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  • Scholz, M
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  • 1
    Language: English
    In: Immunobiology, 2011, Vol.216(3), pp.334-342
    Description: Posttrauma apoptosis resistance of neutrophils (PMN) is related to overshooting immune responses, systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Recently, we have shown that the apoptosis resistance in circulating PMN from severely injured patients which is known to be mediated by high serum levels of pro-inflammatory cytokines can be overcome by the activation of Fas death receptor. Here, we aimed to study whether stimulation of surface Fas leads to the inactivation of hyperactivated PMN from critically ill patients with SIRS. PMN from 23 multiple trauma patients (mean injury severity score (ISS) 34 ± 1.9) were isolated at day 1 after admission to the trauma center. PMN from 17 volunteer blood donors served as controls. Neutrophil activity has been determined after short (1 h) and long-term (4 h) stimulation of freshly isolated PMN with immobilized agonistic anti-Fas antibodies. We found neutrophil chemotactic migration in response to IL-8, phagocytosis and oxidative burst to be significantly inhibited in control cells already after short-term (1 h) Fas stimulation. In contrast, inactivation of trauma PMN by agonistic anti-Fas antibodies was found to be efficient only after long-term (4 h) incubation of cells with agonistic antibodies. Thus, in trauma PMN down-regulation of neutrophil activity seems to be delayed when compared to cells isolated from healthy controls, suggesting impaired susceptibility for Fas stimulation in these cells. Interestingly, whereas Fas-mediated inhibition of phagocytosis and oxidative burst could be prevented by the broad range caspase inhibitor t-butoxycarbonyl-aspartyl(O-methyl)-fluoromethyl ketone (BocD-fmk), the chemotactic activity in response to IL-8 was unaffected. In conclusion, we demonstrate that stimulation of neutrophil Fas does not only initiate apoptosis but also induces inhibition of neutrophil functions, partially by non-apoptotic signaling.
    Keywords: Caspases ; Chemotaxis ; Neutrophils ; Oxidative Burst ; Phagocytosis ; Sirs ; Biology
    ISSN: 0171-2985
    E-ISSN: 1878-3279
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  • 2
    In: Wound Repair and Regeneration, September 2011, Vol.19(5), pp.597-607
    Description: The pathophysiology leading to delayed wound healing is complex and efficient therapeutic approaches for accelerated wound healing currently do not exist. We developed a novel drug‐eluting platform for the potential use in wound dressings. Here, we report on the potential of eluting ascorbic acid‐2‐phosphate (‐2), a highly stable variant of ascorbic acid, to induce angiogenesis and to promote collagen synthesis by fibroblasts. The drug‐eluting platform device () consists of biocompatible polymeric layers comprising polyethylene terephtalate, polyvinyl alcohol (), and polyurethane with as the solvent for ‐2. The angiogenic potential of ‐2 was evaluated in the endothelial cell tube formation assay () and in the chorion allantoic membrane () model. Collagen synthesis by ‐2‐stimulated fibroblasts was determined by irius ed staining. ‐2 significantly induced angiogenesis in five independent and assays and induced collagen synthesis in two different fibroblast cell lines. The eluting kinetics of ‐2 was determined by the ultraviolet anorop method and the functional 2,2′‐Azinobis‐(3‐ethylbenzthiazolin‐6‐sulfonic acid) method. Eluting profiles showed a continuous release in the range of biologically effective concentrations 〉10 days. This is the first report showing the proangiogenic‐ and collagen‐promoting features of ‐2. loaded with ‐2 ought to be further evaluated as wound dressings or as supplementary pads for topical treatment of delayed wound healing in preclinical studies.
    Keywords: Drug Delivery ; Dressings ; Polyethylene ; Angiogenesis ; Solvents ; Wound Healing ; Collagen ; Fibroblasts ; Ascorbic Acid ; Endothelial Cells ; Polyvinyl Alcohol ; U.V. Radiation ; Kinetics ; Polyurethane ; Chorion ; Tissue Engineering;
    ISSN: 1067-1927
    E-ISSN: 1524-475X
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  • 3
    Language: English
    In: Medicinal Research Reviews, May 2005, Vol.25(3), pp.331-342
    Description: Systemically applied agents to modulate the Fas/FasL system, e.g., by stimulation of Fas on activated leukocytes or tumor cells failed as strategies in immune therapy due to severe toxic effects in the host. Recently, a novel strategy has been developed by using immobilized immune active biologicals in a medical device that may allow immune management without expensive systemic therapy. This review reports on the potential role of Fas/FasL in immune therapy and summarizes current experimental and clinical data with the leukocyte inhibition module (LIM), an immobilized anti‐Fas antibody containing device yet used in extracorporeal blood circulation. This proof of principal may stimulate the development of other devices based on the regulation of Fas/FasL or other targets relevant for immune disorders. © 2004 Wiley Periodicals, Inc.
    Keywords: Novel Therapeutic Strategies ; Immune Management ; Apoptosis
    ISSN: 0198-6325
    E-ISSN: 1098-1128
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  • 4
    Language: English
    In: Materials Today, September 2012, Vol.15(9), pp.394-404
    Description: The demand to develop convergent technology platforms, such as bio-functionalized medical devices, is rapidly increasing. However, the loss of biological function of the effector molecules during sterilization represents a significant and general problem. Therefore, we have developed and characterized a nano-coating (NC) formulation capable of maintaining the functionality of proteins on biological-device combination products. As a proof of concept, the NC preserved the structural and functional integrity of an otherwise highly fragile antibody immobilized on polyurethane during deleterious sterilizing irradiation (≥ 25 kGy). The NC procedure enables straight-forward terminal sterilization of bio-functionalized materials while preserving optimal conditioning of the bioactive surface.
    Keywords: Engineering
    ISSN: 1369-7021
    E-ISSN: 1873-4103
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  • 5
    In: Transplantation, 1996, Vol.62(9), pp.1371-1374
    Description: In this study, we investigated the effects of the intracellular metal chelator desferrioxamine (DFO) and the extracellular metal chelator diethylenetriamine penta-acetic acid (DTPA), which were previously shown to have strong anticytomegalovirus potencies, on their ability to elicit immunomodulatory effects in vitro[fcn,3]. The results showed that nontoxic and in vivo attainable concentrations of both DFO and DTPA inhibited mitogen- and allogen-induced proliferation of peripheral blood lymphocytes. The immunomodulatory effects of DFO/DTPA seem to be due to the impaired expression of interleukin-2 receptor and the reduced secretion of interleukin-2. However, metal chelators were more effective than cyclosporine or tacrolimus (FK506) in our in vitro experiments. Moreover, cytotoxicity mediated by lymphokine-activated killer cells and natural killer cells and the expression of HLA and adhesion molecules on cytokine-stimulated endothelial cells were differentially impaired by DFO/DTPA. These results warrant further study of the immunological effects of metal chelators in vivo.
    Keywords: Immunopharmacology ; Immunoregulation ; Metal Chelators ; Desferrioxamine ; Diethylenetriamine Penta-Acetic Acid ; Desferrioxamine ; Diethylenetriamine Penta-Acetic Acid ; Immunoregulation ; Metal Chelators;
    ISSN: 0041-1337
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  • 6
    Language: English
    In: Medical Microbiology and Immunology, 2009, Vol.198(4), pp.211-219
    Description: Neutrophil extracellular traps (NETs) have recently been discovered as a central part of antimicrobial innate immunity. In the meanwhile, evidence accumulated that NETs are also generated upon non-infectious stimuli in various clinical settings. In acute or chronic inflammatory disorders aberrantly enhanced NET formation and/or decreased NET degradation seems to correlate with disease outcome. This review summarizes current knowledge about the relation of NETs in a broad spectrum of clinical settings. Specifically, we focus on the importance of NETs as a predictive marker in severely ill patients and further, we speculate about the potential pathophysiology of NETs.
    Keywords: Neutrophils ; Innate immunity ; Pathophysiology ; Neutrophil extracellular traps
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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  • 7
    Language: English
    In: Trends in Microbiology, 2003, Vol.11(4), pp.171-178
    Description: Human cytomegalovirus (HCMV) retinitis frequently occurs in severely naturally and iatrogenically immunocompromised patients. It has been shown that the immune-privileged retinal pigment epithelium (RPE) is a major site of persistent HCMV. Recently, evidence has accumulated to show that HCMV immediate early (IE) gene expression in RPE cells deviates ocular antiviral inflammation via FasL. Moreover, unlike in other cell types, the HCMV major IE1/2 enhancer promoter (MIEP) resists activation by proinflammatory stimuli mediated by the transcription factor NF- Kappa B. However, tumor necrosis factor- alpha (TNF- alpha ) and interferon- gamma (IFN- gamma ) found at elevated levels in transplant recipients and AIDS patients with retinitis sensitize RPE cells and other retinal cells to FasL-mediated apoptosis, thus contributing to retina destruction and necrosis rather than inflammation. These specific features of RPE cells in conjunction with deregulated immune responses of immunocompromised patients seem to contribute to virus persistence and pathogenesis within the immune-privileged ocular retina.
    Keywords: Biology
    ISSN: 0966-842X
    E-ISSN: 1878-4380
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  • 8
    Language: English
    In: Medicinal Research Reviews, May 2007, Vol.27(3), pp.401-416
    Description: Despite the fact that neutrophils are essential for the protection from invading pathogens, hyperactive neutrophils may elicit detrimental cerebral damage after severe trauma. The neutrophil interactions with the neurovascular unit entail endothelial dysfunction involving endothelial leakage, formation of edema, coagulation abnormalities, disturbed hemodynamics, tissue infiltration etc. These elements of the “whole body inflammation,” designated systemic inflammatory response syndrome (SIRS) in conjunction with intracerebral proinflammatory activities, are important triggers of post‐traumatic cerebral damage and mortality according to the “second hit” concept. From the immunologic point of view, the brain is an immune privileged site, known to resist autodestructive inflammatory activity much more efficiently than other organs because of the highly efficient diverse functions of the blood–brain barrier (BBB). However, both the underlying strategy of the BBB to maintain cerebral protecting functions against the post‐traumatic neutrophil‐mediated “second hit” and how activated neutrophils may overcome the BBB are currently unknown. Therefore, this review summarizes the current understanding of the “second hit,” the BBB physiology, and its role in the maintenance of cerebral immune privilege, and discusses recent findings that may explain the pathophysiologic neutrophil–BBB interactions occurring after severe trauma, thus offering novel therapeutic options to protect from post‐traumatic brain damage. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 3, 401–416, 2007
    Keywords: Blood–Brain Barrier ; Hyperactive Neutrophils ; Second Hit Concept ; Sirs ; Trauma
    ISSN: 0198-6325
    E-ISSN: 1098-1128
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  • 9
    In: Transplantation, 1996, Vol.61(12), pp.1763-1770
    Description: Transplantation-related pathogenic factors such as ischemia or allograft-directed inflammation are associated with oxidative changes that might lead to cellular oxidative stress. The aim of this study was to investigate the impact of oxidative stress on: (1) CMV replication in cultured human endothelial cells and (2) the stimulation of endothelial cells by proinflammatory cytokines. Both pathomechanisms are known to contribute to graft rejection crises in vivo. Oxidative stress was induced in endothelial cell cultures with 10-200 μM buthionine sulfoximine. Western blotting showed a significant increase in the production of CMV-specific immediate early and late proteins in buthionine sulfoximine-treated cultures. Immunocytochemical staining suggested that this effect was caused by increased numbers of CMV antigen expressing cells (66% immediate early; 78%, late). Quantitative polymerase chain reaction for CMV-specific DNA and virus titration revealed that enhanced viral replication levels correlated with increased virion production. As a measure for the endothelial cell activation status, the surface expression of HLA-ABC and HLA-DR and adhesion molecules(ICAM-1, ELAM-1, VCAM-1) was quantified by fluorometric methods. Whereas oxidative stress alone did not modulate any surface molecule expression, the IFN-γ-mediated expression of HLA-ABC and HLA-DR and the IL-1-mediated expression of ICAM-1, but not of ELAM-1 and VCAM-1 (IL-1+TNF-α), was amplified. Interestingly, the amplification of HLA molecule expression was even higher in CMV-infected endothelial cells. This study provides evidence that oxidative stress contributes to the regulation of CMV replication, virus shedding, and the activation of endothelial cells by proinflammatory cytokines as it is observed in transplant recipients.
    Keywords: Human Cytomegalovirus ; Human Cytomegalovirus ; Endothelium ; Replication ; Oxidation ; Stress ; Man ; Endothelium ; Replication ; Oxidation ; Stress ; Man ; Viruses ; Immune Response & Immune Mechanisms ; Cytokines ; Cytokines ; Cytokines;
    ISSN: 0041-1337
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  • 10
    In: Transplantation, 1999, Vol.68(11), pp.1753-1761
    Description: BACKGROUND.: Cytomegalovirus (CMV) infection is associated with acute and chronic allograft rejection. We have recently shown that rat CMV increases portal inflammation and bile duct destruction in a model of rat liver allograft rejection. Desferrioxamine (DFO), an iron chelator and antioxidant, has recently been demonstrated to have antiviral as well as immunomodulatory effects in vitro. We therefore investigated whether DFO inhibits (a) CMV infection and (b) graft destruction in our rat model. METHODS.: One day after liver transplantation, PVG (RT1) into BN(RT1), the rats were infected with rat CMV (RCMV, Maastricht strain; 10 plaque-forming units i.p.). The effects of 100 mg/kg body weight and 200 mg/kg body weight DFO were examined. RESULTS.: In the untreated group, the grafts were uniformly RCMV culture-positive. In the group receiving 200 mg/kg DFO, RCMV replication was effectively inhibited. Inflammatory response in the graft, and especially the number of macrophages, was significantly reduced by DFO. Portal inflammation and bile duct destruction were also significantly reduced. In the untreated group, the bile duct epithelial cells were found to be strongly positive for tumor necrosis factor-α and this expression was clearly decreased by DFO. In addition, DFO significantly inhibited vascular cell adhesion molecule-1 expression on sinusoidal endothelial cells. CONCLUSIONS.: Our in vivo transplant study strongly supports the inhibitory effects of metal chelators on CMV infection and their possible usefulness in the treatment of CMV-induced pathogenic changes.
    Keywords: Adjuvants, Immunologic–Pharmacology ; Animals–Pharmacology ; Antiviral Agents–Metabolism ; Cell Adhesion Molecules–Physiology ; Cytomegalovirus–Immunology ; Cytomegalovirus Infections–Virology ; Deferoxamine–Pharmacology ; Graft Rejection–Complications ; Liver–Drug Effects ; Liver Transplantation–Immunology ; Nephritis–Pathology ; Rats–Virology ; Rats, Inbred Bn–Etiology ; Rats, Inbred Strains–Pathology ; Transplantation, Homologous–Metabolism ; Tumor Necrosis Factor-Alpha–Drug Effects ; Virus Replication–Drug Effects ; Adjuvants, Immunologic ; Antiviral Agents ; Cell Adhesion Molecules ; Tumor Necrosis Factor-Alpha ; Deferoxamine;
    ISSN: 0041-1337
    E-ISSN: 15346080
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