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At least 235 records · Page 13Linked to original sources
PubMed2004

Role of macrophages in a mouse model of postoperative MRSA enteritis.

BACKGROUND: We have established a mouse model for fatal postoperative enteritis due to Staphylococcus aureus to analyze mechanisms of bacterial translocation and determine reasons for the lethality of this infection. In the present study the role of macrophages was ascertained in protection against S. aureus induced enteritis. MATERIALS AND METHODS: Mice were pretreated with cyclophosphamide (CY), an immunosuppressant, and then infected directly into the jejunum with methicillin-resistant S. aureus (MRSA) isolated from a patient. In other groups of mice liposome-encapsulated dichloromethylene diphosphate (Cl2MDP) was administered to deplete macrophages in vivo. Other experimental groups received lipoteichoic acid (LTA), which was used to inhibit the ability of macrophages to bind MRSA, and additionally, to analyze dependence of bacterial clearance on the macrophage scavenger receptor. The ability of macrophages to bind MRSA was compared with survival rates in this mouse model of fatal postoperative enteritis. RESULTS: Injection of liposome-encapsulated Cl2MDP decreased survival rate of mice infected intraintestinally with MRSA in a dose-dependent manner. Cyclophosphamide also decreased survival rate of MRSA-infected mice and was found to correlate with its ability to decrease the number of macrophages in the spleen. Intravenous LTA administration did not affect total splenocyte numbers or the number of splenic macrophages but decreased the ability of macrophages to bind MRSA and adversely affected survival of mice infected with MRSA. CONCLUSIONS: Macrophages play a critical role in protection against MRSA administered directly into the jejunum. LTA recognition sites (probably type A scavenger receptors) on macrophages are required for binding and phagocytosing MRSA.

Animals↗
PubMedDate not supplied

Anti-beta2-glycoprotein I antibodies recognizing platelet factor 4-heparin complex in antiphospholipid syndrome in patient substantiated with mouse model.

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies associated with arterial and/or venous thrombosis, and recurrent abortion accompanied often by thrombocytopenia. These antibodies are heterogeneous and react against phospholipid-binding proteins such as beta2-glycoprotein I (beta2GPI) and prothrombin. The recognition of anti-beta2-glycoprotein I (anti-beta2GPI) by platelet factor 4-heparin complex (PF4-Hc) has been previously evoked and partially confirmed by the present inhibition studies. Further, the anti-beta2-glycoprotein I antibodies were purified from a patient with primary antiphospholipid syndrome using Affi-gel-10-beta2GPI immunoaffinity chromatography. The purified anti-beta2GPI IgM as well as patient serum equally recognized PF4-Hc in ELISA mode. In order to substantiate this data and to better understand we studied an animal model using mouse active immunization with the purified human anti-beta2GPI. The mice showed a significant decrease in their platelet count. In addition the ELISA responses of the immunized mice sera were positive against both beta2GPI and PF4-Hc, substantiating the double recognition. Despite many previous reported animal model studies, this is the first time we have shown the specific recognition of anti-beta2GPI antibodies by PF4-Hc, the results in the induced mice correlating the data observed with some patients.

Adult↗
PubMed2001

Use of genetically modified mouse models for evaluation of carcinogenic risk: considerations for the laboratory animal scientist.

There has been increasing interest in the use of selected genetically modified (GM) mouse models for the testing of chemicals to determine their carcinogenic potential. GM mouse models are believed to be useful tools that offer mechanistically relevant insights for understanding and predicting the human response to chemical exposure. They have been proposed as alternatives to the traditional 2-year mouse oncogenicity bioassay. In this overview we will review the GM mouse models that have been proposed as bioassay alternatives and present some of the key laboratory animal science challenges that need to be considered when using these unique animals.

Animal Husbandry↗
PubMed1998

Ethanol-induced activation of the hypothalamic-pituitary-adrenal axis in a mouse model for binge drinking: role of Ro15-4513-sensitive gamma aminobutyric acid receptors, tolerance, and relevance to humans.

A mouse model for binge drinking has been developed in this laboratory, and several aspects of this model have been characterized. Many of the immunosuppressive effects of ethanol (EtOH) in this model seem to be mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis and consequent increases in the concentration of glucocorticoids, catecholamines, and perhaps other immunosuppressive mediators. The purpose of the work described here is to examine three important issues regarding the EtOH-induced neuroendocrine response in this model: 1) Are Ro15-4513-sensitive gamma aminobutyric acid type A (GABA-A) receptors involved in activation of the HPA axis by EtOH? 2) Does daily administration of EtOH produce tolerance with regard to activation of the HPA axis or with regard to suppression of natural killer cell activity? 3) Is the HPA axis activated by similar blood EtOH concentrations in humans and in the mouse model? Ro15-4513, a partial inverse agonist of GABA-A receptors, did not affect EtOH-induced increases in blood corticosterone levels. This suggests that Ro15-4513-sensitive GABA-A receptors are not involved in EtOH-induced activation of the HPA axis and that inhibition of corticosterone production is not the mechanism by which Ro-15-4513 blocks EtOH-induced immunosuppression. To evaluate tolerance, mice were given a daily dose of EtOH (6.5 g/kg by gavage) or vehicle (water) for 10 days. Control groups received vehicle or EtOH only on the last day of the experiment. At the optimum time after EtOH administration serum corticosterone and splenic NK cell activity were measured. The results indicate no significant alterations in the response to EtOH of mice exposed to EtOH for 10 days compared to those exposed only once. To compare the HPA axis response of mice and humans, lower EtOH dosages than generally used in our model were administered to mice, and the corticosterone response was compared to published data for humans who had similar ranges of blood EtOH levels. The results suggest that humans and mice exhibit activation of the HPA axis only when blood EtOH levels exceed approximately 0.14%. Together these results further characterize a mouse model for binge drinking that seems to provide a reasonable representation of many aspects of binge drinking in humans.

Affinity Labels↗
PubMed2005

A mouse model for S. typhimurium-induced enterocolitis.

Salmonella typhimurium has emerged as a model pathogen that manipulates host cells in a complex fashion, thus causing disease. In humans, S. typhimurium causes acute intestinal inflammation. Intriguingly, type III secreted virulence proteins have a central role in this process. At the cellular level, the functions of these factors are well characterized; at present, animal models are required for elucidating how these factors trigger inflammatory disease in vivo. Calf infection models have been employed successfully and, recently, a mouse model was identified: in streptomycin-pretreated mice, S. typhimurium causes acute colitis. This mouse model provides a new avenue for research into acute intestinal inflammation because it enables the manipulation and dissection of both the bacterial and host contributions to the disease in unsurpassed detail.

Animals↗
PubMed2001

Web-based access to mouse models of human cancers: the Mouse Tumor Biology (MTB) Database.

The Mouse Tumor Biology (MTB) Database serves as a curated, integrated resource for information about tumor genetics and pathology in genetically defined strains of mice (i.e., inbred, transgenic and targeted mutation strains). Sources of information for the database include the published scientific literature and direct data submissions by the scientific community. Researchers access MTB using Web-based query forms and can use the database to answer such questions as 'What tumors have been reported in transgenic mice created on a C57BL/6J background?', 'What tumors in mice are associated with mutations in the Trp53 gene?' and 'What pathology images are available for tumors of the mammary gland regardless of genetic background?'. MTB has been available on the Web since 1998 from the Mouse Genome Informatics web site (http://www.informatics.jax.org). We have recently implemented a number of enhancements to MTB including new query options, redesigned query forms and results pages for pathology and genetic data, and the addition of an electronic data submission and annotation tool for pathology data.

Animals↗
PubMed1995

Identification of four chromosomal loci determining obesity in a multifactorial mouse model.

We previously described a new mouse model for multigenic obesity, designated BSB. We now report the use of a complete linkage map approach to identify loci contributing to body fat and other traits associated with obesity in this model. Four loci exhibiting linkage with body fat, or with the weights of four different fat depots, residing on mouse chromosomes 6, 7, 12, and 15, were identified and confirmed by analysis of additional BSB mice. Each of the four loci differed with respect to their effects on the percent of body fat, specific fat depots and plasma lipoproteins. The loci exhibited allele-specific, non-additive interactions. A locus for hepatic lipase activity was co-incident with the body fat and total cholesterol loci on chromosome 7, providing a possible mechanism linking plasma lipoproteins and obesity. The chromosome 7 locus affecting body fat, total cholesterol and hepatic lipase activity was isolated in congenic strains whose donor strain regions overlap with the chromosome 7 BSB locus. These results provide candidate genes and candidate loci for the analysis of human obesity.

Adipose Tissue↗
PubMed1998

The development of a new mouse model of global ischemia: focus on the relationships between ischemia duration, anesthesia, cerebral vasculature, and neuronal injury following global ischemia in mice.

A new model for mouse global ischemia is presented, and the relationship of ischemia duration, cerebral vasculature, and ischemic neuronal injury has been determined. CD-1 mice anesthetized by chloral hydrate were subjected to global ischemia by bilateral common carotid artery occlusion under controlled ventilation for 3, 5, and 10 min. After evaluating the patency of the posterior communicating artery (PcomA) as hypoplastic or normoplastic, neuronal injury was independently determined in the striatum, cortex, and hippocampus in each hemisphere. Ischemic injury was strongly correlated with not only ischemia duration, but also with the patency of the PcomAs. Furthermore, neuronal injury developed in a delayed fashion after 3-min ischemia, while it was maximized at 24 h after 10-min ischemia. Physiological studies showed the induction of slight hypotension as compared with inhalation anesthesia, and improvement of blood gas data relative to spontaneous respiration. These data demonstrate the usefulness of this method to induce selective vulnerability and delayed neuronal cell death in mice, and to provide a useful model to study the detailed mechanism of global ischemia using transgenic or knockout mutant mice.

Anesthesia↗
PubMed2001

Topical and oral administration of the natural water-soluble antioxidant from spinach reduces the multiplicity of papillomas in the Tg.AC mouse model.

The Tg.AC mouse carrying the v-Ha-ras structural gene is a useful model for the study of chemical carcinogens, especially those acting via non-genotoxic mechanisms. This study evaluated the efficacy of the non-toxic, water-soluble antioxidant from spinach, natural antioxidant (NAO), in reducing skin papilloma induction in female hemizygous Tg.AC mice treated dermally five times over 2.5 weeks with 2.5 microg 12-O-tetradecanoylphorbol-13-acetate (TPA). The TPA-only group was considered as a control; the other two groups received, additionally, NAO topically (2 mg) or orally (100 mg/kg), 5 days/week for 5 weeks. Papilloma counts made macroscopically during the clinical observations showed a significant decrease in multiplicity (P<0.01) in the NAO topically treated group. According to histological criteria, papilloma multiplicity were lower in both topical-NAO and oral-NAO groups, but significantly so only in the oral-NAO mice (P<0.01). The beneficial effect of NAO in the Tg.AC mouse is reported.

Administration, Cutaneous↗
PubMed2006

Role of neutrophils in a mouse model of halothane-induced liver injury.

Drug-induced liver injury (DILI) is a major safety concern in drug development. Its prediction and prevention have been hindered by limited knowledge of the underlying mechanisms, in part the result of a lack of animal models. We developed a mouse model of halothane-induced liver injury and characterized the mechanisms accounting for tissue damage. Female and male Balb/c, DBA/1, and C57BL/6J mice were injected intraperitoneally with halothane. Serum levels of alanine aminotransferase and histology were evaluated to determine liver injury. Balb/c mice were found to be the most susceptible strain, followed by DBA/1, with no significant hepatotoxicity observed in C57BL/6J mice. Female Balb/c and DBA/1 mice developed more severe liver damage compared with their male counterparts. Bioactivation of halothane occurred similarly in all three strains based on detection of liver proteins adducted by the reactive metabolite. Mechanistic investigations revealed that hepatic message levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta); IL-6, and IL-8 were significantly higher in halothane-treated Balb/c mice compared to DBA/1 and C57BL/6J mice. Moreover, a higher number of neutrophils were recruited into the liver of Balb/c mice upon halothane treatment compared with DBA/1, with no obvious neutrophil infiltration detected in C57BL/6J mice. Neutrophil depletion experiments demonstrated a crucial role for these cells in the development of halothane-induced liver injury. The halothane-initiated hepatotoxicity and innate immune response-mediated escalation of tissue damage are consistent with events that occur in many cases of DILI. In conclusion, our model provides a platform for elucidating strain-based and gender-based susceptibility factors in DILI development.

Animals↗
PubMed2006

Impact of ciprofloxacin in the human-flora-associated (HFA) rat model: comparison with the HFA mouse model.

The ecological impact of different doses of ciprofloxacin was investigated in an experimental germ-free rat model into which human fecal flora was inoculated. Animals received oral doses (gavage) of 0, 0.25, 2.5, and 25 mg/kg body weight (bw) of ciprofloxacin once daily for 5 weeks. All doses of ciprofloxacin significantly reduced aerobic populations. Elimination of Enterobacteriaceae and reduction of bifodibacteria were noticed in the group treated with 25 mg/kg of the antibiotic. The rest of the intestinal flora was not affected. These effects were reversible after the treatment ended. The percentage of resistant enterococci increased in rats treated with 2.5 and 25 mg/kg; however, this increase was not statistically significant. There was a significant (P < 0.05) emergence of ciprofloxacin-resistant Bacteroides fragilis group with 25 mg/kg bw, which is equivalent to a human therapeutic dosage of the antibiotic. The MIC values and the percentage of resistance remained elevated 2 weeks after the end of treatment in this anaerobic population. Although sub-populations of enterococci and Enterobacteriaceae showed decreased susceptibility after ciprofloxacin administration, resistance was not evident. The ability of an exogenous strain of Salmonella to colonize the intestine of animals treated with 25 mg/kg of ciprofloxacin confirmed that the drug disrupted the colonization barrier effect of the indigenous flora at the high dose level tested. No changes in the metabolic parameters occurred during the antibiotic treatment. The results obtained in the HFA rat model were similar to those obtained in our previous study using the HFA mice model where ciprofloxacin at 0.125, 1.25, and 12.5 mg/kg bw induced a decrease of enterococci and Enterobacteriaceae populations. The high dose of ciprofloxacin also induced a decrease in bifidobacteria counts, an increase in levels of resistant B. fragilis group and a significant (P < 0.05) disruption of the colonization resistance of the barrier flora in HFA mice.

Animals↗
PubMed2000

A mouse model of galactose-induced cataracts.

Galactokinase (GK; EC 2.7.1.6) is the first enzyme in the metabolism of galactose. In humans, GK deficiency results in congenital cataracts due to an accumulation of galactitol within the lens. In an attempt to make a galactosemic animal model, we cloned the mouse GK gene (Glk1) and disrupted it by gene targeting. As expected, galactose was very poorly metabolized in GK-deficient mice. In addition, both galactose and galactitol accumulated in tissues of GK-deficient mice. Surprisingly, the GK-deficient animals did not form cataracts even when fed a high galactose diet. However, the introduction of a human aldose reductase transgene into a GK-deficient background resulted in cataract formation within the first postnatal day. This mouse represents the first mouse model for congenital galactosemic cataract.

Aldehyde Reductase↗
PubMed1995

Bactericidal activity and kinetics of RP 59500 in a mouse model of Staphylococcus aureus septicaemia.

The bactericidal activity of RP 59500, a semisynthetic streptogramin, was compared with that of vancomycin against Staphylococcus aureus. This activity was evaluated in vitro by the kill curve method and in vivo using a model of mouse septicaemia. In vitro, RP 59500 (MIC = 0.12 mg/L) was more rapidly bactericidal against S. aureus IP 8203 than was vancomycin (MIC = 1 mg/L). In vivo, RP 59500 (120 mg/kg) was bactericidal against staphylococci in the blood of infected mice 1 h after administration, an effect which lasted for up to 7 h, whereas vancomycin at the same dose was bactericidal only 4 h after administration. The serum concentrations of vancomycin were higher than those of RP 59500 for at least 4 h after administration, and the Cmax and AUC of vancomycin were 4.8 and 8.3 times higher, respectively, than those of RP 59500 (Cmax = 13.2 mg/L; AUC0(-1) = 15.2 mg/L/h), although the agents had similar elimination half-lives (about 0.5 h). RP 59500 was also administered to mice as a fractionated dose (30 mg/kg x 4, 40 mg/kg x 3, 60 mg/kg x 2). The onset of its bactericidal effect was delayed by fractionating the dose, but the suppression of bacteria in the blood was prolonged.

Animals↗
PubMed2025

Investigating the genomic landscape of mouse models of breast cancer metastasis.

Metastasis remains a major cause of cancer mortality. AbstractThis study, expanding upon previous findings in the MMTV-PyMT model, investigated four independent mouse models, representing luminal (MMTV-PyMT, MMTV-Myc), HER2-amplified (MMTV-Her2) and triple negative (C3(1)TAg) breast cancer subtypes. Consistent with previous results, limited evidence for metastasis-associated somatic point mutations was found for all models. We also found that oncogenic drivers significantly influenced the number and size of metastasis-specific copy number variations (MSCNVs), but common driver-independent MSCNVs were rare. Furthermore, analyzing a cohort with varying genetic backgrounds while maintaining a constant oncogenic driver (PyMT) revealed that genetic background profoundly impacts MSCNVs. Transcriptome analysis demonstrated that oncogenic drivers strongly shaped metastasis-specific gene expression (MSGE), with each driver exhibiting distinct expression profiles. In contrast, MSGE in the PyMT-F1 cohort was more variable across strains. Despite the diversity of MSCNV and MSGE, functional analysis revealed that both mechanisms converge on the modulation of key cellular processes, including immune responses, metabolism, and extracellular matrix interactions. These findings emphasize the complex interplay between oncogenic drivers and genetic background in shaping the genomic and transcriptional landscapes of metastatic lesions.

Journal Article↗
PubMed2004

Prevention of corneal allograft rejection in a mouse model of high risk recipients.

AIM: To determine the effectiveness of treatment with immunosuppressive drugs and monoclonal antibodies (mAb) after penetrating keratoplasty in two different models of high risk mouse recipients. METHODS: Corneas were grafted orthotopically in mouse models of high risk recipients with either neovascularisation of the graft bed or presensitisation to graft donor antigens. Recipients were treated with mAb against CD4(+) or CD8(+) cells or against T cells, or were treated with cyclosporin A (CsA) or mycophenolate mofetil (MMF), or a combination of both drugs. RESULTS: Control untreated recipients with neovascularised graft bed or presensitised to the graft donor antigens rejected corneal allografts in 12.5 (SD 2.3) and 9.9 (1.6) days, respectively. Treatment of graft recipients with a neovascularised graft bed with mAb anti-CD4 or anti-T cells, but not with mAb anti-CD8 or with immunosuppressive drugs, resulted in a significant prolongation of graft survival; 75% and 28.5%, respectively, of grafts survived for more than 45 days after grafting. However, none of the treatments were successful in presensitised recipients. CONCLUSIONS: Treatment of high risk recipients with mAb anti-CD4 is more effective in preventing corneal allograft rejection than the treatment with mAb anti-CD8 or the immunosuppressive drugs MMF and CsA. However, the effectiveness of the treatment depends on the recipients' pretransplantation risk type.

Animals↗
PubMed2004

Rescue of enzyme deficiency in embryonic diaphragm in a mouse model of metabolic myopathy: Pompe disease.

Several human genetic diseases that affect striated muscle have been modeled by creating knockout mouse strains. However, many of these are perinatal lethal mutations that result in death from respiratory distress within hours after birth. As the diaphragm muscle does not contract until birth, the sudden increase in diaphragm activity creates permanent injury to the muscle causing it to fail to meet respiratory demands. Therefore, the impact of these mutations remains hidden throughout embryonic development and early death prevents investigators from performing detailed studies of other striated muscle groups past the neonatal stage. Glycogen storage disease type II (GSDII), caused by a deficiency in acid alpha-glucosidase (GAA), leads to lysosomal accumulation of glycogen in all cell types and abnormal myofibrillogenesis in striated muscle. Contractile function of the diaphragm muscle is severely affected in both infantile-onset and late-onset individuals, with death often resulting from respiratory failure. The knockout mouse model of GSDII survives well into adulthood despite the gradual weakening of all striated muscle groups. Using this model, we investigated the delivery of recombinant adeno-associated virus (rAAV) vectors encoding the human GAA cDNA to the developing embryo. Results indicate specific high-level transduction of diaphragm tissue, leading to activity levels up to 10-fold higher than normal and restoration of normal contractile function. Up to an estimated 50 vector copies per diploid genome were quantified in treated diaphragms. Histological glycogen staining of treated diaphragms revealed prevention of lysosomal glycogen accumulation in almost all fibers when compared with untreated controls. This method could be employed with disease models where specific rescue of the diaphragm would allow for increased survival and thus further investigation into the impact of the gene deletion on other striated muscle groups.

Animals↗
PubMed2007

Mouse models of IgG- and IgM-mediated hemolysis.

Well-characterized mouse models of allo-immune antibody-mediated hemolysis would provide a valuable approach for gaining greater insight into the pathophysiology of hemolytic transfusion reactions. To this end, mouse red blood cells (mRBCs) from human glycophorin A transgenic (hGPA-Tg) donor mice were transfused into non-Tg recipients that had been passively immunized with IgG or IgM hGPA-specific monoclonal antibodies (mAbs). In this novel murine "blood group system," mRBCs from hGPA-Tg mice are "antigen positive" and mRBCs from non-Tg mice are "antigen negative." Passive immunization of non-Tg mice with the IgG1 10F7 and IgG3 NaM10-2H12 anti-hGPA mAbs each induced rapid clearance of incompatible transfused hGPA-Tg-mRBCs in a dose-response manner. Using various knockout mice as transfusion recipients, both the complement system and activating Fcgamma receptors were found to be important in the clearance of incompatible mRBCs by each of these IgG mAbs. In addition, the IgM E4 anti-hGPA mAb induced complement-dependent intravascular hemolysis of transfused incompatible hGPA-Tg-mRBCs accompanied by gross hemoglobinuria. These initial studies validate the relevance of these new mouse models for addressing important questions in the field of transfusion medicine.

Animals↗