6K inhibition in preventing and reversing lung fibrosis.
Main Methods:
- Utilized a transgenic mouse model with TGF-α-induced progressive lung fibrosis.
- Assessed S6K phosphorylation sites in lung tissue during fibrosis development.
- Administered a specific S6K inhibitor (LY-2584702) to mice before and after fibrosis onset.
- Measured lung fibroblast proliferation in vitro in response to TGF-α and platelet-derived growth factor-β.
- Evaluated fibrotic changes, lung mechanics, and hydroxyproline levels.
Main Results:
- TGF-α expression led to increased S6K phosphorylation in airway and alveolar epithelium, and mesenchymal cells within fibrotic regions.
- S6K inhibition reduced TGF-α and platelet-derived growth factor-β-induced lung fibroblast proliferation in vitro.
- S6K inhibitor treatment prevented subpleural fibrosis development and preserved lung mechanics in TGF-α mice.
- Post-fibrosis S6K inhibition attenuated the progression of subpleural fibrosis and reduced lung hydroxyproline levels.
Conclusions:
- The S6K pathway plays a direct role in regulating pulmonary fibroproliferation.
- Pharmacological inhibition of S6K is a viable strategy to prevent and treat lung fibrosis.
- Targeting S6K selectively impacts fibrosis in the lung's subpleural compartment.
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