Inheritance of susceptibility to bleomycin-induced pulmonary fibrosis in the mouse (original) (raw)
Related papers
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.
Association Analysis Reveals Genetic Variation Altering Bleomycin-Induced Pulmonary Fibrosis in Mice
American Journal of Respiratory Cell and Molecular Biology, 2013
Pulmonary fibrosis is a disease of significant morbidity, with an incompletely defined genetic basis. Here, we combine linkage and association studies to identify genetic variations associated with pulmonary fibrosis in mice. Mice were treated with bleomycin by osmotic minipump, and pulmonary fibrosis was histologically assessed 6 weeks later. Fibrosis was mapped in C57BL6/J (fibrosissusceptible) 3 A/J (fibrosis-resistant) F2 mice, and the major identified linkage intervals were evaluated in consomic mice. Genome-wide and linkage-interval genes were assessed for their association with fibrosis, using phenotypic data from 23 inbred strains and the murine single-nucleotide polymorphism map. Susceptibility to pulmonary fibrosis mapped to a locus on chromosome 17, which was verified with consomic mice, and to three additional suggestive loci that may interact with alleles on chromosome 17 to affect the trait in F2 mice. Two of the loci, including the region on chromosome 17, are homologous to previously mapped loci of human idiopathic fibrosis. Of the 23 phenotyped murine strains, four developed significant fibrosis, and the majority presented minimal disease. Genome-wide and linkage region-specific association studies revealed 11 pulmonary expressed genes (including the autophagy gene Cep55, and Masp2, which is a complement component) to contain polymorphisms significantly associated with bleomycin-induced fibrotic lung disease. In conclusion, genomic approaches were used to identify linkage intervals and specific genetic variations associated with pulmonary fibrosis in mice. The common loci and similarities in phenotype suggest these findings to be of relevance to clinical pulmonary fibrosis.
Experimental mouse model of Bleomycin-induced Pulmonary Fibrosis
2020
Pulmonary fibrosis is a pathologic chronic lung disorder characterized by the deposition of extracellular matrix and damage to lung architecture. Models of pulmonary fibrosis were developed in several animal species. However, murine models are more common due to their low costs, availability and well characterized immune systems. Indeed, these murine models play an important role in understanding the biology of the diseases, deciphering the cellular and molecular mechanisms mediating pulmonary pathobiology and to explore novel therapeutic approaches. Although the majority of these models mimic certain characteristics of human idiopathic pulmonary fibrosis, most of them do not mimic other features especially those related to the progressive and irreversible nature of this disease. The present protocol describes the induction of a pulmonary fibrosis model in mice with bleomycin, which is a risk factor for human lung fibrosis. Specifically, we described the methodology of intratracheal...
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.
International journal of applied research, 2016
Background and objectives: Animal models for human pulmonary fibrosis ideally should reflect detailed characteristics of human disease including inflammation and abnormal epithelial repair with the induction of fibrotic foci. In addition, animal models should be highly reproducible, inexpensive to maintain, easy to perform and accessible. The aim of this study to evaluate the ability of bleomycin to induce pulmonary fibrosis in animal model by different time courses and the best time for its occurrence. Material and methods: This study was conducted in Medical Experimental Research center (MERC) in Mansoura University on C57BL/6 mice. Group (A) C57BL/6 mice (n=6) received 0.25 ml normal saline intraperitoneal twice weekly for 8 weeks and sacrificed two days after last saline dose injection. Group (B) C57BL/6 (n=10) mice received intraperitoneal injection of 0.5mg bleomycin twice weekly for 6 weeks only 6 mice completed the study and sacrificed two days after last bleomycin dose simi...
Cancer research, 1997
From evidence of interpatient variability in normal tissue sensitivity to radiotherapy and from radiation studies using inbred mouse strains, it is hypothesized that individual variation in susceptibility to radiation-induced pulmonary fibrosis is genetically controlled. A genetic model has been developed from the fibrosis-prone C57BL/6J and the fibrosis-resistant C3Hf/Kam mouse strains. Inheritance of the fibrotic phenotype was characterized in F1 and F2 (F1 intercross) generations derived from the parental strains. Genetic mapping was used to determine whether the quantitative trait loci (QTL), which influence susceptibility to bleomycin-induced lung fibrosis in these progenitor strains, could be implicated in susceptibility to radiation-induced lung fibrosis. Mice were treated with 14 or 16 Gy (60Co) to the whole thorax. The doses were selected to investigate the response at the LD50 and LD100 of C3Hf/Kam mice. The animals were sacrificed 33 weeks after treatment or when moribund...
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.
The Effects of the Nude(nu/nu)Mutation on Bleomycin-induced Pulmonary Fibrosis
American Review of Respiratory Disease, 1983
Previous reports have suggested that the immune system is involved in the lung fibrogenic response to certain agents or treatments. In the present study, we have evaluated the impact of the athymic (nude) mutation on the development of pulmonary fibrosis in mice induced by a single intratracheal instillation of bleomycin (0.75 units/animal). Histologic examination revealed that cellular infiltration, fibroblast proliferation, and connective tissue accumulation were diminished in the nude mice when compared with euthymic (het) control mice. In contrast to Control animals treated with saline, total lung hydroxyproline in the nude mouse was not significantly increased at 14 and 30 davs after bleomycin treatment. Net collagen synthesis, as assessed by measuring the rate of incorporation of tritiated proline in an organ culture system, was increased above control values in both nude and euthymic mice at 14 days after bleomycin treatment, although these values returned to normal at 30 days. However, lung collagen synthetic rates, normalized to dry lung weights, were significantly higher at 14 days in euthymic bleomycin-treated control mice than in the nude bleomycin-treated animals. The data indicate that the nude athymic mutation protects, at least partially, against bleomycin-induced pulmonary fibrosis, thus suggesting a role for the cellular immune system in regulating the fibrogenic response to this drug.
Systems biology analysis of lung fibrosis-related genes in the bleomycin mouse model
Scientific Reports
Tissue fibrosis is a major driver of pathology in aging and is involved in numerous age-related diseases. The lungs are particularly susceptible to fibrotic pathology which is currently difficult to treat. The mouse bleomycin-induced fibrosis model was developed to investigate lung fibrosis and widely used over the years. However, a systematic analysis of the accumulated results has not been performed. We undertook a comprehensive data mining and subsequent manual curation, resulting in a collection of 213 genes (available at the TiRe database, www.tiredb.org), which when manipulated had a clear impact on bleomycin-induced lung fibrosis. Our meta-analysis highlights the age component in pulmonary fibrosis and strong links of related genes with longevity. The results support the validity of the bleomycin model to human pathology and suggest the importance of a multi-target therapeutic strategy for pulmonary fibrosis treatment.