Experimental mouse model of Bleomycin-induced Pulmonary Fibrosis (original) (raw)
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Development and time-course of bleomycin-induced pulmonary fibrosis in NMRI mice
DARU, 2007
Bleomycin-induced pulmonary fibrosis is a widely used experimental model for human lung fibrosis. The severity of fibrosis varies among different strains of mice and investigation on different strains and finding the mechanisms of variation is important in understanding the pathogenesis of human lung fibrosis. In the present study, NMRI mice were used to investigate the severity and also time-course of bleomycin-induced pulmonary fibrosis in comparison with C57BL/6 mice. After single dose administration of intratracheal bleomycin, the fibrotic response was studied by biochemical measurement of collagen deposition and semiquantitative analysis of pathological lung changes. NMRI mice developed lung fibrosis from 1 to 4 week after bleomycin instillation, with significant increases in lung collagen content and significant morphological changes (P < 0.05). These findings indicate that NMRI mice might be suitable as an experimental model of bleomycin-induced lung fibrosis.
Background: Idiopathic pulmonary fibrosis (IPF) is a severe and progressive respiratory disease with poor prognosis. Despite the positive outcomes from recent clinical trials, there is still no cure for this disease. Pre-clinical animal models are currently largely limited to small animals which have a number of shortcomings. We have previously shown that fibrosis is induced in isolated sheep lung segments 14 days after bleomycin treatment. This study aimed to determine whether bleomycin-induced fibrosis and associated functional changes persisted over a seven-week period. Methods: Two separate lung segments in nine sheep received two challenges two weeks apart of either, 3U bleomycin (BLM), or saline (control). Lung function in these segments was assessed by a wedged-bronchoscope procedure after bleomycin treatment. Lung tissue, and an ex vivo CT analysis were used to assess for the persistence of inflammation, fibrosis and collagen content in this model.
The International Journal of Biochemistry & Cell Biology, 2008
Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.
Stem Cell Reviews and Reports, 2018
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by fibroblast proliferation, extracellular matrix deposition, destruction of pulmonary alveolar architecture and vascular remodeling. Apart pirfenidone or nintendanib that only slow down the fibrotic process, there is no curative treatment other than lung transplantation. Because cell therapy approaches have been proposed in IPF, we hypothesized that injection of endothelial colony-forming cells (ECFCs), the vasculogenic subtype of endothelial progenitor cells, could modulate fibrosis in a Nude mouse model of bleomycin induced-pulmonary fibrosis. Mice were injected with ECFCs isolated from cord blood and from peripheral blood of adult IPF patients at two time-points: during the development of the fibrosis or once the fibrosis was constituted. We assessed morbidity, weight variation, collagen deposition, lung imaging by microCT, Fulton score and microvascular density. Neither ECFCs isolated from cord blood nor from IPF patients were able to modulate fibrosis or vascular density during fibrogenesis or when fibrosis was constituted. These findings indicate that human ECFCs do not promote an adaptive regenerative response in the lung upon fibrosis or angiogenic process in the setting of bleomycin-induced pulmonary fibrosis in Nude mice.
PLoS ONE, 2013
The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFb was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.
A mouse model of chronic idiopathic pulmonary fibrosis
Physiological reports, 2014
Chronic idiopathic pulmonary fibrosis (IPF) is a progressive, fatal, and untreatable disease with unclear etiology. There are few models of this chronic pathology, and although delivery of bleomycin to induce acute lung injury is the most common animal model of pulmonary fibrosis, there is considerable uncertainty about whether this acute injury resolves in those animals that survive. In this report, we have systematically followed groups of mice for up to 6 months following a single insult of bleomycin. We assessed changes in lung function and pathology over this time course, with measurements of the diffusion capacity for carbon monoxide, lung mechanics, quantitative stereology, and collagen. Our results show that, while there is some repair over this extended time course, the injury in the lung never fully resolves. This persistent degree of fibrosis may have similarities to many features of human IPF. Thus, these chronic fibrotic changes in mouse lungs could be a useful model to...
The importance of interventional timing in the bleomycin model of pulmonary fibrosis
European Respiratory Journal, 2020
Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5–7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical ...
An Experimental Model to Induce Homogeneous and Progressive Pulmonary Fibrosis in Rats
Indian Journal of Pharmaceutical Education and Research, 2021
Background: This study aims to develop a new experimental model of pulmonary fibrosis (PF) as an alternative to conventional bleomycin model to overcome its limitations and effectively screened the therapeutic agents. Similarity of new experimental model to human lung fibrosis particularly as uniform and continuous progression has encouraged us to evaluate the usefulness of this system by assessment of anti-fibrotic drug pirfenidone parallel with bleomycin induced PF. Materials and Methods: In new model, ovalbumin (OVA) related asthma induced rats were set to inhaled nebulized formaldehyde solution (0.5% v/v, 30 min) subsequent with cigarettes smoke exposure twice daily for 14, 28 or 42 days and designated as AFC treated rats. However, bleomycin (BLM) treated rats were administered (5 IU/kg) single dose intratracheal injection. The pulmonary associated effects were assessed through cells permeation study, biochemical evaluation, physical and physiological parameters, survival analysis and histopathological examination. Results: Overall, pulmonary associated effects induced by new as well as conventional bleomycin model exhibited almost similar results. Though, new model developed homogeneous and time dependent advancement in pulmonary severity with enhanced survival ratio as compared to bleomycin model. Comparatively, new model also represented low extent of normalization with pirfenidone treatment due to establishment of progressive fibrosis. Conclusion: This study reflects the role of formaldehyde and cigarette smoke in reinforcement of PF particularly during the lung inflammatory condition. Also, it provides novel idea to induce homogeneous and progressive PF in rats, which could resembles human lung fibrosis more specifically than conventionally induced by intratracheal bleomycin instillation.