Transcriptomic analysis reveals lipid metabolism and macrophage involvement associated with nintedanib treatment in a rat bleomycin model.

Abstract

BACKGROUND AND PURPOSE: Idiopathic pulmonary fibrosis is a progressive lung disease with high clinical need. In this context, nintedanib significantly reduces acute exacerbation risk, however its comprehensive effect on fibrosis remains unclear. This study aims to evaluate nintedanib transcriptomic impact on lung fibrosis to uncover molecular signatures for new therapeutics. EXPERIMENTAL APPROACH: Lung fibrosis was induced by two intratracheal bleomycin administrations. Nintedanib was administered orally daily for 3 weeks. Histological and transcriptome data were obtained using automated fibrosis quantification, Ashcroft Score and RNA sequencing, respectively. Correlation network analysis (WGCNA) modules were identified and examined by cell and pathway enrichment analysis. Lipid peroxidation was tested using malondialdehyde. KEY RESULTS: Nintedanib reduced fibrotic lesions by ~15%, decreased severe Ashcroft scores,. WGCNA identified two clusters correlated with histological parameters, where nintedanib counter-regulates gene expression. One cluster was associated with mesenchymal cells (fibroblast and smooth muscle; -log p-val > 4.45), energy production, cellular metabolism and extracellular matrix-related pathways (-log q-val > 11). The second cluster, enriched predominantly in resident macrophages (-log p-val > 12.36), was related to lysosomal activity and lipid metabolism (-log q-val > 21). Nintedanib inhibited bleomycin elevated malondialdehyde levels. CONCLUSIONS AND IMPLICATIONS: The study highlighted two distinct protective effects of nintedanib on lung fibrosis. One well-known on mesenchymal cells and matrix-related components. Plus, one related to the involvement of the pneumocyte-macrophage paracrine lipid axis, where oxidized lipids alter macrophage activities, leading to the formation of lipid-filled macrophages. This may open new research directions.