Effect of Nintedanib in a rat model of bleomycin-induced lung fibrosis: a transcriptome analysis

Background & Objectives: Aim of this study was to evaluate the transcriptome perturbation and therapeutic effects of Nintedanib (NINT), an anti-fibrotic drug approved for the treatment of Idiopathic Pulmonary Fibrosis (IPF), in a rat model of bleomycin (BLM)-induced lung fibrosis. Methods: Male rats were intratracheally injected with BLM (1 U/kg) or saline (SAL) on day 0 and day 4. Seven days after the first BLM administration, one group of animals received oral NINT for three weeks (endpoint at day 28). Histomorphometric analysis of lung fibrosis was performed on Masson’s trichrome stained left lung sections. Total mRNA extracted from the right lung was sequenced with an Illumina NextSeq500 platform. Results & Conclusions: At day 28, BLM induced a significant increase in lung fibrosis, while a trend toward a reduced fractional area and severity of fibrotic lesions was revealed by histological analysis after treatment with NINT. At the transcriptome level, NINT treatment resulted in the normalization, to different extents, of two clusters of genes whose expression was dysregulated by BLM (like collagen type 1 α 1 (Col1a1) and secreted phosphoprotein 1 (Spp1)). These clusters, whose expression levels correlated with histological parameters, were centred on pathways/biological processes such as oxidative phosphorylation and cellular protein catabolic process that may play a pathogenetic role in IPF. Overall, this analysis delineates a specific subset of the broad-spectrum effects elicited by NINT that may be particularly relevant for IPF amelioration in our rat-BLM model. NINT-sensitive gene clusters may represent new potential therapeutic targets for IPF.