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Berlin Brandenburg

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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
    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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  • 3
    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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  • 4
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 15 November 2009, Vol.183(10), pp.6198-206
    Description: The systemic inflammatory response syndrome and subsequent organ failure are mainly driven by activated neutrophils with prolonged life span, which is believed to be due to apoptosis resistance. However, detailed underlying mechanisms leading to neutrophil apoptosis resistance are largely unknown, and possible therapeutic options to overcome this resistance do not exist. Here we report that activated neutrophils from severely injured patients exhibit cell death resistance due to impaired activation of the intrinsic apoptosis pathway, as evidenced by limited staurosporine-induced mitochondrial membrane depolarization and decreased caspase-9 activity. Moreover, we found that these neutrophils express high levels of antiapoptotic Mcl-1 and low levels of proapoptotic Bax protein. Mcl-1 up-regulation was dependent on elevated concentrations of GM-CSF in patient serum. Accordingly, increased Mcl-1 protein stability and GM-CSF serum concentrations were shown to correlate with staurosporine-induced apoptosis resistance. However, cross-linking of neutrophil Fas by immobilized agonistic anti-Fas IgM resulted in caspase-dependent mitochondrial membrane depolarization and apoptosis induction. In conclusion, the observed impairment of the intrinsic pathway and the resulting apoptosis resistance may be overcome by immobilized agonistic anti-Fas IgM. Targeting of neutrophil Fas by immobilized agonistic effector molecules may represent a new therapeutic tool to limit neutrophil hyperactivation and its sequelae in patients with severe immune disorders.
    Keywords: Apoptosis -- Immunology ; Caspase 9 -- Immunology ; Multiple Trauma -- Immunology ; Neutrophils -- Immunology ; Proto-Oncogene Proteins C-Bcl-2 -- Biosynthesis ; Bcl-2-Associated X Protein -- Metabolism
    E-ISSN: 1550-6606
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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