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At least 55 records · Page 3Linked to original sources
PubMed1993

Bone loss in experimental diabetes. Comparison with the model of inflammation mediated osteopenia.

Osteopenia occurs in diabetes mellitus. Since bone status is altered in Inflammation Mediated Osteopenia (IMO), it was appropriate to study its course in diabetic animals in order to investigate the mechanism of diabetic osteopenia. To this end, we compared the bone loss in streptozotocin (STZ) diabetes with that of IMO. Female rats were studied in total of 8 groups: Control, IMO, Diabetes, IMO with Diabetes (IMO-DIA) on the 3rd and similar groups on the 6th week after induction of IMO with 8 s.c. injections of talcum suspension. Femoral mineral content as reflected by ash weight per femoral volume after 3 weeks was lower in IMO compared to control rats (p < 0.05) while after 6 weeks this difference was not significant. The femur ash weight per volume of diabetic rats was lower than the one of intact rats with and without IMO both after 3 and 6 weeks. Diabetic rats with and without IMO exhibited no difference in this respect. Spleen weight as a measure of the extent of inflammation per body weight was increased only in the IMO group. The diabetic rats with and without IMO did not differ significantly with regard to spleen weight. Similar changes were observed 6 weeks after the induction of IMO. However the difference between IMO and diabetes rats was of borderline significance and no difference existed between the IMO and IMO-diabetic group. The serum calcium levels of intact, IMO and diabetic rats showed no change during both experimental periods. Those of diabetic rats with IMO were higher than those of the diabetic and IMO animals after 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

[Activation of receptor for advanced glycation end products: a mechanism for monocyte-mediated inflammation in chronic renal failure].

OBJECTIVE: To investigate the expression of receptor for advanced glycation end products (RAGE) in chronic renal failure (CRF) and its role in monocyte-mediated inflammation associated with chronic renal failure (CRF). METHODS: Peripheral monocytes (PMC) were isolated from 96 non-diabetic patients with varying severity of CRF. RAGE expression on monocytes was quantitated by flow cytometry. The binding capacity of monocytes with advanced glycation end products (AGE) was determined by 125I-AGEs-HSA binding assay. The plasma level of pentosidine, a marker of AGE, was determined by competitive ELISA. Commercially available kits were used for measuring the plasma levels of neopterin, TNF-alpha and C-reactive protein (CRP), a systemic acute phase reactant. RESULTS: Flow cytometry showed that the RAGE expression at the PMC surface of CRF patients was 8.02 +/- 0.43, significantly higher than that of the normal controls (P < 0.001). The number of functional sites to bind 125I-AGEs-HSA at the surface of PMC of CRF patients was increased in comparison with the normal control group. The biding capacity (Ka) at the surface of PMC of CRF patients was 2 times that of normal control group. Stimulated by AGEs-HAS, the TNF-alpha level in the supernatant of PMC increased dose-dependently in both the normal control and CRF patients, especially in the latter (P < 0.01). After pretreatment of anti-RAGE or non-immune rabbit IgG and then by AGEs-HAS the levels of TNF-alpha in the PMC supernatants of CRF patients and normal controls decreased form 90.52 pg/(10(5) cell) +/- 2.82 pg/(10(5) cell) to 17.86 pg/(10(5) cell) +/- 1.05 pg/(10(5) cell) and from 26.38 pg/(10(5) cell) +/- 1.54 pg/(10(5) cell) to 6.76 pg/(10(5) cell) +/- 0.20 pg/(10(5) cell). HAS not modified by AGEs and non-immune rabbit IgG showed no influence on the secretion of TNF-alpha. The plasma levels of TNF-alpha, neopterin, and CRP increased along with the worsening of renal function. The RAGE expression and pentosidine level at the surface of PMC in CPR patients without hemodialysis were positively correlated with plasma neopterin, TNF-alpha, and CRP levels, even after correction of creatine clearance rate (r = 0.53, P < 0.001; r = 0.58, P < 0.001; r = 0.40, P = 0.001). The expression of RAGE in CRF patients with hemodialysis was positively correlated with the plasma TNF-alpha level (r = 0.33, P = 0.029, n = 36), however, not correlated with neopterin or CRP. CONCLUSION: Enhanced RAGE may trigger a positive feed back loop of AGEs-induced monocyte perturbation, and may contribute to the monocyte-mediated systemic inflammation in CRF.

Adult↗
PubMed2003

Effect of decoy-oligodeoxynucleotides on expression of inflammation mediators in pMPhi cells from rats.

OBJECTIVE: To study the effect of decoy-oligodeoxynucleotides (decoy-ODNs) in dumbbell shape with the oligodeoxynucleotide sequence similar to nuclear factor kappa B (NF-kappaB) cis-elements on expression of inflammation mediators in pMPhi cells from rats. METHODS: With carriers of cationic liposomes, decoy-ODNs were transfected into pMPhi cells of rats. Then the inhibiting effects of the decoy-ODNs on tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6) and IL-10 were analyzed. RESULTS: Decoy-ODNs could decrease the expression of TNFalpha and IL-6 in dose-dependent fashion but had weaker inhibiting effect on IL-10. CONCLUSIONS: Decoy-ODNs targeting NF-kappaB can decrease the expression of inflammatory mediators in pMPhi cells from rats.

Animals↗
PubMed1998

The influence of inflammation-mediated osteopenia (IMO) on the structure of rabbit bone and skin collagen fibrils.

The influence of Inflammation Mediated Osteopenia (IMO) on rabbit skin and bone (trabecular and cortical) collagen fibrils was studied by electron microscopy. Severe abnormalities in collagen fibril structure were detected, at the ultrastructural level, in skin and bone specimens from IMO rabbits. In treated animals the arrangement of fibrils is anarchic. The overall collagen fibril architecture is disturbed compared to normal. IMO collagen fibrils' mean diameter values were significantly larger than those from controls, in all examined tissues. However, the banding patterns of fibrils were normal in all cases. Computer analysis shows no differences in charged amino acid composition between IMO and untreated samples. Our results show a correlation between the effects induced by osteopenia on skin and bone collagen.

Animals↗
PubMed1996

Chemokines in immune-mediated inflammation of the central nervous system.

Inflammatory cell recruitment to the central nervous system (CNS) is a cardinal feature of physiological and pathological processes, including multiple sclerosis (MS). Despite recent progress, the soluble signals that attract inflammatory cells from the vascular compartment into the CNS parenchyma remain obscure. We favor the hypothesis that chemoattractant cytokines termed 'chemokines' are uniquely important for mediating leukocyte entry into CNS tissues during immune-mediated inflammation. Three lines of evidence supporting this hypothesis will be reviewed. The first regards expression of chemokines in animal models of immune-mediated CNS inflammation and in the human disease, multiple sclerosis. The second line of evidence involves interventional studies of chemokine blockade in such model disorders. The third line of evidence comprises function of chemokines in the CNS, as analysed in transgenic mice. Investigation of CNS chemokine function will enhance our understanding of leukocyte recruitment to the CNS and suggest therapeutic strategies for neurological disorders.

Animals↗
PubMed2004

T-cell-mediated inflammation does not contribute to the maintenance of airway dysfunction in mice.

T-cell-mediated airway inflammation is considered to be critical in the pathogenesis of airway hyperresponsiveness (AHR). We have described a mouse model in which chronic allergen exposure results in sustained AHR and aspects of airway remodeling and here sought to determine whether eliminating CD4(+) and CD8(+) cells, at a time when airway remodeling had occurred, would attenuate this sustained AHR. Sensitized BALB/c mice were subjected to either brief or chronic periods of allergen exposure and studied 24 h after brief or 4 wk after chronic allergen exposure. In both models, mice received three treatments with anti-CD4 and -CD8 monoclonal antibodies during the 10 days before outcome measurements. Outcomes included in vivo airway responsiveness to intravenous methacholine, CD4(+) and CD8(+) cell counts of lung and spleen using flow cytometric analysis, and airway morphometry using a computer-based image analysis system. Compared with saline control mice, brief allergen challenge resulted in AHR, which was eliminated by antibody treatment. Chronic allergen challenge resulted in sustained AHR and indexes of airway remodeling. This sustained AHR was not reversed by antibody treatment, even though CD4(+) and CD8(+) cells were absent in lung and spleen. These results indicate that T-cell-mediated inflammation is critical for development of AHR associated with brief allergen exposure, but is not necessary to maintain sustained AHR.

Allergens↗
PubMed2005

Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection.

Converging lines of evidence suggest that neuroinflammatory processes may account for the progressive death of dopaminergic neurons in Parkinson's disease (PD). Therefore, anti-inflammatory strategies have attracted much interest for their potential to prevent further deterioration of PD. Our previous study showed that triptolide, a traditional Chinese herbal compound with anti-inflammatory and immunosuppressive properties, protected dopaminergic neurons from lipopolysaccharide (LPS)-induced damage in primary embryonic midbrain cell cultures. To examine further if triptolide can protect dopaminergic neurons from inflammation-mediated damage in vivo, microglial activation and injury of dopaminergic neurons were induced by LPS intranigral injection, and the effects of triptolide treatment on microglial activation and survival ratio and function of dopaminergic neurons were investigated. Our results demonstrated that microglial activation induced by a single intranigral dose of 10 mug of LPS reduced the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) to 29% and the content of dopamine (DA) in striatum to 37% of the non-injected side. Intriguingly, treatment with triptolide of 5 mug/kg for 24 days once per day dramatically improved the survival rate of TH-ir neurons in the SNpc to 79% of the non-injected side. Meanwhile, treatment with triptolide of 1 or 5 mug/kg for 24 days once per day significantly improved DA level in striatum to 70% and 68% of the non-injected side, respectively. Complement receptor 3 (CR3) immunohistochemical staining revealed that triptolide treatment potently inhibited LPS-elicited deleterious activation of microglia in SNpc. The excessive production of cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, was significantly abolished by triptolide administration. These results, together with our previous data in vitro, highly suggest the effectiveness of triptolide in protecting dopaminergic neurons against inflammatory challenge.

Animals↗
PubMed1984

Inflammation-mediated osteopenia in the rat: a new animal model for pathological loss of bone mass.

We have developed a rat model of inflammation-mediated osteopenia. Generalized loss of trabecular bone occurs in the rat after sc injection of nonspecific irritants such as talcum (magnesium silicate) and cotton wool (Cellulose). Although it appears likely that a systemic mediator of bone resorption is responsible for these effects, the loss of bone was not due to increased PTH secretion, since it occurred in parathyroidectomized rats, nor due to excessive 1,25-dihydroxyvitamin-D3 production. In parathyroidectomized rats, this inflammation was associated with significant increase in serum calcium within 4-7 days independent of its cause. Identification and characterization of this mechanism may provide insight into the bone loss associated with chronic inflammatory diseases such as rheumatoid arthritis and periodontal disease.

Animals↗
PubMed2002

Glucocorticoids suppress the inflammation-mediated tolerance to acute toxicity of cadmium in mice.

Several compounds have been shown to cause acute toxicity to cadmium (Cd). The mechanism of tolerance to Cd toxicity induced by glucocorticoids or by inflammation involves induction of metallothionein (MT) synthesis via glucocorticoid response elements or by inflammatory cytokines. We have demonstrated previously that the synthetic glucocorticoid dexamethasone suppresses inflammation-mediated induction of hepatic MT synthesis. Here we investigated the effect of glucocorticoid on tolerance to Cd induced by inflammation in mice. The LD50 of Cd for mice with induced inflammation by injection with turpentine oil (Tur-mice) was higher than the LD50 in control mice. Pretreatment of Tur-mice with dexamethasone to the Tur-mice (Dex+Tur-mice) resulted in a decrease in LD50 after Cd treatment. A significant increase in plasma alanine aminotransferase and aspartate aminotransferase levels in the Dex+Tur-mice was observed at lower doses of Cd than in the Tur-mice and at higher doses of Cd than in control mice. Dexamethasone did not suppress tolerance to cadmium toxicity in the testes of the Tur-mice. Pretreatment of Tur-mice with dexamethasone resulted in suppression of both plasma interleukin (IL)-6 elevation and in suppression of hepatic MT levels when induced by inflammation but not when induced by Cd. These data suggest that suppression of tolerance to Cd toxicity induced by glucocorticoid may involve hepatic MT synthesis mediated by inflammatory cytokines, such as IL-6. We suggest that the inflammatory response can modulate Cd toxicity by induction of MT by inflammatory cytokines.

Animals↗
PubMed2004

Intra-abdominal sepsis attenuates local inflammation-mediated increases in microvascular permeability at remote sites in mice in vivo.

BACKGROUND: Given that leukocyte delivery to remote sites is diminished in states of systemic inflammation, such as sepsis, and activated leukocytes may be responsible for endothelial injury leading to vascular leakage, we hypothesized that intra-abdominal sepsis would diminish microvascular leakage at remote sites by altering leukocyte-endothelial interactions. METHODS: Using a murine intravital microscopy model, we examined leukocyte-endothelial interactions and vascular leakage at a peripheral site in the presence of local and/or systemic inflammation. Forty mice were randomized to 1 of 4 study groups: local infection (orchitis), systemic infection (intra-abdominal sepsis by cecal ligation and puncture), local and systemic infection, and control. Postcapillary venules of the cremaster muscle were examined by bright light and fluorescence intravital microscopy. Microvascular leakage was determined after intravenous administration of fluorescent albumin. RESULTS: Systemic infection attenuated the increases in both leukocyte adherence and local infection-induced microvascular permeability. Neutrophil cell-surface expression of L-selectin, as determined by flow cytometry, diminished with both local and systemic infection, whereas expression of CD11b increased with systemic, but not local, infection. CONCLUSIONS: These data suggest that systemic (intra-abdominal) sepsis diminishes local inflammation-mediated vascular leakage by attenuating leukocyte adherence.

Abdomen↗
PubMed1979

Measurement of cell-mediated inflammation in experimental murine autoimmune encephalomyelitis by radioisotopic labeling.

A radioisotopic index test was used to detect that time of onset and intensity of cell-mediated immune inflammation of experimental autoimmune encephalomyelitis (EAE) in mice. Mice were tested at various time intervals after an encephalitogenic immunization with mouse spinal cord to homogenate for delayed-type hypersensitivity (DTH) to myelin basic protein (MBP) by intradermal challenge with antigen in the ear pinna. After 25 hr, the intensity of DTH was measured by 125I-radiometry which depends upon the migration of 125I-UdR radiolabeled mononuclear cells into the antigen depot. Cells reactive to MBP were detected by the ear assay as early as 7 days after the initial encephalitogenic sensitization. The degree of cell-mediated immune inflammation in the brain and spinal cord during the evolution of EAE was also measured by a radioisotopic technique; increased 125I-UdR uptake could be detected in the brain 3 to 4 days before the onset of signs of EAE at days 11 to 12, whereas 125I-UdR in the spinal cord was detected only 1 day before, or concomitant with, the onset of signs of EAE. Both, or concomitant with, the onset of signs of EAE. Both the "ear" and "organ" radiometric index tests are useful in measuring the degree of cell-mediated inflammation in EAE, and supplement routine histopathological and observational assessments.

Animals↗
PubMed1998

Influence of inflammation-mediated osteopenia on the regional acceleratory phenomenon and the systemic acceleratory phenomenon during healing of a bone defect in the rat.

We have previously shown that restoration of a local bone defect in the rat not only leads to a regional acceleratory phenomenon (RAP), but also to a systemic acceleration of osteogenesis (SAP) at distant sites of the skeleton. In this study, we investigated whether specific inhibition of osteoblasts would affect the local RAP and the systemic acceleratory phenomenon (SAP) healing sites. Systemic inhibition of osteoblasts was induced by inflammation-mediated osteopenia (IMO), a nonspecific type of inflammation initiated by s.c. injections of sterile talc. A drill hole defect 1.2 mm in diameter was performed at the midshaft of the left tibia of female rats. On day 7, during the formation phase of the local healing process, IMO did not influence the number of osteoblasts or the bone volume in the marrow cavity of the local healing site, whereas it did lead to a significant reduction of osteoblast number and bone volume at the systemic site (subepiphyseal spongiosa of the tibia). By contrast, on days 14 and 21, during the resorption phase of bone healing. IMO led to a significant reduction in both osteoblast number and bone volume in the marrow cavity of the local healing site. At the same time, however, it did not influence the cortical area of the bone defect where newly formed bone is needed to ensure mechanical stability. In summary, our model of bone healing reveals that a humoral noxious osteoblast stimulus such as IMO is able to inhibit systemically osteoblasts stimulated by SAP, whereas it is not able to inhibit osteoblasts either from producing woven bone during a RAP or from producing bone that is needed to mechanically stabilize a defect.

Absorptiometry, Photon↗
PubMed2006

Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.

Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.

Animals↗
PubMed2005

Opposing effects of CXCR3 and CCR5 deficiency on CD8+ T cell-mediated inflammation in the central nervous system of virus-infected mice.

T cells play a key role in the control of viral infection in the CNS but may also contribute to immune-mediated cell damage. To study the redundancy of the chemokine receptors CXCR3 and CCR5 in regulating virus-induced CD8+ T cell-mediated inflammation in the brain, CXCR3/CCR5 double-deficient mice were generated and infected intracerebrally with noncytolytic lymphocytic choriomeningitis virus. Because these chemokine receptors are mostly expressed by overlapping subsets of activated CD8+ T cells, it was expected that absence of both receptors would synergistically impair effector T cell invasion and therefore protect mice against the otherwise fatal CD8+ T cell-mediated immune attack. Contrary to expectations, the accumulation of mononuclear cells in cerebrospinal fluid was only slightly delayed compared with mice with normal expression of both receptors. Even more surprising, CXCR3/CCR5 double-deficient mice were more susceptible to intracerebral infection than CXCR3-deficient mice. Analysis of effector T cell generation revealed an accelerated antiviral CD8+ T cell response in CXCR3/CCR5 double-deficient mice. Furthermore, while the accumulation of CD8+ T cells in the neural parenchyma was significantly delayed in both CXCR3- and CXCR3/CCR5-deficient mice, more CD8+ T cells were found in the parenchyma of double-deficient mice when these were analyzed around the time when the difference in clinical outcome becomes manifest. Taken together, these results indicate that while CXCR3 plays an important role in controlling CNS inflammation, other receptors but not CCR5 also contribute significantly. Additionally, our results suggest that CCR5 primarily functions as a negative regulator of the antiviral CD8+ T cell response.

Animals↗
PubMed2006

FK506 (tacrolimus) improves lung injury through inhibition of Fas-mediated inflammation.

OBJECTIVE: To investigate whether FK506 (tacrolimus) can inhibit Fas- or A23187-induced interleukin (IL)-8 expression and cell death in A549 human alveolar epithelial cells, plus Fas-mediated acute lung injury in vivo. METHODS: Assays for IL-8, cell death, and caspase-3 activity were performed. A549 cells were treated with 25 micromol A23187 or 0.2 microg/ml agonistic anti-Fas antibody plus 5 ng/ml interferon-gamma (IFN-gamma). Tacrolimus was treated at 0.1-10 ng/ml. For in vivo experiment, agonistic anti-Fas antibody (Jo2) at 2.5 microg/g was intratracheally instilled into C57BL/6 mice. Neutrophils and protein contents in bronchoalveolar lavage (BAL) fluid were measured within 24 h of instillation. Mice were orally treated with 32 mg/kg of tacrolimus 24 h and 1 h prior to instillation. RESULTS: Both Fas and A23187 caused significant IL-8 expression and cell death in A549 cells. Tacrolimus inhibited A23187-induced IL-8 expression alone while it protected all Fas-mediated responses. Mice instilled intratracheally with Jo2 at 2.5 microg/g had significant increases in neutrophils, protein contents in BAL fluid and in expression of chemoattractants for neutrophils. These increases were reversed by tacrolimus. CONCLUSIONS: Tacrolimus serves as a therapeutic option for improving lung injury through inhibition of Fas-mediated inflammation.

Animals↗
PubMed1989

1,25-Dihydroxyvitamin D3 prevents the decrease of bone mineral appositional rate in rats with inflammation-mediated osteopenia (IMO).

We have studied the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on bone mass and bone mineral appositional rate in intact rats and rats with inflammation-mediated osteopenia (IMO), where osteoblast number and mineral appositional rate are decreased. 1,25(OH)2D3 prevents IMO-specific bone loss when given in a daily dose of 25 ng per rat, but does not when given in higher doses. The hormone was effective, when given over the complete duration of the experiment (21 days), but not when given over shorter time periods (7 and 14 days, respectively). 1,25(OH)2D3 prevents IMO-dependent reduction in mineral appositional rate and leads to an only moderate increase in intact rats. We conclude, that 1,25(OH)2D3 is more effective in stimulating mineral appositional rate in rats with IMO where mineral apposition is impaired.

Animals↗
PubMed2006

R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation.

Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling (EC(50) for degranulation = 56-64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (K(i) = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.

Animals↗