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PubMed2005

Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis.

There is substantial evidence that both inflammation and oxidative damage contribute to the pathogenesis of motor neuron degeneration in the G93A SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS). Celastrol is a natural product from Southern China, which exerts potent anti-inflammatory and antioxidative effects. It also acts potently to increase expression of heat shock proteins including HSP70. We administered it in the diet to G93A SOD1 mice starting at 30 days of age. Celastrol treatment significantly improved weight loss, motor performance and delayed the onset of ALS. Survival of celastrol-treated G93A mice increased by 9.4% and 13% for 2 mg/kg/day and 8 mg/kg/day doses, respectively. Cell counts of lumbar spinal cord neurons confirmed a protective effect, i.e. 30% increase in neuronal number in the lumbar spinal cords of celastrol-treated animals. Celastrol treatment reduced TNF-alpha, iNOS, CD40, and GFAP immunoreactivity in the lumbar spinal cord sections of celastrol-treated G93A mice compared to untreated G93A mice. TNF-alpha immunoreactivity co-localized with SMI-32 (neuronal marker) and GFAP (astrocyte marker). HSP70 immunoreactivity was increased in lumbar spinal cord neurons of celastrol-treated G93A mice. Celastrol has been widely used in treating inflammatory diseases in man, and is well tolerated; therefore, it may be a promising therapeutic candidate for the treatment of human ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2004

CAI is a potent inhibitor of neovascularization and imparts neuroprotection in a mouse model of ischemic retinopathy.

PURPOSE: This study was performed to characterize the effects of an antimetastatic and antiangiogenic molecule, carboxyamido-triazole (CAI), on retinal neovascularization in a mouse model. METHODS: Neonatal mice were subjected to 75% to 85% oxygen from postnatal day (PND)-7 to -12 and then were abruptly placed in room air. CAI (100 mg/kg) or vehicle control polyethylene glycol-400 (PEG-400) was given daily from PND-14 to -16, and mice were killed on PND-17 to form group A. In group B, CAI (100 mg/kg) or PEG-400 was given daily from PND-17 to -19, and mice were killed on PND-20. RESULTS: A 92% inhibition of neovascular cell nuclei on light microscopy was observed in mice treated with CAI in group A (P < 0.0001). Fluorescein-perfusion demonstrated a similar profound inhibition of neovascular frond formation in CAI-treated mice in group A. In group B, after neovascular fronds had already formed, CAI administration reduced neovascular cell nuclei by 72% (P < 0.001). Fluorescein perfusion studies confirmed that CAI induced regression of neovascular fronds. Similar amounts of posterior retinal ischemia were observed in all mice at both PND-17 and -20. In group A and B animals, CAI increased immunoreactivity of a cellular survival factor, Bcl-2, decreased TUNEL-positive cells, and after CAI treatment the normal morphology of the inner retina remained intact. CONCLUSIONS: CAI almost completely abolished retinal neovascularization in group A, and neovascular fronds involuted after treatment with CAI in group B. Thus, CAI is a potent inhibitor of ischemia-induced neovascularization and also imparts retinal neuroprotection after ischemic injury.

Angiogenesis Inhibitors↗
PubMed2006

Anticancer and cytotoxic properties of the latex of Calotropis procera in a transgenic mouse model of hepatocellular carcinoma.

AIM: To evaluate the anticancer property of the dried latex (DL) of Calotropis procera, a tropical medicinal plant, in the X15-myc transgenic mouse model of hepatocellular carcinoma and to elucidate its mechanism of action in cell culture. METHODS: The young transgenic mice were orally fed with the aqueous suspension of DL (400 mg/kg for 5 d/wk) for 15 wk and their liver was examined for histopathological changes at 20 wk. Serum levels of vascular endothelial growth factor (VEGF) were also measured in these animals. To characterize the active fraction, DL was extracted with petroleum ether followed by methanol. The methanolic extract was sub-fractionated on a silica gel G column using a combination of non-polar and polar solvents and eleven fractions were obtained. Each fraction was analysed for cytotoxic effect on hepatoma (Huh7) and non-hepatoma (COS-1) cell lines and non-transformed hepatocytes (AML12) using tetrazolium (MTT) assay. Finally, the mechanism of cell death was investigated by measuring the levels of Bcl2, caspase 3 and DNA fragmentation. RESULTS: DL treatment of mice showed a complete protection against hepatocarcinogenesis. No adverse effect was observed in these animals. The serum VEGF level was significantly lowered in the treated mice as compared to control animals. Cell culture studies revealed that the methanolic extract of DL as well as its fraction 8 induced extensive cell death in both Huh-7 and COS-1 cells while AML12 cells were spared. This was accompanied by extensive fragmentation of DNA in Huh-7 and COS-1 cells. No change in the levels of canonical markers of apoptosis such as Bcl2 and caspase 3 was observed. CONCLUSION: DL of C. procera has the potential for anti-cancer therapy due to its differentiable targets and non-interference with regular pathway of apoptosis.

Animals↗
PubMed2005

Abnormal distribution of aquaporin-5 in salivary glands in the NOD mouse model for Sjögren's syndrome.

OBJECTIVE: To localize aquaporin-5 in healthy salivary gland acinar cells and to check if it is abnormally translocated in an experimental NOD mouse model for Sjögren's syndrome (SS). METHODS: Healthy BALB/c control mice and autoimmune focal adenitis NOD mice were studied. Aquaporin-5 was stained using avidin-biotin-peroxidase complex and indirect immunofluorescence staining methods, and visualized using light and laser scanning confocal microscopy. RESULTS: Aquaporin-5 was found in the apical domain of the acinar cell plasma membrane in healthy BALB/c mice. In contrast, aquaporin-5 was found in the apical and basolateral acinar plasma cell membrane in parotid, submandibular, and sublingual glands in NOD mice. This was confirmed using laser scanning confocal microscopy for optical sectioning and image reconstruction. CONCLUSION: Our findings reveal an abnormal translocation of aquaporin-5 in an experimental SS animal model and support observations that implied a similar loss of the ordered and polarized expression of aquaporin-5 in human SS labial and lacrimal glands.

Animals↗
PubMedDate not supplied

Synergistic therapy of breast cancer with Y-90-chimeric L6 and paclitaxel in the xenografted mouse model: development of a clinical protocol.

BACKGROUND: Paclitaxel (Taxol) has demonstrated synergistic enhancement of radioimmunotherapy (RIT) of breast cancer with Y-90 labeled antibody ChL6, in the xenografted mouse model. To determine the optimal sequence and timing of RIT and Taxol for a prospective clinical trial, efficacy and dosimetry in mice, and dosimetry in patients receiving RIT alone, were examined. MATERIALS AND METHODS: Mice bearing human breast cancer xenografts (HBT 3477) received i.v. Y-90-DOTA-peptide-ChL6 (260 microCi), and i.p. Taxol (300 or 600 micrograms) 72, 48, or 24 hours prior to RIT, or 6, 24, 48, or 72 hours after RIT. RESULTS: Taxol after RIT resulted in cure, CR, or PR of all mice (70/70 tumors) and demonstrated greater therapeutic enhancement (p = 0.001) than Taxol before RIT. Mice receiving 600 micrograms Taxol 48 hours after RIT achieved 88% cure (7/8 tumors). In mice, 57% and 42% of the radiation dose to tumor and marrow, respectively, was delivered from 48-336 hours after RIT; in patients receiving 90Y-DOTA-peptide-ChL6, the corresponding values were 56% and 22%. CONCLUSIONS: Taxol given approximately 48 hours after RIT provides coincident peak deposition of Taxol and Y-90 in tumor, and no Taxol in the marrow during the major radiation dose to marrow, resulting in therapeutic enhancement without observable additive toxicity. A clinical trial of low dose Taxol given after RIT to patients with metastatic breast cancer is planned.

Adenocarcinoma↗
PubMed1994

Neutralization of transforming growth factor-beta 1 in a mouse model of immune-induced lung fibrosis.

We examined the contribution of the cytokine transforming growth factor beta 1 (TGF-beta 1) in the inflammatory response and fibrotic reaction in a mouse model of immune-induced lung fibrosis caused by repeated intranasal exposure to heat-killed bacillus Calmette-Guérin (BCG). Mice received 200 micrograms of BCG 3 days/week for 4 weeks, and simultaneous intraperitoneal injections of a monospecific rabbit antiserum against mouse TGF-beta 1 or a preimmune serum (normal rabbit globulin). BCG instillations generated a copious release of antigenic TGF-beta 1 in the lungs at 1, 2, 3 and 4 weeks (up to 15 ng/lungs/mouse). Treatment with anti-TGF-beta 1 antiserum significantly diminished the number of free lung cells recovered by bronchoalveolar lavage (BAL), although the BAL cellular profile was not affected. Moreover, anti-TGF-beta 1 treatment of challenged mice diminished very significantly the total levels of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) in the lungs of animals challenged with BCG. Histological examination and morphometric analysis of Masson's Trichrome-stained sections and measurements of total lung hydroxyproline levels showed a substantial decrease in lung fibrosis and granulomatous response of challenged mice given anti-TGF-beta 1. These data argue for a role for TGF-beta 1 in inducing inflammation and lung fibrosis in response to an immune stimulus.

Animals↗
PubMed2004

A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging.

Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here, we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy. The ultrastructure of the storage material accurately replicated the abnormalities in human patients revealing mixture of lamellar profiles including fingerprint profiles as well as curvilinear and rectilinear bodies in electronmicroscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in the Cln5-/- mice. Transcript profiling of the brains of the Cln5-/- mice revealed altered expression in several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected and this agrees well with the hypomyelination seen in the human vLINCL patients. In general, the progressive pathology of the Cln5-/- brain mimics the symptoms of the corresponding neurodegenerative disorder in man. Since the Cln5-/- mice do not exhibit significant brain atrophy, these mice could serve as models for studies on molecular processes associated with advanced aging.

Aging↗
PubMed2000

Cardiomyocyte death induced by myocardial ischemia and reperfusion: measurement with recombinant human annexin-V in a mouse model.

INTRODUCTION: Phosphatidylserine (PS) externalization is regarded as one of the earliest hallmarks of cells undergoing programmed cell death. We studied the use of labeled human recombinant annexin-V, a protein selectively binding to PS, to detect cardiomyocyte death in an in vivo mouse model of cardiac ischemia and reperfusion (I/R). METHODS AND RESULTS: I/R was induced in mouse hearts by ligation and subsequent release of a suture around the left anterior descending coronary artery. Annexin-V (25 mg/kg) fused to a marker molecule was injected intra-arterially 30 minutes before euthanasia. After 15 minutes of ischemia followed by 30 minutes of reperfusion, 1.4+/-1. 2% (mean+/-SD) of the cardiomyocytes in the area at risk were annexin-V positive (n=6). This increased to 11.4+/-1.9% after 15 minutes of ischemia followed by 90 minutes of reperfusion (n=7) and to 20.2+/-3.3% after 30 minutes of ischemia followed by 90 minutes of reperfusion (n=7). In control mice, including those injected with annexin-V at the binding site of PS, no annexin-V-positive cells were observed. DNA gel electrophoresis showed typical laddering starting after 15 minutes of ischemia followed by 30 minutes of reperfusion, suggesting activation of the cell death program. Intervention in the cell death program by pretreatment with a novel Na(+)-H(+) exchange inhibitor substantially decreased annexin-V-positive cardiomyocytes from 20.2% to 2.2% in mice after 30 minutes of ischemia followed by 90 minutes of reperfusion. CONCLUSIONS: These data suggest that labeled annexin-V is useful for in situ detection of cell death in an in vivo model of I/R in the heart and for the evaluation of cell death-blocking strategies.

Animals↗
PubMed1998

Dietary chitosan inhibits hypercholesterolaemia and atherogenesis in the apolipoprotein E-deficient mouse model of atherosclerosis.

Chitosan, the deacetylated form of chitin, is extracted from the shells of crustaceans. The strong positive charge carried by the chitosan molecule causes it to bind negatively charged substrates such as lipids. Orally administered chitosan binds fat in the intestine, blocking absorption, and has been shown to lower blood cholesterol in animals and humans. As a result it has been proposed that dietary supplementation with chitosan may inhibit the formation of atherosclerotic plaque. We have tested this hypothesis using the apolipoprotein E-deficient mouse model of atherosclerosis. This hypercholesterolaemic animal develops atherosclerosis without the need for dietary or surgical intervention. The apolipoprotein E-deficient mouse therefore provides an ideal model in which to study the effects of dietary chitosan on both blood cholesterol and atherosclerosis. Animals were fed for 20 weeks on a diet containing 5% chitosan or on a control diet. Blood cholesterol levels were significantly lower in the chitosan fed animals throughout the study, and at 20 weeks were 64% of control levels. When the area of aortic plaque in the two groups was compared a highly significant inhibition of atherogenesis, in both the whole aorta and the aortic arch, was observed in the chitosan fed animals--42 and 50%, respectively. Body growth was significantly greater in the chitosan fed animals. This study is the first to show a direct correlation between lowering of serum cholesterol with chitosan and inhibition of atherogenesis, and suggests that the agent could be used to inhibit the development of atherosclerosis in individuals with hypercholesterolaemia.

Animals↗
PubMed1995

Development of mouse models for cystic fibrosis.

Using gene targeting in embryonal stem cells it is now possible to create accurate genetic models of inherited human disease in the mouse. The value of an animal model of cystic fibrosis is in providing clarification of disease pathogenesis, genotype-phenotype correlation, the identification of other relevant genetic factors, and as the optimal test system for novel therapeutic intervention. Correction of the basic defect by a somatic gene therapy approach is an attractive approach to disease treatment. CF mouse models have been described which display the characteristic electrophysiological defect and thus both safety and efficacy can be monitored in these animals. Modulation of Cftr levels in transgenic animals and the results on disease phenotype give some indication of the level of gene expression necessary to give clinical effect.

Animals↗
PubMed2004

alpha-Lipoic acid inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma.

BACKGROUND: Oxidative stress may play an important role in the pathogenesis of bronchial asthma. OBJECTIVE: We evaluated the therapeutic effect of alpha-lipoic acid, a nonenzymatic antioxidant, in a mouse model of asthma. METHODS: BALB/c mice were immunized intraperitoneally with ovalbumin (OVA) on days 1 and 14 and challenged with inhaled OVA on days 28, 29, and 30. Mice were fed OVA-free standard mouse chow with 0%, 0.125%, 0.25%, 0.5%, and 1% (wt/wt) alpha-lipoic acid during the immunization and challenge periods. On day 31, mice were challenged with inhaled methacholine, and enhanced pause was measured as an index of airway hyperresponsiveness. Severity of airway inflammation was determined by means of differential cell count of bronchoalveolar lavage (BAL) fluid and by means of histopathologic lung analysis. Levels of OVA-specific IgE in serum, IL-4 and IL-5 in BAL fluid, and intracellular reactive oxygen species in alveolar macrophages and lymphocytes obtained from regional perihilar lymph nodes were measured. Nuclear factor kappaB DNA-binding activity in lung tissues was analyzed by means of electrophoretic gel mobility shift assay. RESULTS: Compared with untreated asthmatic mice, mice treated with alpha-lipoic acid had significantly reduced airway hyperresponsiveness, a lower proportion of eosinophils among BAL cells, and significantly improved pathologic lesion scores of the lungs. alpha-Lipoic acid also significantly reduced serum OVA-specific IgE concentrations, IL-4 and IL-5 concentrations in BAL fluid, and intracellular reactive oxygen species and nuclear factor kappaB DNA-binding activity. CONCLUSION: These results suggest that oxidative stress plays an important role in asthmatic airway inflammation and that alpha-lipoic acid may be useful as adjuvant therapy for bronchial asthma.

Animals↗
PubMed2003

A chimeric mouse model established by allogenic in utero transplantation.

In utero stem cells transplantation is a promising approach to the prenatal treatment of diseases. In order to investigate the fate of the stem cells after in utero transplantation, we have established a chimeric mouse model with the method of in utero transplantation. Mononuclear cells (including stem cells/progenitor cells) derived from male mouse bone marrow were injected into fetal mouse peritoneal cavity during the pre-immune period. The donor cells in the circulatory blood of female recipients were identified by fluorescence in situ hybridization (FISH), and the Y-chromosome specific DNA was detected by PCR as well as real-time quantitative PCR after the recipient mice were born. The results showed that a total of 4 female recipient mice were chimeric in their peripheral blood. Significantly, the donor cells in three chimeric mice persisted up to six months.

Animals↗
PubMed2001

Estrogen and estrogen plus progestin act directly on the mammary gland to increase proliferation in a postmenopausal mouse model.

Hormone replacement therapy (HRT) with ovarian hormones is an important therapeutic modality for postmenopausal women. However, a negative side effect of HRT is an increased risk of breast cancer. Surgical induction of menopause by ovariectomy (OVX) in mice is an experimental model that may provide insights into the effects of hormone replacement therapy on the human breast. We have developed a mouse model of early and late postmenopausal states to investigate the effects of HRT on the normal mammary gland. The purpose of this study was to determine if HRT-induced proliferation was due to the direct action of the hormones on the mammary gland, or mediated systemically by hormones or growth factors produced elsewhere in the body. Estrogen (E) or E plus the synthetic progestin, R5020, were implanted directly into the mammary glands of early (1 week post OVX) and late (5 week post OVX) postmenopausal mice instead of administration by injection. We report that responses of early and late postmenopausal mice to implanted hormones were the same as those observed previously with systemically administered hormones. Implanted E conferred an enhanced proliferative response in the late postmenopausal gland characterized morphologically by enlarged duct ends. E+R5020 implants induced similar degrees of cell proliferation in both postmenopausal states but the morphological responses differed. Ductal sidebranching was observed in early postmenopausal mice, whereas duct end enlargement was observed in late postmenopausal mice. The differences in morphological response to E+R5020 in 5 week post OVX were associated with an inability of E to induce progesterone receptors (PR) in the late postmenopausal gland. The responses of the late postmenopausal glands to E and E+P were very similar to that observed previously in immature pubertal glands in ovary-intact mice. In pubertal mice, PR cannot be induced by E unless the mammary gland is pre-treated with EGF-containing implants. Similarly, herein pre-treatment of the late postmenopausal mammary gland with EGF-containing implants restored PR induction by E. Thus, EGF may determine the sensitivity of the mammary gland to E and E+P in late postmenopause and at puberty.

Animals↗
PubMed2003

Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats.

Huntington's disease (HD) is caused by an abnormal expansion of CAG repeats in the gene encoding huntingtin. The development of therapies for HD requires preclinical testing of drugs in animal models that reproduce the dysfunction and regionally specific pathology observed in HD. We have developed a new knock-in mouse model of HD with a chimeric mouse/human exon 1 containing 140 CAG repeats inserted in the murine huntingtin gene. These mice displayed an increased locomotor activity and rearing at 1 month of age, followed by hypoactivity at 4 months and gait anomalies at 1 year. Behavioral symptoms preceded neuropathological anomalies, which became intense and widespread only at 4 months of age. These consisted of nuclear staining for huntingtin and huntingtin-containing nuclear and neuropil aggregates that first appeared in the striatum, nucleus accumbens, and olfactory tubercle. Interestingly, regions with early pathology all receive dense dopaminergic inputs, supporting accumulating evidence for a role of dopamine in HD pathology. Nuclear staining and aggregates predominated in striatum and layer II/III and deep layer V of the cerebral cortex, whereas neuropil aggregates were found in the globus pallidus and layer IV/superficial layer V of the cerebral cortex. The olfactory system displayed early and marked aggregate accumulation, which may be relevant to the early deficit in odor discrimination observed in patients with HD. Because of their early behavioral anomalies and regionally specific pathology, these mice provide a powerful tool with which to evaluate the effectiveness of new therapies and to study the mechanisms involved in the neuropathology of HD.

Animals↗
PubMed1999

Inhibition of Ras and related guanosine triphosphate-dependent proteins as a therapeutic strategy for blocking malignant glioma growth: II--preclinical studies in a nude mouse model.

OBJECTIVE: Preliminary studies have demonstrated that the Ras family and related guanosine triphosphate-dependent proteins are overactivated in malignant gliomas and that inhibition of the activation of such proteins, by blockade of their post-translational processing, reduces tumor cell growth in vitro. The current study evaluates the utility of this therapeutic strategy in vivo, using preclinical glioma model systems. METHODS: We examined the efficacy against U-87 human malignant glioma cells, in both subcutaneous and intracranial nude mouse models, of selective peptidomimetic inhibitors of farnesyltransferase (FTI-276) and geranylgeranyltransferase (GGTI-297), which are involved in critical steps in the post-translational processing of Ras and related guanosine triphosphate-dependent proteins. For the subcutaneous model, 2 x 10(5) U-87 cells were implanted; after measurable tumors were detected on Day 7, animals were treated with either FTI-276, GGTI-297, or vehicle, administered by continuous infusion for 7 days. Differences in tumor volumes among the treatment groups were examined for significance using a Student's t test. For the intracranial model, 2 x 10(5) U-87 cells were implanted in the right frontal lobe and treatment was initiated on Day 7. In initial studies, animals received a 7-day course of either FTI-276, GGTI-297, or vehicle. In subsequent studies, a 28-day treatment period was used. Comparisons of survival times among treatment groups were performed using a rank-sum test. RESULTS: Although the two agents exhibited comparable antiproliferative activities in previous in vitro studies, an obvious difference in efficacy was apparent in this study. Whereas the geranylgeranyltransferase inhibitor failed to improve survival rates, compared with those observed for control animals, in either the subcutaneous or intracranial model, the farnesyltransferase inhibitor produced objective regression of tumor growth in the subcutaneous model and significant prolongation of survival times in the intracranial model, without apparent toxicity. In the subcutaneous model, tumor volumes for the control, GGTI-297-treated, and FTI-276-treated animals on Day 28 after implantation were 621+/-420, 107+/-104, and 18.5+/-12.7 mm3, respectively (P < 0.05). In the 7-day-treated intracranial model, survival times for the control, GGTI-297-treated, and FTI-276-treated groups were 27.7+/-2.9, 29.8+/-2.1, and 43.6+/-2.7 days, respectively (P < 0.001). In the 28-day-treated intracranial model, survival times for the control, GGTI-297-treated, and FTI-276-treated groups were 29.2+/-3.7, 28.3+/-3.9, and 58.7+/-6.2 days, respectively, with five of six animals in the latter group surviving more than 55 days after tumor implantation (P < 0.001). CONCLUSION: These studies demonstrate that farnesyltransferase inhibition is effective in diminishing the growth of human glioma cells in vivo. Evaluation of this treatment approach in clinical trials is warranted.

Alkyl and Aryl Transferases↗
PubMed2005

A new mouse model of lung allergy induced by the spores of Alternaria alternata and Cladosporium herbarum molds.

Asthma is a serious health problem and during the last decade various experimental models of asthma have been developed to study the pathogenesis of this disease. In this study we describe a new mouse model of asthma that uses the spores of Alternaria alternata and Cladosporium herbarum, two allergenic molds recognized as common inducers of rhinitis and asthma in humans. Here we demonstrate that A. alternata and C. herbarum spores are immunogenic when injected into BALB/c mice, and induce the production of specific IgM and IgG1 antibodies and strongly increase IgE serum levels. To induce the allergic response, mice were sensitized by two intraperitoneal (i.p.) injections and then intranasaly (i.n.) challenged with A. alternata and C. herbarum spores. Bronchoalveolar lavages (BALs) from these mice contained numerous macrophages, neutrophils, eosinophils and lymphocytes whereas neutrophils were the predominant BAL inflammatory cells in nonsensitized mice. Histological studies demonstrated an influx of eosinophils in peri-vascular and peri-bronchial areas and the presence of numerous epithelial goblet cells only in sensitized mice. Increased expression of mRNA specific for various chemokines (eotaxin, MIP-1alpha, MIP-2) and chemokine receptors (CCR-1, CCR-2 and CCR-5) was observed in the lungs of nonsensitized mice challenged with the spores. Expression of CCR-3 mRNA in the lungs and Th2 cytokine (IL-4, IL-5 and IL-13) secretion in the BAL was additionally observed in sensitized and challenged mice. Finally we demonstrate through whole-body plethysmography that mold spore sensitization and challenge induce the development of an airway hyperreactivity in response to nebulized methacholine.

Alternaria↗
PubMed2006

Cystic fibrosis mouse models.

Animal models of cystic fibrosis (CF) are powerful tools that enable the study of the mechanisms and complexities of human disease. Murine models have several intrinsic advantages compared with other animal models, including lower cost, maintenance, and rapid reproduction rate. Mice can be easily genetically manipulated by making transgenic or knockout mice, or by backcrossing to well-defined inbred strains in a reasonably short period of time. However, anatomic and immunologic differences between mice and humans mean that murine models have inherent limitations that must be considered when interpreting the results obtained from experimental models and applying these to the pathogenesis of CF disease in humans. This review will focus on the different CF mouse models available that represent diverse phenotypes observed in humans with CF and that can help researchers elucidate the diverse functions of the CFTR protein.

Animals↗
PubMed2005

Genetic mouse models of parkinsonism: strengths and limitations.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Patients with PD display a combination of motor symptoms including resting tremor, rigidity, bradykinesia, and postural instability that worsen over time. These motor symptoms are related to the progressive loss of dopamine neurons in the substantia nigra pars compacta. PD patients also suffer from nonmotor symptoms that may precede the cardinal motor symptoms and that are likely related to pathology in other brain regions. Traditional toxin models of PD have focused on the nigrostriatal pathway and the loss of dopamine neurons in this region, and these models have been important in our understanding of PD and in the development of symptomatic treatments for the disease. However, they are limited in that they do not reproduce the full pathology and progression seen in PD, thus creating a need for better models. The recent discovery of specific genes causing familial forms of PD has contributed to the development of novel genetic mouse models of PD. This review discusses the validity, benefits, and limitations of these new models.

Animals↗