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Schneider EM Flacke S Liu F Lorenz MR Schilling P Nass ME Foehr KJ Huber-Lang M Weiss ME 《Journal of cell communication and signaling》2011,5(2):145-156
Severe trauma and the systemic inflammatory response syndrome (SIRS) occur as a result of a cytokine storm which is in part
due to ATP released from damaged tissue. This pathology also leads to increased numbers of immature antigen presenting cells
(APC) sharing properties of dendritic cells (DC) or macrophages (MΦ). The occurrence of immature APC appears to coincide with
the reactivation of herpes virus infections such as Epstein Barr virus (EBV). The aim of this study was the comparative analysis
of the ultrastructural and functional characteristics of such immature APC. In addition, we investigated EBV infection/ reactivation
and whether immature APC might be targets for natural killers (NK). Significant macroautophagy, mitochondrial degradation
and multivesicular body formation together with the identification of herpes virus particles were morphological findings associated
with immature APC. Exogenous stressors such as ATP further increased morphological signs of autophagy, including LC3 expression.
Functional tests using fluorescent bacteria proved impaired phagolysosome fusion. However, immature APC were susceptible to
NK-92-mediated cytolysis. We found evidence for EBV latency state II infection by detecting EBV-specific LMP1 and EBNA2 in
immature APC and in whole blood of these patients. In summary, trauma-induced cytokine storms may induce maturation arrest
of APC, promote ATP-induced autophagy, support EBV persistence and impair the degradation of phagocytozed bacteria through
inefficient phagolysosome fusion. The susceptibility to NK-mediated cytolysis supports the hypothesis that NK function is
likely to contribute to immune reconstitution after major trauma by regulating immature APC, and ATP-induced autophagy and
survival. 相似文献
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Jan-Paul Flacke Sanjeev Kumar Sawa Kostin H. Peter Reusch Yury Ladilov 《Apoptosis : an international journal on programmed cell death》2009,14(1):90-96
To analyze the underlying cellular mechanisms of adaptation to ischemia-induced apoptosis through short acidic pretreatment,
i.e. acidic preconditioning (APC), Wistar rat coronary endothelial cells (EC) were exposed for 40 min to acidosis (pH 6.4)
followed by a 14 h recovery period (pH 7.4) and finally treated for 2 h with simulated in vitro ischemia (glucose-free anoxia
at pH 6.4). APC led to a transient activation of p38 and Akt kinases, but not of JNK and ERK1/2 kinases, which was accompanied
by significant reduction of the apoptotic cell number, caspase-12/-3 cleavage and Bcl-xL overexpression. These effects of
APC were completely abolished by prevention of Akt- or p38-phosphorylation during APC. Furthermore, knock-down of Bcl-xL by
siRNA-transfection also abolished the anti-apoptotic effect of APC. Therefore, APC leads to protection of EC against ischemic
apoptosis by activation of Akt and p38 followed by overexpression of Bcl-xL, which is a key anti-apoptotic mechanism of APC. 相似文献
4.
After-Potentials and Large Depolarizations of Single Nodes of Ranvier Treated with Veratridine 总被引:2,自引:1,他引:1
Potential differences between normal nodes of Ranvier (single fiber from the sciatic nerve of the frog, air-gap method) and a node exposed to 1 to 2.5 x 10-6 gm veratridine per ml were measured. Negative after-potentials occurred immediately after application of the alkaloid when spike configuration and resting potential were virtually unchanged. The after-potentials decreased in magnitude and their time constant increased as the resting membrane was depolarized either by outward currents or by a train of impulses. Increase of (Na)o markedly increased the amplitude of the after-potential. After prolonged application of veratridine or with higher concentrations, a large slow depolarization (rate of potential change about 7 mv per second) could be triggered by a train of impulses or even a single spike. This depolarization could promptly be terminated by withdrawing Na. It is concluded that, once the nodal membrane has become permeable to Na (as during a spike), veratridine prevents the normal return of PNa to its resting value. 相似文献
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A Saccharomyces cerevisiae strain in which the GPP1 and GPP2 genes, both encoding glycerol-3-phosphate phosphatase isoforms, are deleted, displays both osmo- and thermosensitive (ts)
phenotypes. We isolated genes involved in cell wall maintenance as multicopy suppressors of the gpp1gpp2 ts phenotype. We found that the gpp1gpp2 strain is hypersensitive to cell wall stress such as treatment with β-1,3-glucanase containing cocktail Zymolyase and chitin-binding
dye Calcofluor-white (CFW). Sensitivity to Zymolyase was rescued by overexpression of SSD1, while CFW sensitivity was rescued by SSD1, FLO8 and WSC3—genes isolated as multicopy suppressors of the gpp1gpp2 ts phenotype. Some of the isolated suppressor genes (SSD1, FLO8) also rescued the lytic phenotype of slt2 deletion strain. Additionally, the sensitivity to CFW was reduced when the cells were supplied with glycerol. Both growth on glycerol-based
medium and overexpression of SSD1, FLO8 or WSC3 had additive suppressing effect on CFW sensitivity of the gpp1gpp2 mutant strain. We also confirmed that the internal glycerol level changed in cells exposed to cell wall perturbation. 相似文献
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Kansas (USA) could represent a transition area between contrasting epidemiologic patterns of hemorrhagic disease (HD) in the midwestern United States. In this study, we compare the distribution of reported clinical HD with serologic data to determine whether the risk of HD in white-tailed deer (Odocoileus virginianus) is associated with geographic location corresponding to the reported distribution of two white-tailed deer subspecies. On the basis of a high prevalence of antibodies (91-100%) to multiple serotypes of epizootic hemorrhagic disease virus (EHDV) and bluetongue virus (BTV), with correspondingly few reports of clinical HD, it appears that a state of enzootic stability exists in central and western Kansas. This area corresponds to the reported range of O. virginianus texanus. In contrast, in the eastern third of the state, which corresponds to the reported range of O. virginianus macronurus, antibody prevalence is significantly lower (45%), EHDV serotypes appear to predominate, and HD, as confirmed by virus isolation, has been consistently reported. These results suggest an abrupt demarcation between enzootic stability in central and western Kansas to a pattern of epizootic HD within the eastern part of this state. Understanding host, vector, and environmental variables responsible for these contrasting patterns could have application to understanding the risk of HD in the midwestern United States. 相似文献
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Sanjeev Kumar Sawa Kostin Jan-Paul Flacke H. Peter Reusch Yury Ladilov 《The Journal of biological chemistry》2009,284(22):14760-14768
The cAMP signaling pathway plays an essential role in modulating the
apoptotic response to various stress stimuli. Until now, it was attributed
exclusively to the activity of the G-protein-responsive transmembrane adenylyl
cyclase. In addition to transmembrane AC, mammalian cells possess a second
source of cAMP, the ubiquitously expressed soluble adenylyl cyclase (sAC).
However, the role of this cyclase in apoptosis was unknown. A mitochondrial
localization of this cyclase has recently been demonstrated, which led us to
the hypothesis that sAC may play a role in apoptosis through modulation of
mitochondria-dependent apoptosis. To prove this hypothesis, apoptosis was
induced by simulated in vitro ischemia or by acidosis, which is an
important component of ischemia. Suppression of sAC activity with the
selective inhibitor KH7 or sAC knockdown by small interfering RNA transfection
abolished endothelial apoptosis. Furthermore, pharmacological inhibition or
knockdown of protein kinase A, an important cAMP target, demonstrated a
significant anti-apoptotic effect. Analysis of the underlying mechanisms
revealed (i) the translocation of sAC to mitochondria under acidic stress and
(ii) activation of the mitochondrial pathway of apoptosis, i.e.
cytochrome c release and caspase-9 cleavage. sAC inhibition or
knockdown abolished the activation of the mitochondrial pathway of apoptosis.
Analysis of mitochondrial co-localization of Bcl-2 family proteins
demonstrated sAC- and protein kinase A-dependent translocation of Bax to
mitochondria. Taken together, these results suggest the important role of sAC
in modulating the mitochondria-dependent pathway of apoptosis in endothelial
cells.Increasing evidence suggests that apoptosis of endothelial cells
(EC)3 may be
responsible for acute and chronic vascular diseases, e.g. through
atherogenesis (1), endothelial
dysfunction (2), or thrombosis
(3). Within several signaling
mechanisms, a cAMP-dependent signaling pathway plays a substantial role in
mediating apoptotic cell death induced by various stress factors. Elevation of
the cellular cAMP either by forskolin-induced stimulation of the
G-protein-responsive transmembrane adenylyl cyclase (tmAC) or by treatment
with cAMP analogs has been shown to lead to both induction and suppression of
apoptosis in different cell types
(4–7).
This discrepancy may be due to differences in cell types and experimental
models. Alternatively, a lack of specificity of tmAC-induced signals,
especially directed to distant intracellular targets like mitochondria, may be
a cause of the discrepancy. Indeed, the classical model of cAMP signaling
requires the diffusion of cAMP from plasma membrane-localized tmAC to targets
localized throughout the cell. Diffusion of cAMP throughout the cytosol makes
it difficult to selectively activate distally localized targets without also
activating more proximal targets. Therefore, such diffusion of cAMP would
likely diminish specificity, selectivity, and signal strength. This model is
further complicated by the presence of phosphodiesterases, which degrade cAMP,
thus preventing its diffusion.In addition to tmAC, a second source of cAMP, soluble adenylyl cyclase
(sAC), was demonstrated for mammalian cells
(8,
9). Cytosolic localization of
sAC provides both specificity and selectivity by permitting generation of cAMP
proximal to intracellular targets. Furthermore, this model for cAMP action
incorporates phosphodiesterases, which would act to limit diffusion and
prevent nonspecific effector activation.Whether sAC participates in apoptosis was unknown. A previous report
demonstrated that sAC is co-localized with mitochondria
(10). Because mitochondria
play a fundamental role in apoptosis
(11), we hypothesized that sAC
may influence the development of apoptosis by modulating the mitochondrial
pathway of apoptosis. Therefore, we aimed to examine the role of sAC in
apoptotic cell death, especially its role in the modulation of the
mitochondria-dependent pathway of apoptosis. For this purpose, apoptosis was
induced in rat coronary EC by simulated in vitro ischemia or by
acidosis. By applying pharmacological inhibition of sAC or small interfering
RNA (siRNA)-mediated sAC knockdown, we found that sAC activity is required for
the induction of apoptosis by ischemia or acidosis. Additionally,
translocation of sAC to mitochondria and the sAC-dependent release of
cytochrome c suggest that this cyclase specifically regulates the
mitochondrial pathway of apoptosis. 相似文献
10.
ten Hallers EJ Marres HA Rakhorst G Jansen JA Sommers MG Van der Houwen EB Schutte HK Van Kooten TG Van Loon JP Verkerke GJ 《Laboratory animals》2007,41(2):270-284
A modern way of voice rehabilitation after total laryngectomy includes the use of shunt valves and tracheostoma valves. Problems of fixation to the surrounding tissue are a major drawback in the use of the shunt valve, heat and moisture exchange (HME) filters and, especially, the tracheostoma valve. To solve these problems different tissue connectors were developed. The main objective was to test the feasibility of these prototypes in a new animal model. Here we discuss the results, problems and complications of the selected Saanen goat model. In this prospective laboratory study, 19 healthy adult female Saanen goats (Capra hircus) were used and observed post-surgically for 12 weeks. Selection criteria such as comparable anatomy to humans and easy handling were used for animal model development. Also a literature search using the Medline and the ISI Web of Science databases was performed. The anatomy of the Saanen goat was investigated in a separate postmortem study. Surgery consisted of a laryngotracheal separation and implantation of a tracheo-oesophageal and tracheostoma tissue connector with fibrin tissue glue. Postoperative care consisted of frequent stoma care, monitoring appetite, weight, vital signs and administration of antibiotics, analgesics and mucolytic agents. All animals survived the surgical procedure. However, postoperative care was extensive, labour intensive and was accompanied by several complications. Eleven animals died spontaneously before the end of the experiment. The tracheostoma tissue connector caused signs of local infection in all cases. There was no evidence of infection around the tracheo-oesophageal tissue connector in 18 cases. It was concluded that the use of goats in this tracheostoma model was associated with major complications and should, therefore, only be used for short-term experiments with intensive care. Additional research is needed to see if clinical application of the tissue connectors is possible in the future. 相似文献