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Transcriptomics-based Screening of Repurposing Drug for Idiopathic Pulmonary Fibrosis

ABSTRACT: IPF is a pathological condition resulting from injury to the lungs and an ensuing fibrotic response leading to thickening of the alveolar walls and the obliteration of the alveolar space. The etiology of IPF and the role of the microenvironment in disease progression are largely unknown. We first used the repurposing pipeline to explore disease biology for the identification of relevant cell populations and then applied the screening pipeline to discover novel compounds. Using various types of RNAseq data from multiple datasets, we constructed signatures that capture different aspects of IPF biology, such as those related to cell type-specific transcriptional changes and those associated with disease development in animal models. We predicted and tested drugs targeting various IPF signatures and identified Pyrithyldione as our top candidate for reduction of fibrosis in the human precision-cut lung slices PCLS model and RNAseq was conducted on treated and untreated paired adjacent patient samples to determine its the effects on gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291190 | GEO | 2025/12/16

REPOSITORIES: GEO

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Project description:Intratracheal application of bleomycin is known to induce inflammatory and fibrotic reactions in the lung within a short period of time and histological features include infiltration of inflammatory cells, collagen deposition and obliteration of alveolar spaces. Because some of these features are found in patients with idiopathic pulmonary fibrosis (IPF), the bleomycin-induced lung fibrosis animal model is commonly used. However, exploratory treatments that were successfully used in this animal model and progressed to clinical trials lacked significant efficacy in humans. Here, the bleomycin-induced rat lung fibrosis model was studied using whole genome expression data that was collected at various time points and the relevance to human disease was evaluated through comparison with whole genome expression data from IPF patient-derived lung biopsies. The highest gene expression correlation between both species was observed in animals 7 days after bleomycin instillation. These gene expression signatures helped to identify a set of twelve novel disease-relevant translational gene markers that were able to separate IPF patients from controls. Furthermore, three Wnt/-catenin pathway-related genes that belong to this translational gene marker set showed, together with clinical diffusing capacity of the lung for carbon monoxide (DLCO) measurements, the potential to stratify IPF patients according to disease severity. Pirfenidone attenuated a subset of the translational gene markers in the bleomycin-induced fibrosis model, in particular those related to Wnt/-catenin-signaling. This novel translational gene marker panel offers improved possibilities to evaluate disease-modifying efficacy of novel therapeutic concepts in the bleomycin-induced rat lung fibrosis model and could be applied as a diagnostic and prognostic tool for IPF patient care. Comparison of bleomycin-treated and control rats after 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks; 5 animals per group

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Transcriptomics-based Screening of Repurposing Drug for Idiopathic Pulmonary Fibrosis

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