More antioxidants in sepsis: still paved with uncertainties.
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Acetylcysteine↗
Biomedical subjects
B S van Asbeck
Publications and source records attributed to B S van Asbeck.
Iron enhances endothelial cell activation in response to Cytomegalovirus or Chlamydia pneumoniae infection.
BACKGROUND: Chronic inflammation has been implemented in the pathogenesis of inflammatory diseases like atherosclerosis. Several pathogens like Chlamydia pneumoniae (Cp) and cytomegalovirus (CMV) result in inflammation and thereby are potentially artherogenic. Those infections could trigger endothelial activation, the starting point of the atherogenic inflammatory cascade. Considering the role of iron in a wide range of infection processes, the presence of iron may complicate infection-mediated endothelial activation. MATERIALS AND METHODS: Endothelial intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial selectin (E-selectin) expression were measured using flow cytometry, as an indication of endothelial activation. Cytotoxicity was monitored using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Immunostaining was applied to measure Cp and CMV infectivity to endothelial cells. RESULTS: An increased number of infected endothelial cells in a monolayer population leads to a raised expression of adhesion molecules of the whole cell population, suggesting paracrine interactions. Iron additively up-regulated Cp-induced VCAM-1 expression, whereas synergistically potentiated Cp-induced ICAM-1 expression. Together with CMV, iron also enhanced ICAM-1 and VCAM-1 expression. These iron effects were observed without modulation of the initial infectivity of both microorganisms. Moreover, the effects of iron could be reversed by intracellular iron chelation or radical scavenging, conforming modulating effects of iron on endothelial activation after infections. CONCLUSIONS: Endothelial response towards chronic infections depends on intracellular iron levels. Iron status in populations positive for Cp or CMV infections should be considered as a potential determinant for the development of atherosclerosis.
Animals↗
Effects of rosuvastatin on postprandial leukocytes in mildly hyperlipidemic patients with premature coronary sclerosis.
We investigated whether pro-inflammatory aspects of the postprandial phase can be modulated by rosuvastatin in premature coronary artery disease (CAD) patients. Herefore standardized 8 h oral fat loading tests were performed off-treatment and after rosuvastatin 40 mg/d in 20 male CAD patients (50 +/- 4 years). The expression of leukocyte activation markers CD11a, CD11b, CD62L and CD66b was studied using flowcytometry. Migration of isolated neutrophils towards chemoattractants was determined in a fluorescence-based assay. Rosuvastatin did not affect baseline leukocyte counts nor the postprandial neutrophil increment (maximum mean increase +10% pre- and +14% post-treatment, P < 0.01 for each). Rosuvastatin reduced baseline platelets (from 266 +/- 78 to 225 +/- 74 x 10(9) cells/L, P < 0.001) and blunted the postprandial platelet count change (maximum mean increase +6%, P = 0.01, and 0%, respectively). The baseline expression of CD11a, CD11b and CD62L increased on most types of leukocytes by rosuvastatin, whereas the postprandial responses were unaffected. Pretreatment, postprandial neutrophil migration increased dose-dependently, but there were no postprandial changes after rosuvastatin. The latter effect was unrelated to changes in lipoprotein concentrations. In conclusion, in CAD patients postprandial pro-inflammatory and pro-coagulant changes can be modified by rosuvastatin. These apparently lipid-lowering independent effects may render protection against atherosclerosis.
Adult↗
Iron chelation and hydroxyl radical scavenging reduce the inflammatory response of endothelial cells after infection with Chlamydia pneumoniae or influenza A.
BACKGROUND: Chronic low-grade inflammation is associated with increased risk of vascular diseases. The source of inflammation is unknown but may well be chronic and/or repetitive infections with microorganisms. Direct infection of endothelial cells (ECs) may also be a starting point for atherogenesis by initiating endothelial procoagulant activity, increased monocyte adherence and increased cytokine production. We hypothesized that iron-mediated intracellular hydroxyl radical formation after infection is a key event in triggering the production of interleukin-6 (IL-6) by ECs in vitro. METHODS: Cultured ECs were incubated with Fe(II) and Fe(III) or infected with Chlamydia pneumoniae or influenza A/H1N1/Taiwan/1/81 for 48 and 24 h, respectively. To determine the role of iron and reactive oxygen species, cells were coincubated with the H2O2 scavenger N-acetyl-l-cysteine, with the iron chelator deferoxamine (DFO) or with the intracellular hydroxyl radical scavenger dimethylthiourea (DMTU). After the incubation periods, supernatants were harvested for IL-6 determination. RESULTS: Incubating ECs with Fe(II) and Fe(III) resulted in increased IL-6 production. Similarly, infection with C. pneumoniae and influenza A also induced an IL-6 response. Coincubating ECs with DFO or DMTU blocked this response. Nuclear factor-kappaB activity was increased after infection and blocked by coincubation with DFO or DMTU. CONCLUSION: Cultured ECs respond to infection and iron incubation with increased production of IL-6. Iron, the generation of intracellular hydroxyl radical and NF-kappaB activity are essential in cellular activation, suggesting that reactive oxygen species generated in the Haber-Weiss reaction are essential in invoking an immunological response to infection by ECs.
Antioxidants↗
Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis.
BACKGROUND: The iron chelators deferoxamine (DF) and deferiprone (CP20) have been shown to inhibit human immunodeficiency virus type 1 (HIV-1) replication in human peripheral blood lymphocytes (PBL). The orally active bidentate chelators CP502 and CP511, which also belong to the 3-hydroxypyridin-4-one family, but with higher affinities for iron than CP20, were monitored for their antiviral properties by checking for p24 antigen production and nuclear factor (NF)-kappaB activation, and their ability to induce apoptosis. MATERIALS AND METHODS: Human PBLs were isolated from HIV-1 seronegative donors and subsequently infected with HIV-1(Ba-L) for 2 h. After 5 days' incubation, HIV-1 replication was monitored by p24 antigen production. Cellular proliferation as well as caspase-3 activity were monitored in uninfected cells after a period of 5 days and after 1 day infection, respectively. NF-kappaB activity was also monitored by electromobility shift assays (EMSA) performed on nuclear extracts of Jurkat cells treated with the different chelators for 4 h. RESULTS: CP502 and CP511 decrease HIV-1 replication by decreasing cellular proliferation in a similar manner to DF and CP20. CP511 seemed to be more potent than either CP502 or CP20. Due to the reduction in cellular proliferation, there was an increase in caspase-3 activity after 24 h incubation. NF-kappaB activity was not affected by any of the chelators. CONCLUSIONS: Iron chelators with high affinities for iron, which are under development for the treatment of iron overload, could contribute to the reduction of HIV-1 replication in infected patients by cellular proliferation inhibition rather than by a direct antiviral action.
Apoptosis↗
Chemiluminescence in inflammatory bowel disease patients: a parameter of inflammatory activity.
BACKGROUND: Reactive oxygen species (ROS) are produced in excess in the inflamed mucosa and peripheral blood of patients with inflammatory bowel disease. These species have emerged as a common pathway of tissue injury in a wide variety of inflammatory and other disease processes. The present study was conducted to assess ROS production and to correlate this with parameters of inflammatory activity. METHODS: In 25 patients with Crohn's disease (CD), 20 patients with ulcerative colitis (UC) and 65 age- and sex-matched healthy volunteers ROS production was measured using the whole blood luminol enhanced chemiluminescence assay (LECA). Disease activity was assessed using the Crohn's disease activity index and the Ulcerative Colitis Symptoms Score (UCSS) for CD and UC, respectively. Furthermore, the effect of various scavengers, enzymes and enzyme inhibitors on LECA was studied to assess the contribution of different ROS. RESULTS: LECA was significantly higher in CD and UC patients compared with healthy controls (7.1+/-4.7 and 9.8+/-6 vs. 5.2+/-2.8 x 10(3) counts per minute (cpm), p<0.05 and <0.001). In CD, relative LECA (patient/control) was correlated with the Crohn's disease activity index and C-reactive protein (CRP) (r=0.54, p=0.001 and r=0.51, p=0.01). In UC, CRP but not LECA was correlated with the Ulcerative Colitis Symptoms Score (C-reactive protein: r=0.42, p=0.01). Addition of azide, superoxide dismutase, deferoxamine and dimethylthiourea resulted in a decrease of LECA values. CONCLUSION: Whole blood LECA is increased in patients with CD and UC. This parameter is correlated with disease activity in CD. The observed chemiluminescence is probably due to generation of superoxide and the hydroxyl radical.
Adult↗
The chemotherapeutic agent bleomycin in a two-drug combination with zidovudine, ritonavir or indinavir synergistically inhibits HIV Type-1 replication in peripheral blood lymphocytes.
It has been suggested that the combination of cancer chemotherapy with antiviral therapy is helpful for the containment of lymphomas in HIV-infected patients. Since we have recently shown that the nucleic acid binding chemotherapeutic agent bleomycin in itself has antiviral properties, we looked to see if there was any possible synergy with current anti-HIV agents. Combinations of zidovudine, indinavir or ritonavir with bleomycin, synergistically inhibited HIV-1(AT) replication in stimulated peripheral blood lymphocytes (combination index at 50% virus inhibition was 0.427, 0.604 and 0.535, respectively) and this synergism was not accompanied by any synergistic effects on cytotoxicity. We conclude from these data that further studies to investigate the clinical efficacy of combinations of antiviral and cancer chemotherapeutic agents are warranted in relation to viral load improvement.
Anti-HIV Agents↗
Anti-HIV effect of iron chelators: different mechanisms involved.
BACKGROUND: Drugs for the treatment of AIDS have been directed to specific events in the human immunodeficiency virus (HIV-1) life cycle, aimed to stop viral replication by inhibition of reverse transcriptase or protease activity. Studies showing that oxidative stress and iron may be important in the activation of HIV-1 have focused attention on the potential therapeutic use of iron chelators. OBJECTIVES: The goal of this review is to describe several possibilities as to how iron is involved in the replication of HIV and how iron chelation may interfere in this process. STUDY DESIGN: First some physico-chemical properties of iron concerning solubility, oxidation-reduction potential, catalysis, and chelation will be discussed. In the second part, the role of iron in various biochemical systems is explained. RESULTS: Nuclear factor kappa B (NF-kappaB) activation, regulating proviral transcription, can be influenced by iron through the production of reactive oxygen species. A second route by which iron chelation could influence HIV replication, is by inhibition of DNA synthesis through inactivation of iron-dependent ribonucleotide reductase. Another strategy which can be employed in targeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA attack. This could be achieved by bleomycin, a cytostatic agent with the ability to form a complex with DNA and RNA. CONCLUSION: Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease.
Anti-HIV Agents↗
Glutathione and alpha-lipoate in diabetic rats: nerve function, blood flow and oxidative state.
BACKGROUND: Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and alpha-lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats. MATERIALS AND METHODS: Streptozotocin-diabetic rats were treated with different doses of alpha-lipoic acid, reduced glutathione or placebo, and were compared with nondiabetic controls. We measured systemic and endoneurial antioxidants, malondialdehyde and whole blood hydrogen peroxide. Furthermore, we evaluated sciatic and tibial motor and sensory nerve conduction velocity, caudal nerve conduction velocity, and assessed sciatic nerve blood flow and vascular resistance by Laser-Doppler flowmetry. RESULTS: We observed a rise in erythrocyte glutathione by 27 % (P < 0.05), and a trend towards decreased plasma malondialdehyde in alpha-lipoic acid, but not in glutathione-treated animals in comparison with the placebo group. Simultaneously, sciatic nerve blood flow and vascular resistance were improved by daily alpha-lipoic acid administration by 38% (P < 0.05). Peripheral nerve conduction velocity and endoneurial glutathione were not significantly influenced by antioxidant treatment. CONCLUSIONS: Only minor beneficial effects of alpha-lipoic acid on nerve blood flow and oxidative state occur at the given doses; these effects were insufficient to improve nerve conduction deficits.
Animals↗
Effect of corticosteroids on nuclear factor-kappaB activation and hemodynamics in late septic shock.
OBJECTIVE: To describe the underlying pathophysiologic mechanisms of the effect of corticosteroids in a patient with late septic shock. DESIGN: Case report. SETTING: The medical intensive care unit at University Medical Center Utrecht. PATIENT: An 86-yr-old female patient with late septic shock requiring mechanical ventilation and vasopressive agents. INTERVENTIONS: Administration of hydrocortisone, 300 mg daily. MEASUREMENTS AND MAIN RESULTS: Within 3 days of corticosteroid treatment, the patient could be weaned of vasopressive agents and mechanical ventilation. Serum C-reactive protein levels normalized. Nuclear factor-kappaB activation in unstimulated and in vitro lipopolysaccharide-stimulated peripheral blood mononuclear cells decreased to background level within 5 days. Repeated functional tests of the hypothalamic-pituitary-adrenal axis were normal. CONCLUSION: Our data suggest that the pathophysiologic mechanism behind the clinical effects of supraphysiologic doses of corticosteroids in late septic shock is directly related to the inhibition of nuclear factor-kappaB in peripheral blood mononuclear cells.
Aged↗
The effect of deoxynucleosides on cell proliferation of peripheral blood lymphocytes treated with deferoxamine or hydroxyurea.
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Antisickling Agents↗
Combining iron chelators with the nucleoside analog didanosine in anti-HIV therapy.
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Anti-HIV Agents↗
Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin.
Replication of human immunodeficiency virus type 1 (HIV-1) can be influenced by iron. Hence, decreasing the availability of iron may inhibit HIV-1 replication. Deferoxamine and deferiprone, both forming catalytically inactive iron-chelator complexes, and bleomycin, by use of which iron catalyzes oxidative nucleic acid destruction, were investigated. Expression of p24 antigen in human monocyte-derived macrophages and peripheral blood lymphocytes (PBL) was reduced by all 3 iron chelators. In PBL, p24 reduction was mirrored by a decrease in proliferation after incubation with deferoxamine or deferiprone, suggesting that viral inhibition is closely linked to a decrease in cellular proliferation. In contrast, clinically relevant bleomycin concentrations reduced p24 levels by approximately 50% without affecting proliferation. When deferoxamine and the nucleoside analogue dideoxyinosine were used in combination, they acted synergistically in inhibiting HIV-1 replication. These observations suggest that iron chelators with different mechanisms of action could be of additional benefit in antiretroviral combination therapy.
Anti-HIV Agents↗
Pressure-induced skin lesions in pigs: reperfusion injury and the effects of vitamin E.
The pathogenesis of the development of pressure ulcers is still unclear. The aim of this study was to investigate the role of ischaemia and reperfusion in pressure-induced tissue necrosis in the trochanteric region in pigs. Pressure application was achieved with a newly developed computer-controlled pressure device. Histological examination showed damage in the subcutis and muscle tissue comparable with inflammation, extending in a vascular pattern beyond the area of pressure application. Electron-microscopic studies revealed neutrophil adherence to the capillary endothelium, which showed signs of injury. These observations were manifest two hours after the cessation of pressure. Pre-treatment with 500 mg vitamin E per day resulted in significantly less tissue damage compared with untreated animals. Pressure alone caused a significant decrease in reduced glutathione and total glutathione, suggesting oxidative stress. After pressure release there was a significant increase in hydrogen peroxide concentration, suggesting a decreased antioxidant protection. After pre-treatment with vitamin E, however, there was no increase of hydrogen peroxide. It is concluded that the early signs of necrosis after pressure application are concordant with typical ischaemia-reperfusion damage and this can be prevented in part by treatment with vitamin E. Prophylactic administration of vitamin E may influence the occurrence of pressure ulcers in humans undergoing elective surgery.
Animals↗
[Clinical thinking and decision-making in practice. A patient with arthritis, skin lesions and a perforated nasal septum].
A man aged 38 years had arthritis, skin lesions and a perforation of the nasal septum. He had slight deterioration of renal function and a few granular casts in the urine. Antineutrophil cytoplasmic antibody and other immune parameters were normal. A biopsy of the nasal septum did not show granulomatous lesions. The differential diagnosis on the available clinical grounds could be narrowed to Wegener's disease, Henoch-Schönlein vasculitis or microscopic polyangiitis. A biopsy of the skin showed leukocytoclastic vasculitis, with IgA and IgM depositions compatible with Henoch-Schönlein vasculitis. A renal biopsy showed small segmental necrotising lesions of the glomerular capillaries, with minimal extracapillary proliferation; immune fluorescence did not detect any significant depositions. The picture was compatible with Wegener's disease. A nasal septum defect together with glomerulonephritis, which could be suspected from only minimal abnormalities in the urine, is almost conclusive for the diagnosis.
Adult↗
High rat food vitamin E content improves nerve function in streptozotocin-diabetic rats.
Antioxidants can improve nerve dysfunction in hyperglycaemic rats. We evaluated whether the standard supplementation of rat food with vitamin E (normally added for preservation purposes) or high-dose vitamin E treatment improves nerve conduction in maturing streptozotocin-diabetic rats, a model widely used to study diabetic neuropathy. Hyperglycaemic rats received food containing 25 mg/kg (non-supplemented), 70 mg/kg (standard food) or 12 g/kg (high-dose) vitamin E. Non-diabetic controls received non-supplemented food. Sciatic and tibial sensory and motor nerve conduction velocity were decreased in all diabetic animals. In comparison with standard feeding, the non-supplemented diabetic rats showed lower plasma vitamin E levels but no significant change in nerve conduction. High-dose treatment prevented nerve dysfunction by 50%, and led to attenuated endoneurial lipid peroxidation (measured as malondialdehyde). We conclude that high doses of vitamin E, but not standard vitamin E supplementation of rat food partially prevent nerve dysfunction in young adult streptozotocin-diabetic rats.
Animals↗
Potential role of CCR5 polymorphism in the development of AIDS dementia complex.
The chemokine receptor CCR5 and to a lesser extent CCR2b and CCR3 have been shown to serve as coreceptors for HIV-1 entry into macrophages. Individuals that are homozygous for a defective CCR5 allele (DeltaCCR5) are highly, but not fully, resistant to infection with HIV-1. Here, we want to emphasize the importance of DeltaCCR5 in in vitro as well as in vivo studies. We provide data that suggest that CCR5 polymorphism may affect the onset of AIDS dementia complex in vivo and data that show that HIV-1 replication is influenced by the DeltaCCR5 allele in vitro. Knowing the CCR5 genotype of an individual will help to better interpret research results and may even provide new information about mechanisms of disease.
AIDS Dementia Complex↗
Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway.
During gram-negative sepsis, human monocytes are triggered to produce large quantities of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) in response to endotoxin (lipopolysaccharide [LPS]). Several studies have identified signal transduction pathways that are activated by LPS, including activation of nuclear factor-kappaB (NF-kappaB) and activation of mitogen-activated protein kinases (MAPKs), including ERK1 and ERK2, c-Jun N-terminal kinase, and p38. In this study, the relevance of ERK1 and ERK2 activation for LPS-induced TNF-alpha production by primary human monocytes has been addressed with PD-098059, which specifically blocks activation of MAPK kinase (MEK) by Raf-1. TNF-alpha levels in the monocyte culture supernatant, induced by 10 ng of LPS/ml, were reduced by PD-098059 (50 microM). In addition, PD-098059 also reduced TNF-alpha mRNA expression when cells were stimulated for 1 h with LPS. On the other hand, LPS-induced interleukin-10 (IL-10) levels in the monocyte supernatant were only slightly inhibited by PD-098059. Ro 09-2210, a recently identified MEK inhibitor, completely abrogated TNF-alpha levels at nanomolar concentrations. IL-10 levels also were strongly reduced. To show the efficacy of PD-098059 and Ro 09-2210, ERK1 and -2 activation was monitored by Western blotting with an antiserum that recognizes the phosphorylated (i.e., activated) forms of ERK1 and ERK2. Addition of LPS to human monocytes resulted in activation of both ERK1 and ERK2 in a time- and concentration (50% effective concentration between 1 and 10 ng of LPS/ml)-dependent manner. Activation of ERK2 was blocked by PD-098059 (50 microM), whereas ERK1 seemed to be less affected. Ro 09-2210 completely prevented LPS-induced ERK1 and ERK2 activation. LPS-induced p38 activation also was prevented by Ro 09-2210. These data further support the view that the ERK signal transduction pathway is causally involved in the synthesis of TNF-alpha by human monocytes stimulated with LPS.
Calcium-Calmodulin-Dependent Protein Kinases↗