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000282916 1001_ $$00000-0003-3183-6831$$aBonatti, Martina$$b0
000282916 245__ $$aTime-course transcriptome analysis of a double challenge bleomycin-induced lung fibrosis rat model uncovers ECM homoeostasis-related translationally relevant genes.
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000282916 520__ $$aIdiopathic pulmonary fibrosis (IPF) is an irreversible disorder with a poor prognosis. The incomplete understanding of IPF pathogenesis and the lack of accurate animal models is limiting the development of effective treatments. Thus, the selection of clinically relevant animal models endowed with similarities with the human disease in terms of lung anatomy, cell biology, pathways involved and genetics is essential. The bleomycin (BLM) intratracheal murine model is the most commonly used preclinical assay to evaluate new potential therapies for IPF. Here, we present the findings derived from an integrated histomorphometric and transcriptomic analysis to investigate the development of lung fibrosis in a time-course study in a BLM rat model and to evaluate its translational value in relation to IPF.Rats were intratracheally injected with a double dose of BLM (days 0-4) and sacrificed at days 7, 14, 21, 28 and 56. Histomorphometric analysis of lung fibrosis was performed on left lung sections. Transcriptome profiling by RNAseq was performed on the right lung lobes and results were compared with nine independent human gene-expression IPF studies.The histomorphometric and transcriptomic analyses provided a detailed overview in terms of temporal gene-expression regulation during the establishment and repair of the fibrotic lesions. Moreover, the transcriptomic analysis identified three clusters of differentially coregulated genes whose expression was modulated in a time-dependent manner in response to BLM. One of these clusters, centred on extracellular matrix (ECM)-related process, was significantly correlated with histological parameters and gene sets derived from human IPF studies.The model of lung fibrosis presented in this study lends itself as a valuable tool for preclinical efficacy evaluation of new potential drug candidates. The main finding was the identification of a group of persistently dysregulated genes, mostly related to ECM homoeostasis, which are shared with human IPF.
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000282916 650_7 $$2Other$$aInterstitial Fibrosis
000282916 7001_ $$aPitozzi, Vanessa$$b1
000282916 7001_ $$aCaruso, Paola$$b2
000282916 7001_ $$aPontis, Silvia$$b3
000282916 7001_ $$aPittelli, Maria Gloria$$b4
000282916 7001_ $$aFrati, Caterina$$b5
000282916 7001_ $$aMangiaracina, Chiara$$b6
000282916 7001_ $$aLagrasta, Costanza Anna Maria$$b7
000282916 7001_ $$aQuaini, Federico$$b8
000282916 7001_ $$0P:(DE-He78)b3d59900e4cf346355cb161fcbda07e0$$aCantarella, Simona$$b9$$udkfz
000282916 7001_ $$aOttonello, Simone$$b10
000282916 7001_ $$aVilletti, Gino$$b11
000282916 7001_ $$aCivelli, Maurizio$$b12
000282916 7001_ $$00000-0002-5419-7975$$aMontanini, Barbara$$b13
000282916 7001_ $$aTrevisani, Marcello$$b14
000282916 773__ $$0PERI:(DE-600)2736454-9$$a10.1136/bmjresp-2022-001476$$gVol. 10, no. 1, p. e001476 -$$n1$$pe001476$$tBMJ Open Respiratory Research$$v10$$x2052-4439$$y2023
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