A time-course transcriptome analysis of a double challenge bleomycin-induced lung fibrosis rat model

Backgroud: Idiopathic pulmonary fibrosis (IPF) is an irreversible disorder with a poor clinical outcome. The partial understanding of IPF pathogenesis and, consequently, the lack of appropriate relevant animal models is limiting the development of effective treatments. In this context, the intratracheal bleomycin (BLM) administration murine model is regarded as the most reliable preclinical approximation of human IPF. We present, here, the results of an integrated histological and transcriptome analysis that was used to monitor the time-course of BLM-induced lung fibrosis development in a rat model of disease and to assess its overlap with IPF. Methods: Male rats were injected intratracheally (IT) with a double dose of BLM or saline (day 0 – 4) and sacrificed at day 7, 14, 21, 28 and 56. Histomorphometric analysis of lung fibrosis was performed on Masson’s trichrome stained sections on the left lung lobe. Transcriptome profiling by RNAseq was performed on total RNA extracted from the right lung lobe Results and Conclusions: Transcriptomic analysis provided a detailed overview of BLM-induced lung fibrosis development and identified three clusters of differentially co-regulated genes whose expression was modulated in a time-dependent manner in response to BLM. One of these clusters centred on extracellular matrix-related pathways and process was found to be significantly correlated with histological parameters and gene sets derived from human IPF studies, thus indicating its translational potential as a signature biomarker for future IPF-related target validation and drug discovery studies. Evaluation of right lung mRNA profiles derived from a time course study of a rat model of lung fibrosis induced by a double bleomycin administration