Project description:Analysis of whole genome gene expression levels in distal lung tissue from mice with systemically bleomycin-induced pulmonary fibrosis. The hypothesis is that bleomycin promotes a specific genotype associated with development of pulmonary fibrosis and that treatment with compound EXT reduces the induction of genes related to the early progression of fibrosis.
Project description:Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic pulmonary fibrosis, yet in this model it spontaneously resolves over time. We studied molecular mechanisms of fibrosis resolution and lung repair, focusing on transcriptional and proteomic signatures and the effect of aging. Young (3 months) and old (21 months) mice were treated with Bleomycin or with control saline solution and analyzed transcript and protein expression over 8 weeks (Day 0, 14, 21, 28, 35, 42, 49, 56).
Project description:Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic pulmonary fibrosis, yet in this model it spontaneously resolves over time. We studied molecular mechanisms of fibrosis resolution and lung repair, focusing on transcriptional and proteomic signatures and the effect of aging. Young (3 months) and old (21 months) mice were treated with Bleomycin or with control saline solution and analyzed transcript and protein expression over 8 weeks (Day 0, 14, 21, 28, 35, 42, 49, 56).
Project description:Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of TGFβ1 as the major player in the pathogenesis of the disease. This study designed novel human- and mouse-specific siRNAs and siRNA/DNA chimeras targeting both human and mouse common sequences and evaluated their inhibitory activity in pulmonary fibrosis induced by bleomycin and lung-specific transgenic expression of human TGFβ1. Selective novel sequences of siRNA and siRNA/DNA chimeras efficiently inhibited pulmonary fibrosis, indicating their applicability as tools for treating fibrotic disease in humans. Total RNA was extracted from lung tissue from mice with bleomycin (BLM)-induced lung fibrosis treated with mouse TGFβ1 siRNAs or vehicle on different days after BLM infusion.
Project description:Bleomycin-induced pulmonary fibrosis in mice mimics major hallmarks of idiopathic pulmonary fibrosis, yet in this model it spontaneously resolves over time. We studied molecular mechanisms of fibrosis resolution and lung repair, focusing on transcriptional and proteomic signatures and the effect of aging. Old mice showed delayed and incomplete lung function recovery 8 weeks after Bleomycin instillation. This shift in structural and functional repair in old Bleomycin-treated mice was reflected in a temporal shift in gene and protein expression. We reveal gene signatures and signaling pathways which underpin the lung repair process.
Project description:Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF. This DIA-MS dataset entails the raw data and peptide-centric DIA-NN search results of both, lung tissue and bronchoalveolar lavage fluid of n=5 mice profiled across the treatment groups bleomycin combined with TH (BTH), dexamethasone (DEX), TH alone (TH) and vehicle control (V) relative to bleomycin alone (B) as control. Different animals within protein groups were considered biological replicates of the respective treatment condition.
Project description:In our previous study, mice with pulmonary fibrosis induced by a bleomycin insult in the context of short telomeres develop pulmonary fibrosis. By using AAV9 vectors carrying the telomerase Tert gene to treat those mice, we explore the possibility of telomerase gene therapy as a possible treatment for IPF patients carrying short telomeres. To further understand gene expression changes undergoing in ATII cells upon telomerase activation, we isolated ATII cells from pulmonary fibrosis Tert-treated and empty vector-treated lungs at 1 week after AAV9 inoculation by FACS.
Project description:To investigate the role of Dectin-1 in the development of pulmonary fibrosis, we used Dectin-1-deficient (Clec7a–/–, KO) mice to establish a bleomycin-induced pulmonary fibrosis model and compared it with WT mice.
Project description:Osteopontin (OPN, Spp1-/-) is considered detrimental in pulmonary fibrosis. However, effect of OPN produced by AMs during pulmonary fibrosis is not known. We used bulk RNA sequencing to analyze the effect of OPN in AMs from bleomycin treated mice.
Project description:The most preclinical used in vivo model to study lung fibrosis is the bleomycin-induced lung fibrosis model in 2-3-month-old mice. Although this model resembles key aspects of idiopathic pulmonary fibrosis (IPF), there are limitations in its predictability for the human disease. One of the main differences is the juvenile age of animals that are usually used in experiments, resembling humans of around 20 years. Because IPF patients are usually older than 60 years, aging appears to play an important role in the pathogenesis of lung fibrosis. We here compared young (3 months) and old (21 months) mice 21 days after intratracheal bleomycin instillation.