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Nintedanib and Pirfenidone affect growth and differentiation of human alveolar type 2 cells

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterized by epithelial cell senescence. Pirfenidone and nintedanib are approved drugs for the treatment of IPF. They significantly slow disease progression, but their mechanisms of action, especially on Alveolar type 2 (AT2) cells, are poorly understood. We addressed this question by evaluating colony formation and growth of human AT2 cells co-cultured with fibroblasts in organoid culture in the presence of pirfenidone and nintedanib. We further evaluated molecular changes induced by these drugs via single cell RNA-seq of treated organoids. Results. AT2 cell organoids cultured in the presence of pirfenidone or nintedanib resulted in increased colony formation and, in the case of nintedanib, in larger colonies. We observed that untreated or pirfenidone treated AT2 cells lost surfactant protein C (SFTPC) expression and acquired an expression profile consistent with keratin (KRT)17high/KRT5- basaloid cells, whereas a larger proportion of nintedanib treated cells retained SFTPC expression. In contrast, AT2 cells treated with TGFb inhibitor exhibited intermediate (SFTPC-/KRT17low) gene expression profile. Conclusion. These results suggest that nintedanib prevents transdifferentiation of AT2 cells to KRT17+/KRT5- cells in culture and likely acts proximal to TGFb.

ORGANISM(S): Homo sapiens

PROVIDER: GSE322959 | GEO | 2026/07/31

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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Nintedanib and Pirfenidone affect growth and differentiation of human alveolar type 2 cells

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