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At least 109 records · Page 6Linked to original sources
PubMed2000

Inducible nitric oxide synthase-knockout mice exhibit resistance to pleurisy and lung injury caused by carrageenan.

In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenan-treated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated iNOS-WT mice. Lung tissue sections from carrageenan-treated iNOS-WT mice showed positive staining for poly adenosine diphosphate (ADP)-ribose synthetase that was mainly localized in alveolar macrophages and in airway epithelial cells. The intensity and degree of staining for nitrotyrosine and poly-ADP-ribose synthetase were markedly reduced in tissue sections from carrageenan-treated iNOS-KO mice. The inflamed lungs of iNOS-KO mice also showed an improved histologic status. Furthermore, a significant reduction in the suppression of energy status, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD(+)) was observed ex vivo in macrophages harvested from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an important role in the acute inflammatory response.

Animals↗
PubMed1998

Complementation of lymphotoxin alpha knockout mice with tumor necrosis factor-expressing transgenes rectifies defective splenic structure and function.

Lymphotoxin (LT)alpha knockout mice, as well as double LTalpha/tumor necrosis factor (TNF) knockout mice, show a severe splenic disorganization with nonsegregating T/B cell zones and complete absence of primary B cell follicles, follicular dendritic cell (FDC) networks, and germinal centers. In contrast, as shown previously and confirmed in this study, LTbeta-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks. We show here that similar to the splenic phenotype of LTbeta-deficient mice, complementation of LTalpha knockout mice with TNF-expressing transgenes leads to a p55 TNF receptor-dependent restoration of B/T cell zone segregation and a partial preservation of primary B cell follicles, FDC networks, and germinal centers. Notably, upon lipopolysaccharide challenge, LTalpha knockout mice fail to produce physiological levels of TNF both in peritoneal macrophage supernatants and in their serum, indicating a coinciding deficiency in TNF expression. These findings suggest that defective TNF expression contributes to the complex phenotype of the LTalpha knockout mice, and uncover a predominant role for TNF and its p55 TNF receptor in supporting, even in the absence of LTalpha, the development and maintenance of splenic B cell follicles, FDC networks, and germinal centers.

Animals↗
PubMed2003

Stress-induced dura vascular permeability does not develop in mast cell-deficient and neurokinin-1 receptor knockout mice.

Migraine headaches are often precipitated by stress and seem to involve neurogenic inflammation (NI) of the dura mater associated with the sensation of throbbing pain. Trigeminal nerve stimulation had been reported to activate rat dura mast cells and increase vascular permeability, effects inhibited by neonatal pretreatment with capsaicin implicating sensory neuropeptides, such as substance P (SP). The aim of the present study was to investigate NI, assessed by extravasation of 99-Technetium-gluceptate (99Tc-G), as well as the role of mast cells, SP and its receptor (NK-1R) in dura mater of mice in response to acute stress. Restraint stress for thirty min significantly increased 99Tc-G extravasation in the dura mater of C57BL mice. This effect was absent in W/W(v) mast cell-deficient mice and NK-1 receptor knockout mice (NK-1R-/-), but was unaltered in SP knockout mice (SP-/-). Acute restraint stress also resulted in increased dura mast cell activation in C57BL mice, but not in NK-1R-/- mice. These data demonstrate for the first time that acute stress triggers NI and mast cell activation in mouse dura mater through the activation of NK-1 receptors. The fact that SP-/- mice had intact vascular permeability response to stress indicates that some other NK-1 receptor agonist may substitute for SP. These results may help explain initial events in pathogenesis of stress-induced migraines.

Animals↗
PubMed2005

Alterations in reproductive function in SRC tyrosine kinase knockout mice.

The role of Src tyrosine kinase in regulating reproductive processes in female mice was investigated using Src wild-type (+/+), heterozygous (+/-), and knockout (-/-) mice. Ovarian Src kinase activity transiently increased in Src +/+ mice following eCG administration. Src knockout mice were infertile. Estrous cycles and vaginal opening in Src knockouts were variable and altered compared with Src +/+ and +/- mice. Follicle development was compromised in Src knockout mice as evidenced by reduced numbers of large pre-antral and antral follicles compared to Src +/+ mice. Corpora lutea were not observed in the ovaries of Src knockout mice; however, administration of eCG and hCG did result in ovulation. Serum LH and FSH on d 40 and 52 of age did not differ between Src wild-type and knockout females. Results from these studies reveal that female Src knockout mice are infertile due to reduced follicle development and anovulation.

Animals↗
PubMed2004

Role of somatostatin receptors on gastric acid secretion in wild-type and somatostatin receptor type 2 knockout mice.

Somatostatin, probably acting through somatostatin type 2 receptors (SSTR2), is the main inhibitor of gastric acid secretion. We characterized gastric acid secretion in SSTR2 knockout mice, and used preferential somatostatin receptor agonists to assess the relative role of SSTR1, 2, 3, 4, and 5 on gastric acid secretion. Basal gastric acid secretion and the secretory response to a meal were similar in conscious wild-type and knockout mice. However, under urethane anesthesia, which releases endogenous somatostatin, SSTR2 knockout mice had a basal secretion 11-15-fold higher than wild-type animals (micromol/10 min:1.40+/-0.09 vs. 0.10+/-0.01, p<0.05). Gastrin immunoneutralization or H(2) receptors blockade (cimetidine), but not cholinergic blockade (atropine), reduced the high basal secretion in SSTR2 knockout mice. In SSTR2 knockout mice, gastrin and histamine stimulated acid secretion with similar efficacy, while in wild-type mice histamine was more effective than gastrin. SSTR2 knockout mice showed also a hypersecretory response to pylorus ligation compared with wild-type animals. In wild-type mice, somatostatin-14, SMS 201-995, and the SSTR2-preferential agonist, DC 32-87, inhibited gastrin-stimulated acid secretion with an order of potency SMS 201-995>DC 32-87>somatostatin-14. Preferential agonists for the SSTR1, 3, 4, and 5 were devoid of any effect. None of the compounds tested affected the high basal secretion observed under urethane anesthesia in SSTR2 knockout mice. These results show that gastric antisecretory effects of peripheral somatostatin are mediated solely through SSTR2. In the absence of functional SSTR2 other somatostatin receptors do not compensate for the lack somatostatin-SSTR2-mediated inhibition. Basal acid secretion and the response to a meal are normal in conscious SSTR2 knockout mice, suggesting the presence of somatostatin-independent mechanisms that compensate for the lack of somatostatin-SSTR2-mediated inhibitory responses.

Animals↗
PubMed2005

A novel model of polyhydramnios: amniotic fluid volume is increased in aquaporin 1 knockout mice.

OBJECTIVE: To test the hypothesis that amniotic fluid volume is increased in aquaporin 1 knockout mice. STUDY DESIGN: Transgenic mice deficient in aquaporin 1 protein were generated by targeted gene disruption, as described previously. After a cesarean section was performed, intact, individual gestational sacs were removed from the uterus and weighed. Amniotic fluid volume, osmolality, and fetal and placental weights were determined. Data were analyzed by a 1-way analysis of variance for ranks; Dunn's post hoc test was used to analyze significant trends. RESULTS: Analysis of 16 litters showed 35 wild-type, 52 heterozygote, and 33 aquaporin 1 knockout mice. The knockout mice had a greater volume of amniotic fluid and lower amniotic fluid osmolality than their wild-type and heterozygote counterparts. There were no significant differences in fetal or placental weights among the groups. CONCLUSIONS: Aquaporin 1 null fetuses produce a greater volume of more dilute amniotic fluid. Our findings show that aquaporin 1 water channels in fetal membranes may contribute to amniotic fluid volume regulation. We speculate that idiopathic polyhydramnios may be associated with a deficiency of aquaporin 1 channels in human fetal membranes. Transgenic aquaporin 1 knockout mice provide a unique animal of polyhydramnios.

Amniotic Fluid↗
PubMed2000

Increased severity of glomerulonephritis in C-C chemokine receptor 2 knockout mice.

UNLABELLED: Increased severity of glomerulonephritis in C-C chemokine receptor 2 knockout mice. BACKGROUND: The C-C chemokine receptor 2 (CCR2) is expressed on monocytes and facilitates monocyte migration. CCR2 is a prominent receptor for monocyte chemoattractant protein-1 (MCP-1). This chemokine recruits monocytes to sites of inflammation. It has been suggested that CCR2 and its ligand, MCP-1, play a role in the pathogenesis of glomerulonephritis. The goal of this study was to determine the contribution of CCR2 in a murine model of accelerated nephrotoxic nephritis. We measured the extent of development of renal disease in CCR2 wild-type and knockout mice after the administration of antiglomerular basement membrane antibody. METHODS: Eight groups of animals were treated (N = 10 per group). Four days after IgG immunization, CCR2 wild-type and knockout mice received control serum or nephrotoxic serum. The urinary protein/creatinine ratio was measured on days 1 and 3; plasma and kidneys were collected on days 4 and 7. Kidneys were evaluated by light microscopy, immunohistochemistry, and immunofluorescence. The genotype of mice was confirmed by tissue analysis. RESULTS: Protective effects of CCR2 knockout on the urinary protein/creatinine ratio were observed on day 1, as values for this parameter were significantly lower (35 +/- 3.6) than in nephritic wild-type mice (50 +/- 6.8). There was a marked increase in proteinuria in nephritic wild-type mice on day 1 compared with vehicle-treated, wild-type animals (5 +/- 1.0). On day 3, the ameliorative effects of CCR2 knockout were not observed; the increase in the urinary protein/creatinine ratio was similar in nephritic CCR2 wild-type (92 +/- 11.2) and knockout mice (102 +/- 9. 2). Plasma markers of disease were evaluated on days 4 and 7. At these time points, there were no beneficial effects of CCR2 receptor knockout on plasma levels of urea nitrogen, creatinine, albumin, or cholesterol. On day 7, blood urea nitrogen (248 +/- 19.9 mg/dL) and plasma cholesterol were higher in nephritic CCR2 knockout mice than in wild-type mice (142 +/- 41.7 mg/dL) that received nephrotoxic serum. Histopathologic injury was more severe in nephritic CCR2 knockout mice than nephritic wild-type mice on day 4 (3.1 +/- 0.3 vs. 2.0 +/- 0.3) and day 7 (3.6 +/- 0.2 vs. 2.9 +/- 0.3). By immunohistochemical analysis at day 4, there were significantly fewer mac-2-positive cells, representative of macrophages in the glomeruli of nephritic CCR2 knockout (2.1 +/- 0.6) mice than nephritic wild-type (3.9 +/- 0.5) animals. By indirect immunofluorescence, there was a moderate, diffuse linear IgG deposition of equivalent severity present in glomeruli of both wild-type and CCR2 knockout nephritic mice. CONCLUSION: These results suggest that our strategy was successful in reducing macrophage infiltration, but this model of glomerulonephritis is not solely dependent on the presence of CCR2 for progression of disease. After a transient ameliorative effect on proteinuria, CCR2 knockout led to more severe injury in nephritic mice. This raises the intriguing possibility that a CCR2 gene product ameliorates glomerulonephritis in this murine model. Although effects that occur in chemokine knockout mice are not equivalent to those expected with prolonged use of a chemokine antagonist, this study may nevertheless have implications for consideration of long-term use of chemokine antagonists in renal disease.

Animals↗
PubMed2003

5-Lipoxygenase knockout mice exhibit a resistance to pleurisy and lung injury caused by carrageenan.

In the present study, by comparing the responses in wild-type (WT) mice and mice lacking [knockout (KO)] the 5-lipoxygenase (5-LO), we investigated the role played by 5-LO in the development of acute inflammation. When compared with carragenan-treated 5-LOWT mice, 5-LOKO mice, which had received carrageenan, exhibited a reduced degree of pleural exudation, polymorphonuclear cell migration. Lung myeloperoxidase activity, an index of neutrophil infiltration, was significantly reduced in 5-LOKO mice in comparison with 5-LOWT. Lung-tissue sections from carrageenan-treated 5-LOWT mice showed positive staining for intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and E-selectin, which were mainly localized around vessels. The intensity and degree of ICAM-1, VCAM-1, P-selectin, and E-selectin were markedly reduced in tissue section from carrageenan-5-LOKO mice, which also improved the histological status of the inflamed lungs. Taken together, our results clearly demonstrate that 5-LO modulates neutrophil infiltration in the acute lung inflammation.

Animals↗
PubMed2002

Blood-aqueous barrier in prostaglandin EP2 receptor knockout mice.

The role of prostaglandin EP(2) receptors in the disruption of the blood-aqueous barrier was examined using EP(2) receptor-deficient mice. Eyes were topically treated with EP receptor agonists or subjected to paracentesis. Fluorescein angiography was performed after topical treatment with 2.0 icrog butaprost. The results show that EP receptor agonists, PGE( 2) and the EP(2) receptor-selective agonist butaprost, increased aqueous humor protein in EP(2) +/+ wild-type mice to 18.0 mg/ml and 12.0 mg/ml, respectively, from the control value of 2.7 mg/ml. The increase in aqueous humor protein concentration in response to these EP receptor agonists was reduced significantly in EP(2) receptor-deficient mice. Fluorescein leakage into the anterior chamber, two minutes after its injection, was significantly greater in butaprost-treated wild-type mice than in butaprost-treated knockout mice. Protein concentration, 15 min after paracentesis, increased from 2.2 mg/ml to 25.0 mg/ml in the aqueous humor of the eyes of wild-type mice, while the increase in knockout mice was 10.6 mg/ml. These results suggest that EP( 2) and EP(4) receptors mediate the disruption of the blood-aqueous barrier induced by EP receptor agonists and paracentesis.

Alprostadil↗
PubMed2002

Cardiac function in neuropeptide Y Y4 receptor-knockout mice.

Autonomic control of cardiovascular function in neuropeptide Y (NPY) Y4 receptor-knockout mice was investigated using pancreatic polypeptide (PP), NPY and specific agonists and antagonists for other NPY receptors well characterised in cardiovascular function. Y4 receptor-knockout mice, anaesthetised with sodium pentobarbitone, displayed slower heart rate, indicated by a higher pulse interval and lower blood pressure compared to control mice. After vagus nerves were cut heart rate increased but was still significantly slower than in control mice. PP had no effect on blood pressure or cardiac vagal activity in either group of mice, which was consistent with earlier studies in other species. Injection of NPY evoked an increase in blood pressure but the response was significantly reduced in Y4 receptor-knockout mice compared to the controls. The reduction in pressor activity was not Y1 mediated as the selective Y1 antagonist, BIBP 3226, was effective in blocking NPY pressor activity in knockout mice. In addition, cardiac vagal inhibitory activity evoked by low doses of NPY was also reduced when compared to control responses. As N-acetyl [Leu(28, 31)] NPY 24-36 inhibited vagal activity dose dependently in both groups of mice with no difference in response at any dose, it is unlikely that this effect also is receptor mediated. We propose that the reduced vasoconstrictor and vagal inhibitory activity evoked by NPY in Y4 receptor-knockout mice is due to a lack of adrenergic tone bought about by a proposed reduction in sympathetic activity, possibly resulting from altered NPY activity secondarily affecting adrenergic transmission. We conclude that Y4 receptor deletion disrupts autonomic balance within the cardiovascular system.

Animals↗
PubMed2005

Biomineralization and adaptive plasticity of the temporomandibular joint in myostatin knockout mice.

Mice lacking myostatin (GDF-8), a negative regulator of skeletal muscle growth, show a significant increase in muscle mass versus normal mice. We compared wild-type and myostatin deficient mice to assess the postnatal effect of elevated masticatory loads due to increased jaw-adductor muscle activity and greater bite forces on mandibular condyle morphology. Microcomputed tomography (microCT) was used to provide details of internal condylar morphology and quantify bone density in three condylar regions. Biomineralization levels, as well as external mandibular dimensions, were used to characterize within-slice, within-joint, within-group and between-group variation. Dimensions of the mandible and mandibular condyle were similar between the myostatin knockout and normal mice. Knockout mice exhibited significantly more biomineralization on the outer surface of the condylar subchondral bone and along the condylar neck, most notably on the buccal side of the condylar neck. The buccal side of the inner aspect of the condyle was significantly less biomineralized in knockout mice, both for the pooled data and for the posterior and anterior condylar slices. Whilst normal mice had symmetric subchondral bone surfaces, those of knockout mice were asymmetric, with a lower, less convex surface on the buccal side versus the lingual side. This appears related to the ontogenetic effects of increased masticatory stress in the mandibles of knockout mice as compared to normal mice. Significant differences in biomineralization between normal and myostatin knockout mice, coupled with the lack of significant differences in certain external dimensions, underscores a need for information on the external and internal morphology of mineralized tissues vis-à-vis altered or excessive mechanical loads.

Adaptation, Physiological↗
PubMed2003

Characterization of aortic root atherosclerosis in ApoE knockout mice: high-resolution in vivo and ex vivo MRM with histological correlation.

In vivo, cardiac-gated, black-blood, and ex vivo magnetic resonance microscopy (MRM) images of the aortic root, and histopathology data were obtained from 12 transgenic and wild-type (WT) mice. MRM was performed using a black-blood imaging spin-echo sequence with upstream and downstream in-flow saturation pulses to obtain aortic root images in three contrast techniques: proton density-weighted (PDW), T(1)- (T(1)W), and T(2)-weighted (T(2)W). Aortic wall thickness and area were measured and correlated with histopathology data (R > 0.90). Ex vivo lesion components (lipid core, fibrous tissue, and cell tissue) were identified and characterized by differing image contrast in PDW, T(1)W, and T(2)W MRM, and by histopathology. The differences between WT and transgenic mice for maximal wall thickness and area were statistically significant (P < 0.05). This study demonstrates the feasibility of in vivo murine aortic root lesion assessment and ex vivo plaque characterization by MRM.

Animals↗
PubMed2005

Novel roles of aquaporins revealed by phenotype analysis of knockout mice.

The aquaporins (AQPs) are small integral membrane proteins that transport water and in some cases small solutes such as glycerol. Physiological roles of the ten or more mammalian AQPs have been proposed based on their expression in epithelial, endothelial and other tissues, their regulation, and in some cases the existence of humans with AQP mutation. Here, the role of AQPs in mammalian physiology is reviewed, based on phenotype analysis of transgenic mouse models of AQP deletion/mutation. Phenotype studies support the predicted roles of AQPs in kidney tubule and microvessel fluid transport for urinary concentrating function, and in fluid-secreting glandular epithelia. The phenotype studies have also shown unexpected roles of AQPs in brain and corneal swelling, in neural signal transduction, in regulation of intracranial and intraocular pressure, and in tumor angiogenesis and cell migration. The water/glycerol-transporting AQPs were found to play unexpected roles in skin hydration and in fat metabolism. However, many phenotype studies were negative, such as normal airway/lung and skeletal muscle function, despite AQP expression, indicating that tissue-specific AQP expression does not indicate physiological significance. The mouse phenotype data suggest that modulators of AQP expression/function may have such wide-ranging clinical applications as diuretics and in the treatment of brain swelling, glaucoma, epilepsy, obesity, and cancer.

Animals↗
PubMed1996

Mean corpuscular hemoglobin is not increased in Fmr1 knockout mice.

A slight increase in mean corpuscular hemoglobin (MCH) has been reported in erythrocytes from human fragile X patients. As it is difficult to perform case-controlled studies in patients with fragile X syndrome, we studied MCH in erythrocytes from transgenic mice with an Fmr1 knockout. None of the knockout mice showed increased MCH levels when compared with normal littermates. We conclude that it is unlikely that the FMR1 gene product has an effect on MCH.

Animals↗
PubMed1996

Transgenic and knockout mice in the study of neurodegenerative diseases.

Accurate animal models are essential for detailed analysis of the mechanisms underlying human neurodegenerative diseases. In addition, they can offer useful paradigms for the development and evaluation of new therapeutic strategies. We review the most popular techniques for modification of the mammalian genome in vivo, and provide a critical evaluation of the available transgenic mouse models for several neurological conditions of humans, including prion diseases, human retroviral diseases, Alzheimer's disease, and motor neuron diseases.

Animals↗