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Published on: May 9, 2018
Molecular characterization of a precision-cut rat lung slice model for the evaluation of antifibrotic drugs
Xinqiang Huang1, Li Li1, Ron Ammar1
1Department of Cardiovascular and Fibrotic Diseases Drug Discovery, Bristol-Myers Squibb, Pennington, New Jersey.
Abstract:
The translation of novel pulmonary fibrosis therapies from preclinical models into the clinic represents a major challenge demonstrated by the high attrition rate of compounds that showed efficacy in preclinical models but demonstrated no significant beneficial effects in clinical trials. A precision-cut lung tissue slice (PCLS) contains all major cell types of the lung and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study pulmonary fibrosis. In this study, using RNA sequencing, we demonstrated that transforming growth factor-β1 (TGFβ1) induced robust fibrotic responses in the rat PCLS model, as it changed the expression of genes functionally related to extracellular matrix remodeling, cell adhesion, epithelial-to-mesenchymal transition, and various immune responses. Nintedanib, pirfenidone, and sorafenib each reversed a subset of genes modulated by TGFβ1, and of those genes we identified 229 whose expression was reversed by all three drugs. These genes define a molecular signature characterizing many aspects of pulmonary fibrosis pathology and its attenuation in the rat PCLS fibrosis model. A panel of 12 genes and three secreted biomarkers, including procollagen I, hyaluronic acid, and WNT1-inducible signaling pathway protein 1 were validated as efficacy end points for the evaluation of antifibrotic activity of experimental compounds. Finally, we showed that blockade of αV-integrins suppressed TGFβ1-induced fibrotic responses in the rat PCLS fibrosis model. Overall, our results suggest that the TGFβ1-induced rat PCLS fibrosis model may represent a valuable system for target validation and to determine the efficacy of experimental compounds.
Insights
A novel rat precision-cut lung slice model effectively mimics pulmonary fibrosis, identifying key gene changes and drug responses. This ex vivo system aids in validating antifibrotic therapies and targets for lung fibrosis.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Biomarker Discovery
Background:
- Translating pulmonary fibrosis therapies to clinic is challenging due to high preclinical-to-clinical attrition rates.
- Precision-cut lung slices (PCLS) offer a promising ex vivo model preserving lung microenvironment for fibrosis studies.
Purpose of the Study:
- To establish and validate a rat PCLS model for studying pulmonary fibrosis.
- To identify molecular signatures and therapeutic targets for pulmonary fibrosis using RNA sequencing.
- To evaluate the efficacy of antifibrotic drugs and validate biomarkers in this model.
Main Methods:
- Utilized RNA sequencing to analyze gene expression changes in rat PCLS induced by transforming growth factor-β1 (TGFβ1).
- Treated TGFβ1-induced fibrotic PCLS with nintedanib, pirfenidone, and sorafenib to assess drug effects.
- Validated a panel of genes and secreted biomarkers as efficacy endpoints.
- Investigated the effect of αV-integrin blockade on TGFβ1-induced fibrosis.
Main Results:
- TGFβ1 robustly induced fibrotic responses in rat PCLS, altering genes related to extracellular matrix, cell adhesion, and epithelial-to-mesenchymal transition.
- Nintedanib, pirfenidone, and sorafenib each reversed subsets of TGFβ1-modulated genes; 229 genes were reversed by all three drugs, forming a molecular signature.
- A panel of 12 genes and three biomarkers (procollagen I, hyaluronic acid, WNT1-inducible signaling pathway protein 1) were validated as efficacy endpoints.
- Blockade of αV-integrins suppressed TGFβ1-induced fibrotic responses in the PCLS model.
Conclusions:
- The TGFβ1-induced rat PCLS model accurately recapitulates key aspects of pulmonary fibrosis.
- This model is valuable for identifying molecular signatures of fibrosis and evaluating antifibrotic compound efficacy.
- The validated gene panel and biomarkers serve as reliable endpoints for assessing antifibrotic activity.
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