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Consistent lack of efficacy of nintedanib in a spirometry-confirmed and bleomycin-induced mouse model of idiopathic pulmonary fibrosis

ABSTRACT: Nintedanib, a multitargeted tyrosine kinase inhibitor, is approved for idiopathic pulmonary fibrosis (IPF) for its ability to slow lung function decline. This study systematically evaluated the effects of nintedanib across three independent treatment intervention studies in the single-dose bleomycin (BLEO) mouse model of IPF. In each study, male C57BL/6J mice received a single intratracheal instillation of BLEO (n=15-18 per study) or saline (n=10 per study) and were randomized and stratified to treatment according to body weight and non-invasive whole-body plethysmography measured seven days after BLEO administration. BLEO-IPF mice were administered (PO, BID) vehicle, nintedanib (50 or 60 mg/kg), or an activin receptor-like kinase 5 inhibitor (ALK5i, SB525334, 60 mg/kg) for up to 21 days. In all studies, nintedanib consistently failed to improve lung health, as evaluated by lung function tests, biochemistry, histology and RNA sequencing. Plasma concentrations of nintedanib showed no correlation to any efficacy endpoint applied. Lung transcriptome signatures in nintedanib-treated BLEO-mice indicated upregulated mRNA expression of p-glycoprotein (P-gp), a known nintedanib efflux transporter, suggesting limited lung bioavailability of nintedanib in the model. In comparison, ALK5i significantly improved lung function and exhibited robust anti-fibrotic efficacy in the model. Collectively, these findings challenge the use of nintedanib as a benchmarking drug in the BLEO-IPF model.

ORGANISM(S): Mus musculus

PROVIDER: GSE308578 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis, causing irreversible lung parenchymal damage. Pirfenidone and nintedanib exhibit some benefits on IPF, although they cannot cure or reverse its progression. Moreover, the molecular mechanisms responsible for their effects remain not entirely comprehended. Nintedanib, a multi-kinase receptor modulator, suppresses diverse proliferative pathways and displays antifibrotic effects in lung fibrosis models. However, the effects of its administration on the lung transcriptome have not yet been deeply investigated in in vivo models of lung fibrosis. This study aims to assess nintedanib's comprehensive transcriptomic profile in a rat model of bleomycin-induced lung fibrosis. MATERIALS & METHODS: Lung fibrosis was induced by two intratracheal administrations of bleomycin. Nintedanib “curative” protocol included three weeks of daily oral treatments (100 mg/kg) beginning seven days after the first bleomycin dose. At the end of the experiment, left lungs were processed for histological fibrosis evaluation by using an automated quantification system and the Ashcroft Score assessment. Right lungs were employed for RNA sequencing to undertake Differential Expression Analysis (DEGs) and a correlation network analysis (WGCNA). WGNA modules were thoroughly examined by cell and pathway enrichment analysis. Moreover, lipid peroxidation was assessed through the measurement of malondialdehyde (MDA) amount in right lung lysates. RESULTS: Bleomycin induced significant fibrotic lesions, as confirmed by the automated quantification and the Ashcroft Score. Nintedanib reduced the size of fibrotic lesions (≃15%) and the incidence of severe Ashcroft scores. The number of differentially expressed genes decreased from over 2000 in fibrotic animals to barely more than 400 in nintedanib-treated rats, when compared to controls. WGCNA identified two gene clusters correlated to histological parameters, both characterized by gene expression patterns where nintedanib-treated animals resemble the profile observed in control animals. One cluster was associated with mesenchymal cells and focused on epithelial to mesenchymal transition and extracellular matrix organization pathways, in line with the exhibited anti-fibrotic effect of nintedanib. The second cluster, involving resident macrophages and inflammatory pathways, was specifically related to lipid homeostasis, potentially uncovering a new mechanistic role of nintedanib in modulating lung fibrosis. CONCLUSIONS: The mechanisms involving macrophages and lipid metabolism, both of which were influenced by nintedanib treatment in this in vivo study, may open new research directions to better inquire about the role of this cellular type in the regulation of lipid homeostasis and fibrosis, influencing both tissue repair and pathological lung fibrosis.

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Consistent lack of efficacy of nintedanib in a spirometry-confirmed and bleomycin-induced mouse model of idiopathic pulmonary fibrosis

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